EMJ Oncology 11.1 2023

Volume 11.1 December 2023

Oncology

Review of

ESMO 2023 Editor’s Pick

Improving Inclusivity, Equity, and Diversity in Oncology Clinical Trials: A European Perspective

Interviews Karen Canfell and John Marshall discuss personalised approaches in cancer care and prevention

emjreviews.com

Contents 4

Editorial Board

7

Welcome

9

Foreword

10

17 20 23

Congress Review Review of the European Society for Medical Oncology (ESMO) Congress 2023, 20th–24th October

Congress Features Pregnancy After Breast Cancer: Is it Safe?

Victoria Antoniou

The Hallmarks of Cancer in 2023 Lucy Anderson

Symposium Reviews Clinical Perspectives on the Evolution of Non-small Cell Lung Cancer Treatment With Immuno-oncology and ROS1 Tyrosine Kinase Inhibitors

33

Current and Upcoming Treatment Strategies After CDK4/6 Inhibitors for Patients with ER+/HER2Advanced Breast Cancer

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Abstract Reviews

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Abstract Highlights

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Interviews Karen Canfell John Marshall

Feature Isolated Tumour Cells in Early Endometrial Carcinomas: A New Concept with Controversial Therapeutic and Prognostic Impact Ahmed

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Articles Editor's Pick: Improving Inclusivity, Equity, and Diversity in Oncology Clinical Trials: A European Perspective Langley et al.

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The Plate Matters: Exploring the Intersection of Food Insecurity in Patients with Cancer Pérez et al.

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The Role of Radical Radiotherapy in Sinonasal Myopericytoma: A Case Report and Literature Overview Merlotti et al.

98

Synergistic Immune-Mediated Anti-tumour Effect of Dostarlimab and Radiotherapy in the Management of MSI-H/dMMR Endometrial Cancer: A Case Report Scandurra et al.

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Acquired PTEN Loss May Mediate Dabrafenib and Trametinib Resistance in BRAF V600E-Mutated Epithelioid Glioblastoma: A Case Report and Literature Review Ahmed et al.

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Editorial Board Editor-in-Chief Prof Ahmad Awada

Université Libre de Bruxelles, Belgium

Editorial Board Dr Mohammad Akheel

Greater Kailash Hospitals, India

Prof Dr Yves Chalandon

Geneva University Hospitals, Switzerland

Dr Javier Cortés

Ramón y Cajal University Hospital, Spain

Dr Jyoti Dabholkar

King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, India

Dr Jad Degheili

American University of Beirut Medical Center, Lebanon

Prof Paul Dent

Virginia Commonwealth University, USA

Dr Divyanshu Dua

Canberra Hospital, Australia

Dr Abdulmajeed Hammadi

Alyermook Teaching Hospital, Iraq

Prof Antoine Italiano

Institut Bergonié, France

Dr Caroline Michie

Edinburgh Cancer Centre & University of Edinburgh, UK

Dr Aniket Mohite

Arogyam Multispeciality Clinic and Kolhapur Cancer Centre, India

Dr Katarazyna Rygiel

Medical University of Silesia (SUM), Poland

Dr Francesco Sclafani

Institut Jules Bordet, Belgium

Dr Klaus Seiersen

Aarhus University Hospital, Denmark

Prof Yong Teng

Georgia Cancer Center, USA

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Aims and Scope EMJ is an online only, peer-reviewed, open access general journal, targeted towards readers in the medical sciences.

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Congress Notice Staff members attend medical congresses as reporters when required.

This Publication ISSN 2054-619X EMJ Oncology is published once a year. For subscription details please visit: www.emjreviews.com All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible.

However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (ESMO 2023) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever.

Front cover and contents photograph: Madrid, Spain home of the ESMO 2023 © Anibal Trejo / stock.adobe.com

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Welcome letter Editor Evgenia Koutsouki Editorial Manager Anaya Malik Copy Editors Noémie Fouarge, Kirsty Hewitt

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Editorial Co-ordinator Natasha Meunier-McVey Editorial Assistants Lucy Anderson, Victoria Antoniou, Abigail Craig, Ada Enesco, Evan Kimber, Darcy Richards Design Manager Stacey Rivers Senior Designer Roy Ikoroha Designer Steven Paul Junior Designers Dillon Benn Grove, Shanjok Gurung Head of Sales Robert Hancox Senior Project Manager Nabihah Durrani Director of Performance Keith Moule Chief Operating Officer Dan Scott Chief Commercial Officer Dan Healy Founder and Chief Executive Officer Spencer Gore

Editor Dear Readers, Welcome to the latest issue of EMJ Oncology, which spotlights the highlights from the European Society for Medical Oncology (ESMO) International Congress 2023, which was hosted in Madrid, Spain. With nearly 600 speakers, discussions covered rare cancers, the use of AI in enhancing cancer detection and diagnosis, and the promising potential of therapies targeting tumour cell mutations to treat non-small cell lung cancer. Key clinical trials presented at the congress shed light on treatments that delay relapse for locally advanced cervical cancer; senaparib, a new, targeted therapy that delays the time to relapse in patients with ovarian cancer; and the positive outcomes of adding immunotherapy to standard chemotherapy for endometrial cancer.

You might be interested to read our coverage of a thought-provoking debate session that examined the safety and feasibility of pregnancy amongst survivors of early breast cancer, where both sides of the argument were covered.

Among the plethora of peer-reviewed articles is our Editor’s pick, offering insights into strategies for improving inclusivity and diversity in oncology clinical trials. Another compelling article explores food insecurity, and how this relates to outcomes, and risk of complications.

Among the featured case reports is an interesting case from Canada, where acquired PTEN loss conferred resistance to dabrafenib and trametinib in epithelioid glioblastoma, unveiling potential avenues for improved outcomes through earlier targeted therapy treatment.

I would like to close by thanking our esteemed peer reviewers, contributors, interviewees, and the Editorial Board, for their invaluable help in curating this high-quality issue. Our team will be looking to bring you all the key updates in oncology throughout the year! Until next year’s issue, we are eagerly anticipating your article submissions to EMJ Oncology!

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Stay up to date with new advancements across European healthcare Visit EMJ for our comprehensive collection of peerreviewed research articles, latest interviews, and features across a range of therapeutic disciplines.

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Foreword Dear Colleagues, It brings me great pleasure to introduce the latest issue of EMJ Oncology. This edition features peer-reviewed articles, interviews with experts in the field, and a review of the 2023 European Society for Medical Oncology (ESMO) Annual Meeting, which took place from the 20th–24th October in Madrid, Spain. This year’s congress saw leading experts in oncology from around the world come together to present the latest research and findings on topics ranging from early stage breast cancer to the newest developments in immunotherapy.

The topics at the forefront of discussion were primarily breast and lung cancers, with several illuminating sessions highlighting the latest developments in diagnosis and treatment strategies in each cancer. In a rousing controversy session on the safety of pregnancy after breast cancer, Sibylle Loibl, Goethe University of Frankfurt, Germany, and Patrick Neven, Universitair Ziekenhuis (UZ) Leuven, Belgium, debated either side of the argument, analysing the latest research and guidelines.

In addition to these key topics, EMJ Oncology 11.1 features insightful articles delving into topics such clinical trials in oncology, food insecurity in patients with cancer around the globe, and the role of radiotherapy in sinonasal myopericytoma, along with several highlights covering some of the most fascinating abstracts presented at this year’s congress.

Moreover, in this issue you can find fascinating interviews with expert oncologists such as John Marshall, who gives us an insight into the latest developments in gastrointestinal cancers, as well as the ways in which he hopes to increase access to cancer care not only in the USA, but around the world.

Lastly, I would like to take this opportunity to thank everyone who has contributed to this spectacular issue, including all the authors, peer reviewers, interviewees, and the Editorial Board.

I hope you enjoy reading this journal.

Ahmad Awada Head of the Medical Oncology and Medicine Department, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Belgium

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Congress Review

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ESMO 2023 Review of the European Society for Medical Oncology (ESMO) Congress 2023

Location:

Madrid, Spain

Date:

20th–24th October 2023

Citation:

EMJ Oncol. 2023;11[1]:10-16. DOI/10.33590/emjoncol/10301588. https://doi.org/10.33590/emjoncol/10301588.

RENOWNED for its art, history, and above all, churros, Madrid, Spain, saw thousands flock to the city this October for the European Society for Medical Oncology (ESMO) Annual Congress 2023. Featuring talks by nearly 600 speakers from 155 countries around the globe, this year’s congress covered all the latest developments and groundbreaking new research in the field of oncology, with debates, abstracts, and education sessions aplenty during its 4-day run.

The presentations kicked off with a welcome speech and presidential address from ESMO President, Andrés Cervantes, in which he addressed setting new standards in oncology, as well as the importance of inclusivity and global connections for new developments in the field. Bente Mikkelsen, from the World Health Organization (WHO), added to the welcome, briefly speaking about the relationship between WHO and ESMO. An address from Scientific Chair, Silke Gillessen, followed, thanking the many contributors who made this year’s ESMO congress one of the best yet.

Recipient of the ESMO Award 2023, Isabelle Ray-Coquard, Claude Bernard University, Lyon, France, went on to give a talk entitled ‘The Beauty of Rarity’, focusing on how oncologists may find the beauty in rare cancers as we find it

in the rarity of other phenomena. Ray-Coquard highlighted the value of working together, at the level of the workplace, as well as on national and global scales. Improved organisation and optimal medical practices are essential, however impossible without the collaboration of physicians and patients alike. Beauty in cancer, she adds, can be found in both the diversity and inclusivity of the disease. Lastly, Ray-Coquard pointed out the ways in which understanding the beauty of rare cancers may help to improve treatment, as well as overall survival rates of patients with more common cancers.

The ESMO Award for Translational Research was given to Nicholas Turner, Ralph Lauren Centre for Breast Cancer Research, London, UK. Turner’s consequent talk covered the use of circulating tumour DNA in order to guide breast cancer therapy, and the impact of the heterogeneity of breast cancer on targeted therapies. He discussed how circulating tumour DNA may be used in selecting patients for intensification of first-line therapy, and subsequently moving treatment into the molecular relapse and minimal residual disease setting.

"Ray-Coquard highlighted the value of working together, at the level of the workplace, as well as on national and global scales."

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Further awards were granted to Georgina Long, Melanoma Institute Australia, Sydney, Australia, who spoke about neoadjuvant combination immunotherapy and its feasibility in certain patients with glioblastoma; and Anthony Chan, The Chinese University of Hong Kong, Hong Kong, whose speech addressed the international nature of cancer treatment and the contributions of the East to oncology, before moving on to highlight the prevalence of nasopharyngeal carcinoma, particularly in China, as well as its treatment pathways.

The opening ceremony of ESMO 2023 highlighted many of the most prominent and

exciting topics in oncology today, several of which went on to be explored in various oral sessions, proffered paper sessions, or patient advocacy sessions. The common theme throughout each of the talks given throughout the opening ceremony was undoubtedly the importance of working together and helping one another when it comes to diagnosis, treatment, and care.

Read on for our key insights into the ESMO 2023 congress, and come back next year for updates from ESMO 2024, which will be held in Barcelona, Spain, from 13th–17th September. ●

"Turner’s consequent talk covered the use of circulating tumour DNA in order to guide breast cancer therapy."

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Introducing AI to Enhance Cancer Detection and Diagnosis SESSIONS at the ESMO Congress 2023, held in Madrid, Spain, focused on the potential of artificial intelligence (AI) technologies in helping to improve prompt detection of cancer, and prevent delays in diagnosis across Europe. The application in oncology has been limited, and researchers have been investigating the potential of AI to transform cancer care, and improve patient outcomes. Thus far, digital technologies, such as AI, have been implemented slowly, and practice has been far from uniform.

A qualitative study presented at the ESMO Congress explored the potential of AI to improve cancer detection, through enhancing cancer imaging and time to diagnosis. It is thought that using digital technologies could support prevention programmes by identifying individuals at risk of developing cancer. AI could then intervene upstream, and prioritise those patients for screening based on their medical records.

However, Raquel Perez-Lopez, a radiologist at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, stated “these resources remain underutilised,” and that there is an insufficient legal framework to allow patient data to be used in such a manner.

AI algorithms have begun to be utilised to analyse data in real-world evidence, such as in genomic reports used to match patients with targeted therapies. This has been achieved through comparing the genetic profiles of hundreds and thousands of patients, and making predictions on the role of certain genes in developing cancer.

This is particularly applicable in generating evidence for rare cancers, where traditional clinical trials cannot be undertaken. In a hospital setting, AI could transform data processing in electronic medical records and information systems by summarising large quantities of data and generating research insights, respectively.

Although AI is becoming more common, and shows great promise, oncologists will need to be able to accurately use these tools in order to interpret the evidence generated. The ESMO Guidance for Reporting Oncology Real-World Evidence (GROW) aims to assist with this by standardising oncology research practices through recommendations on how to report real-world data using AI transparently and accurately. With entry of AI into the workflow, the educational needs of physicians need to be met, as the combination of machine and physicians will achieve the best results for patients. ●

"Digital technologies could support prevention programmes by identifying individuals at risk of developing cancer."

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Link Between Air Pollution and Breast Cancer INCREASED air pollution may lead to a higher risk of developing breast cancer, according to research presented at the ESMO Annual Congress 2023. The study, conducted by Béatrice Fervers, Léon Bérard Comprehensive Cancer Centre, Lyon, France, and colleagues, is amongst the first to take account of the effects of both residential and workplace exposure to air pollution on the risk of breast cancer.

versus urban areas of Europe. Smaller increases in breast cancer risk were also noted in females exposed to high levels of larger particle air pollution (PM10 and nitrogen dioxide). Experts in the field have discovered that these small particles are able to penetrate deep into the lungs and enter the bloodstream, where they may be absorbed into the breast and other tissues.

Previous studies into this relationship have only looked at fine particle exposure where females were living, and showed no significant connection to breast cancer risk. This study analysed home and workplace exposure to air pollution in 2,419 females with breast cancer and 2,984 females without breast cancer, between 1990–2011.

The findings from this study have emphasised the importance of understanding the role of small pollutant particles in promoting cancer. “There is an urgent need to set up laboratory studies to investigate the effects of these small air pollutant particles on the latency, grade, aggression, and progression of breast tumours,” added Charles Swanton, Francis Crick Institute, London, UK. The team concluded that more research is needed into the connection between air pollution and all cancers, and that policies need to be put in place to reduce PM2.5 particles, not only in Europe, but worldwide. ●

Results demonstrated that risk of breast cancer increased by 28% when exposure to fine particle (PM2.5) air pollution increased by 10 µg/m3, which is roughly equivalent to the difference in PM2.5 particle concentration seen in rural

"Previous studies into this relationship have only looked at fine particle exposure where females were living."

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Improving the Treatment Possibilities in Gynaecological Cancers RECENT findings presented at the ESMO Annual Congress 2023, held in Madrid, Spain, have the potential to change the way gynaecological cancers are managed, screened, and treated. The results from the Phase III clinical trial suggest that new therapies for females with cervical, ovarian, and endometrial cancers may delay relapse time and, in certain cases, lengthen survival.

Krishnansu S. Tewari, University of California, Irvine (UCI), USA, and colleagues, presented their research, which aimed to address the unmet needs in gynaecological cancers, commenting: “These trials have set the stage for women with gynaecological cancers to receive state-of-the-art therapies that delay the time to relapse.”

A study presented on cervical cancer found that 68% of females who received the immunotherapy drug pembrolizumab, as well as standard treatment, were cancer-free after 2 years, compared to 57% of females given a placebo alongside their standard treatment.

Another study tested the usefulness of induction chemotherapy, a method consisting of combining two different chemotherapy drugs before standard treatment with chemotherapy plus radiation. Those who underwent this treatment plan were 35% more likely to be cancer-free at 5 years, and 39% more likely to be alive at 5 years compared to those who received standard treatment alone.

These results have the potential to significantly change the landscape of cancer treatment.

Endometrial cancer is currently the most common gynaecological cancer; however, aggressive forms of the disease are often difficult to treat.

"These trials have set the stage for women with gynaecological cancers to receive state-of-the-art therapies."

These results have a very good chance of leading to regulatory approval of new treatments for gynaecological cancers, according to Tewari.

He added that his findings “will allow women struggling with these cancers to live longer and live better.” ●

The team went on to present further studies focusing on metastatic cervical cancer, exploring how relapse may be delayed and survival lengthened by combining an antibody and an anti-cancer drug, as well as studies on ovarian and endometrial cancers. Data from a randomised trial showed that senaparib, a novel targeted therapy, may delay time to relapse in patients with recently diagnosed advanced ovarian cancer. Additionally, findings from a further two studies suggested that combining immunotherapy and standard chemotherapy significantly delays relapse in females with advanced or recurrent endometrial cancer.

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Targeting Tumour Mutations Could Improve Outcomes for Patients with Lung Cancer NOVEL research presented at the ESMO Congress 2023 in Madrid, Spain, emphasised that targeting tumour cell mutations in patients with non-small cell lung cancer (NSCLC) could cause major changes in treatment. Evidence from multiple clinical trials suggests that a large proportion of patients with NSCLC, the predominant form of lung cancer, would benefit from therapies targeting tumour cell alterations, and are more effective over traditional treatments, such as chemotherapy.

Data collected from the studies revealed that better outcomes were reported with combinations of experimental new drugs targeting tumour cell mutations, over the current therapies. When new drug combinations were used alongside chemotherapy, the outcome was significantly improved when compared to chemotherapy as the sole treatment. Similar results were also observed when chemotherapy was used in combination with ongoing immunotherapy that was maintained pre- and post-surgery. Further results presented also suggested that mutation-targeted treatment may even reduce the need for chemotherapy for some patients. This is particularly valuable for patients with rare tumour alterations who have previously had limited targeted options available to them, such as those with rearranged during transfection-mutated advanced NSCLC.

There was also promising news for those patients with advanced or late-stage NSCLC. For example, a new combination of targeted drugs for patients with late-stage NSCLC with an epidermal growth factor receptor mutation significantly improved progression-free survival.

For advanced patients who were previously only eligible for chemotherapy, undertaking chemotherapy alongside antibody conjugates improved progression-free survival compared to current chemotherapy regimens. Although further studies are needed to better appreciate the side effects of such a combination, this may lead to “major changes in the way we care for patients whose previous treatment has stopped working,” said author Alessandra CurioniFontecedro, University of Fribourg, Switzerland.

The next step is to better understand the sequences of treatments that will result in the best outcome for patients. Elene Mariamidze, Todua Clinic, Tbilisi, Georgia, stated: “The future of lung cancer care lies in finding the right combination of targeted treatment, or chemotherapy with immunotherapy for each patient.” Therefore, it is important that lung cancer is treated by experts who understand molecular testing and findings to know when and how to target different mutations, establish new targets, and come up with the best treatment plans for patients with lung cancer. ●

"Targeting tumour cell mutations in patients with non-small cell lung cancer could cause major changes in treatment."

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Pregnancy After Breast Cancer: Is it Safe?

Authors:

Victoria Antoniou, EMJ, London, UK

Citation:

EMJ Oncol. 2023;11[1]:17-19. DOI/10.33590/emjoncol/10308535. https://doi.org/10.33590/emjoncol/10308535.

AN INSIGHTFUL session featuring a debate analysed the safety and feasibility of pregnancy amongst survivors of early breast cancer (EBC) at the European Society for Medical Oncology (EMSO) Annual Congress 2023, held in Madrid, Spain, from 20ᵗʰ–24ᵗʰ October. Chaired by Ann H. Partridge, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, both sides of the argument were covered, before concluding with a vote from the audience, both in person and virtually.

FOR THE SAFETY OF PREGNANCY AFTER EARLY BREAST CANCER Patrick Neven, Universitair Ziekenhuis (UZ) Leuven, Belgium, began by explaining that the age at which females are choosing to undergo their first full-term pregnancy is being delayed, leading to an increased need for assisted reproductive technologies. Such reproductive methods are also often used by females who have had EBC, and therefore these methods and their safety have been studied extensively, reported Neven. He discussed the ESMO 2020 guidelines, which state that part of the treatmentplanning process for any type of cancer at any stage must involve oncofertility counselling.

These guidelines further state that every patient is at risk of gonadotoxicity after taking anticancer drugs, and that special attention should be paid to hereditary cancer syndromes.

To demonstrate the safety of pregnancy after EBC, Neven presented a case of a female who had undergone surgery for pT2N1 Grade II ER+ PR+ HER2- breast cancer. Years later, at age 39, despite a uterine myoma and adenomysosis, she unintentionally fell pregnant again, gave birth at 38 weeks, and was able to breastfeed

with the one breast that had not undergone radiation therapy. Neven went on to discuss a study which included 92 females who had been pregnant after EBC, aged 17–40 (median age: 32 years), only 39% of whom required the assistance of reproductive technologies (onethird of females required fertility treatment, and 29 out of 92 used in vitro fertilisation).

Guarantee-time bias (GTB) was highlighted as an important factor to correct for when considering pregnancy after breast cancer. GTB occurs when an analysis timed from enrolment is compared across two groups defined by a classifying event, such as pregnant after EBC or not pregnant after EBC. One must correct for changes during this time; for example, relapse, or females not wanting to become pregnant after breast cancer, as these factors may skew the data.

Neven presented a retrospective cohort study including 3,805 patients with ER+ EBC, of whom 2,285 had a subsequent pregnancy, and 2,520 did not, and where GTB was taken into account. The results showed that there was no harm in females becoming pregnant after EBC, and there was no difference in the breast cancer outcome between the two groups.

"This trial showed that there was no negative effect of interrupting the treatment for these individuals."

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Neven concluded by presenting the results of the recent Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsive breast cancer (POSITIVE) trial,1 which included an analysis of 516 females who had experienced treatment for either Stage I or Stage II EBC. This trial showed that there was no negative effect of interrupting the treatment for these individuals; nor was it dangerous to have a baby after therapy. The safety of the baby is dependent on the time after treatment; however, Neven explained that there is no risk for the baby if the mother falls pregnant more than 1 year after treatment. This part of the discussion concluded with a summary of Neven’s points, highlighting the evidence in the literature that pregnancy after breast cancer is safe, so long as risk of recurrence and time after treatment is taken into account.

AGAINST THE SAFETY OF PREGNANCY AFTER EARLY BREAST CANCER Sibylle Loibl, Goethe University of Frankfurt, Germany, agreed that more young females suffer from breast cancer today. She opened her presentation by pointing out, however, that younger females have higher risk of relapse, a higher likelihood of being treated with

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chemotherapy, and a lower chance of having had children already. Younger females have a worse breast cancer prognosis in HER2- forms of the disease; however, age differences are not significant in triple negative or HER2+ forms of breast cancer. Loibl also addressed chemotherapy-induced ovarian function suppression, a valid prognostic factor.

Research has previously shown that females who have had breast cancer are less likely to be able to become pregnant at all, for a variety of reasons, including limited ovarian reserve, which happens naturally to females above the age of 35 years. Those that do become pregnant after EBC, however, do not have a lower chance of disease-free survival than those who do not get pregnant, and in certain cases, pregnancy may even lead to a better outcome. Loibl highlighted that these studies, though they appear to support the safety of pregnancy after EBC, were all retrospective studies, and are therefore more biased than any prospective data. This type of research is also inherently non-randomised, which also makes it more biased, leading to potentially misinformed conclusions.

Furthermore, germline mutations (gBRCA) are vital to account for when analysing safety of pregnancy in patients with breast cancer, as

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they may affect outcomes. Loibl discussed a prospective cohort study conducted in the UK, looking into germline mutations in breast cancer, which can lead to increased risk of contralateral breast cancer, ipsilateral breast cancer, and ovarian cancer. Patients need to be informed about this before attempting to become pregnant, in order to avoid relapse during pregnancy. Carriers of gBRCA2 mutations also appear to have higher risk of chemotherapy-induced ovarian failure, which Loibl argued is an important factor often overlooked by studies supporting the safety of pregnancy after breast cancer.

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Congress Feature

cancer, were mostly split amongst the audience.

Partridge, Chair of this session, and lead author in the POSITIVE trial,1 acknowledged the shortcomings of many of the studies in favour of becoming pregnant after breast cancer, and pointed out the higher rates of low birthweight and premature birth amongst females who have had EBC. Additionally, little data are available with regards to the safety of pregnancy after treatment with newer methods, such as CDK4/6 inhibitors or immune checkpoint inhibition.

VOTING AND CHAIR’S PERSPECTIVE

Partridge concluded there is evidence to suggest that there is no worsening of diseasefree survival or overall survival for pregnant groups versus non-pregnant groups, and that there is little risk in pregnancy after EBC, as long as females get through the early risk of recurrence period, and receive optimal endocrine therapy. Partridge went on to explain that pregnancy after EBC can be done safely, despite the drawbacks of the real-world study, including females not going back on their endocrine therapy. She argued that although the POSITIVE trial lacks long-term follow-up data, it adds significantly to the literature supporting the safety of pregnancy after EBC.

Audience members were able to vote on five different questions addressing the wait time of patients with triple-negative EBC before pregnancy, which patients should become pregnant, the results of the POSITIVE trial,1 and the treatments used on patients with EBC. The results, though in some cases leaning towards the safety of pregnancy after breast

The second round of voting saw the results more often skew to the side of pregnancy being safe after breast cancer. Overall, it can be said that despite strong evidence to suggest that pregnancy after EBC is safe, these studies have several shortcomings that should be taken into account, and opinions on the topic are still divided. ●

Loibl concluded her side of the debate by also discussing the POSITIVE trial,1 arguing that the results of the trial do not support the safety of pregnancy after EBC, but rather show that it is possible to interrupt endocrine therapy in patients, so long as this is resumed after a period of up to 2 years. She explained that this trial, in which patients were heavily selected, does not provide sufficient data to support safe pregnancy after EBC.

References 1.

Partridge AH et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388(18):1645-56.

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The Hallmarks of Cancer in 2023 Authors:

Lucy Anderson, EMJ, London, UK

Citation:

EMJ Oncol. 2023;11[1]:20-22. DOI/10.33590/emjoncol/10302504. https://doi.org/10.33590/emjoncol/10302504.

CURRENT cancer hallmarks, their capabilities, and potential targeted therapies were the focus of the presentation given by Douglas Hanahan, Ludwig Institute for Cancer Research, Lausanne, Switzerland, at the European Society for Medical Oncology (ESMO) Congress 2023, held in Madrid, Spain. Hanahan began by defining hallmarks as acquired functional capabilities that contribute to the manifestation of the disease, which are a “conceptual framework for rationalising the daunting complexity of cancer.”

ESTABLISHED HALLMARKS Currently, there are eight hallmarks recognised as necessary for cancer to develop and progress. The first two hallmarks identified, sustained proliferative signalling and evading growth suppressors, both facilitate uncontrolled cell growth. Another hallmark is resisting cell death, which cancerous cells are able to achieve by resisting apoptosis, the most prominent mechanism inducing cell death. The fourth hallmark discussed is replicative immortality, whereby cancerous cells bypass cell replication limits, often through inducing telomerase enzyme mechanisms. For oxygen and nutrients to reach tumours, and to evacuate waste, access to the blood vasculature is needed.

The major mechanism to achieve this hallmark is to induce angiogenesis. The sixth hallmark, activation and metastasis, is the foundation of morbidity and mortality that has become synonymous with cancer. The penultimate hallmark identified so far is regulating cellular metabolism. Unlike differentiated cells that have specific metabolic programmes, cancerous cells harness energy sources of varying kinds, to provide the energy needed to continue cell

proliferation. Lastly, cancer cells are able to avoid immune destruction at various stages during multistep tumour development. The infrequent efficacy of immunotherapy seen across the spectrum of cancer reflects avoiding immune destruction as a hallmark of cancer.

ACQUISITION OF HALLMARK CAPABILITIES Hanahan explained that the capabilities of hallmarks are acquired through enabling characteristics, also known as phenotypes. It is well established that genome instability and mutation is one such phenotype. A more recently discovered phenotype is tumour-promoting inflammation. Tumours harness a programme of inflammatory-mediated wound healing, which also involves several hallmark capabilities, such as activating invasion, cell proliferation, immune inhibition, and angiogenesis.

Differing cell types in tumour cells also contribute functionally to cancer hallmarks.

As such, tumours become assemblages of cell types that are capable of collaborating.

"Currently, there are eight hallmarks recognised as necessary for cancer to develop and progress."

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"The infrequent efficacy of immunotherapy seen across the spectrum of cancer reflects avoiding immune destruction as a hallmark of cancer."

Normal and neoplastic cell types and subtypes assemble to become components of tumours, helping to provide hallmark capabilities.

Cell types included in these interactions include cancer stem cells, cancer-associated fibroblasts, endothelial cells, and pericytes.

mechanisms contribute to the activities of both the cancer cells and genomically stable cells in the tumour microenvironment (TME). This has been established to be fundamental in cancer development, progression, and adaptive resistance, and could be an important enabling characteristic.

POSSIBLE HALLMARKS

Polymorphic microbiomes are another possible enabling capability. Microbiomes in our gut can modulate the development of cancer, its progression, and the response to therapy.

There are distinct microbiomes in the gut, lung, oral, cervical canal, and skin with incredible polymorphism. Thus far, microbiomes have been implicated in modulating proliferation, inflammation, immune evasion, gene mutation, and contributing to therapy resistance.

Hanahan alluded to emerging parameters that could be incorporated into cancer hallmarks, as there are additional phenotypic characteristics that could be contributing to the progression of cancer.

One potential hallmark capability is phenotypic plasticity, since there is a lot of dynamic variation inside tumours. As a result, a differentiated cell that is not terminal can dedifferentiate into a progenitor cell with hallmark capabilities. As has been newly documented, cell lineages can trans-differentiate into another lineage with hallmark capabilities, particularly in response to therapy.

Another potential enabling capability is nonmutational epigenetic reprogramming. Evidence increasingly suggests that purely epigenetic

Hanahan also discussed whether senescent cells could play a role in cancer hallmarks and the TME. Due to the variable senescence-associated secretory programme, which can promote tumour development, senescent cells have been implicated as tumour-promoting. However, this has yet to be generally validated, and it is unclear whether senescent cells do play a role in the TME.

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Lastly, it should be noted that accessory ‘stromal’ cells recruited in the TME can also contribute to the hallmark capabilities observed. In some stages of tumour development and progression, accessory cells have facilitated the maintenance of hallmarks, and could be a potential avenue for therapeutic targeting.

THERAPEUTIC TARGETING OF HALLMARKS There has been a continuous development of ‘smart drugs’ that target individual hallmarks and their corresponding phenotypes. Currently, we have therapies that disrupt the majority of hallmarks, which have produced notable therapeutic responses previously. One such example has been treating mutant BRAF in metastatic melanoma with vemurafenib, targeting the proliferative signalling hallmark.

However, targeting single hallmarks is often followed by adaptive resistance and relapse.

Hanahan suggests that this “could be an area where drugs that have not worked as monotherapies can show significant benefits when combined.”

Therefore, one avenue to explore is hallmark co-targeting. By targeting different functions of complementary contributions to the tumour, it may be harder for it to adapt. Hanahan noted several successful clinical trials that have involved hallmark co-targeting of immune invasion and tumour vasculature. For example, atezolizumab alongside chemotherapy and bevacizumab has been approved for first-line treatment of metastatic non-small cell lung cancer. There has also been trial success when co-targeting the tumour vasculature

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and proliferative signalling. For example, ramucirumab plus erlotinib has been approved for first-line treatment of metastatic EGFRmutant non-small cell lung cancer.

One hypothesis is that co-targeting could be used in conjunction with complex sequence regimens.

In the future, alongside better mechanisms for early detection of therapy responses and treatment failure, it may be plausible to detect that the cancer is expansive, and switch therapy.

Theoretically, using sequential variation in hallmark co-targeting would make it impossible for the tumour to adapt and resist. However, this premise is in its early stages, and not yet proven.

CANCER NEUROBIOLOGY Recent studies have shown that neurons and their axonal projections could be enabling constituents of the TME. Tumours are also able to induce neural remodelling, encouraging nerve ingrowth, increasing neuronal excitability, and therefore reinforcing nerve-cancer interactions.

Overall, it has been established that innervation of the TME alongside co-opted neuronal signalling in cancer modulates six of the current core hallmark parameters, and could be “an exciting frontier in cancer biology.”

CONCLUSION Hanahan finished the presentation by clarifying that, so far, none of the hallmark co-targeting examples have been transformative with long-term survival benefits. However, hallmark co-targeting is still very much in its novel form, and the case studies thus far have been encouraging. ●

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Clinical Perspectives on the Evolution of Non-small Cell Lung Cancer Treatment With Immuno-oncology and ROS1 Tyrosine Kinase Inhibitors This symposium took place on 21st October 2023, as part of the European Society for Medical Oncology (ESMO) Annual Congress held in Madrid, Spain Chairperson:

Jürgen Wolf1

Speakers:

Tina Cascone,2 Jose Luis Campo-Cañaveral de la Cruz3 1. University Hospital Cologne, Germany 2. MD Anderson Cancer Center, Houston, Texas, USA 3. Puerta de Hierro Majadahonda University Hospital, Madrid, Spain

Disclosure:

Wolf has received advisory board/lecture fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo Oncology, Medicament, Merck, Mirati, MSD, Novartis, Nuvalent, Pierre Fabre, Pfizer, Regeneron, Roche, Seagen, Takeda, and Turning Point Therapeutics; and research funding from BioNTech, BMS, Janssen, Novartis, and Pfizer. Cascone has received speaker fees/honoraria from BMS, CCOPharma, IDEOlogy Health, The Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, PER®, Roche, and The Society for Immunotherapy of Cancer; advisory/consulting fees from Arrowhead Pharmaceuticals, BMS, Genentech, MedImmune/AstraZeneca, Merck, Pfizer, and Regeneron; research funding from BMS and MedImmune/ AstraZeneca; and expenses from AstraZeneca, BMS, DAVA Oncology, The International Association for the Study of Lung Cancer (IASLC), IDEOlogy Health, OncLive, The Parker Institute for Cancer Immunotherapy, PER®, and The Society for Immunotherapy of Cancer. Campo-Cañaveral de la Cruz has received speaker fees/honoraria from BMS.

Acknowledgements:

Medical writing assistance provided by OPEN Health Scientific Communications, London, UK.

Support:

This article was developed and funded by the medical department of Bristol Myers Squibb.

Keywords:

Adjuvant, immuno-oncology (I-O), metastatic, multidisciplinary team (MDT), neoadjuvant, non-metastatic, non-small cell lung cancer (NSCLC), programmed cell death ligand 1 (PD-L1), ROS1, tyrosine kinase inhibitor (TKI).

Citation:

EMJ Oncol. 2023;11[1]:23-32.

DOI/10.33590/emjoncol/10305999. https://doi.org/10.33590/emjoncol/10305999.

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Session Summary The non-small cell lung cancer (NSCLC) treatment landscape has rapidly evolved over the last two decades. The addition of immuno-oncology (I-O) and targeted agents has improved treatment options for patients with non-metastatic and metastatic NSCLC; however, there remains significant unmet need. In this symposium, Jürgen Wolf, University Hospital Cologne, Germany; Tina Cascone, MD Anderson Cancer Center, Houston, Texas, USA; and Jose Luis Campo-Cañaveral de la Cruz, Puerta de Hierro Majadahonda University Hospital, Madrid, Spain, discussed the increasingly complex NSCLC treatment landscape, and how the latest data may impact treatment selection. This symposium focused on I-O monotherapy and I-O combinations in treatment-naïve metastatic NSCLC, as well as the application of I-O in non-metastatic or resectable NSCLC in the neoadjuvant, peri-operative, and adjuvant settings. In addition, the latest data regarding treatment options for patients with targetable alterations, such as ROS1, were discussed, with a focus on next generation tyrosine kinase inhibitors (TKI), and how these may impact treatment selection in the future. The role of the surgeon as part of the multidisciplinary team was also discussed, with particular attention to assessment and definition of surgical complexity, as well as the importance of close collaboration and communication between the multidisciplinary team (MDT) and the patient, to ensure they are receiving the optimal treatment at the right time to improve outcomes.

A Foundation for Survivorship With Immuno-oncology and Potential New Approaches for Patients With ROS1+ Non-small Cell Lung Cancer Jürgen Wolf set the scene, providing an overview of the advancements in available therapies for patients with cancer over the past two decades, highlighting I-O and targeted agents as key pillars in modern treatment approaches in oncology. In terms of NSCLC specifically, he outlined how the landscape has evolved rapidly to include several I-O options for patients in the non-metastatic and metastatic settings, as well as targeted treatments, specifically ROS1 TKIs (Figure 1).1,2 Providing an overview of the potential first-line (1L) treatment options for metastatic NSCLC (mNSCLC), Wolf highlighted the multitude of available I-O treatment options for patients without driver mutations, including I-O monotherapy, and I-O based combinations.

He noted that there is currently one validated biomarker, programmed cell death ligand 1 (PD-L1), of which expression can help guide treatment selection for patients who are eligible to receive I-O regimens. For patients with ROS1

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fusions, several treatment options are now recommended.1,2

Immuno-oncology Monotherapy for First-Line Metastatic Non-small Cell Lung Cancer

Focusing on recent developments in 1L mNSCLC, Wolf noted the availability of long-term follow-up data from key Phase III trials of I-O monotherapy in patients with tumour PD-L1 ≥50%. He highlighted data from KEYNOTE-024, a study of pembrolizumab versus chemotherapy, in which the benefit of pembrolizumab treatment was maintained over time with a hazard ratio (HR) of 0.62 (95% confidence interval [CI]: 0.48–0.81) after a median of 59.9 months of follow-up.3 Wolf also highlighted the long-term efficacy observed in the EMPOWER-Lung1 and IMpower110 trials, where cemiplimab and atezolizumab continued to show a trend in overall survival benefit versus chemotherapy over a median follow-up of 37.1 months and 31.3 months, respectively.4,5

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Figure 1: Potential first-line treatment options for metastatic non-small cell lung cancer as discussed in the symposium.

Treatment-naïve NSCLC without targetable alterations I-O monotherapy

• Pembrolizumab3 • Atezolizumab4 • Cemiplimab5

I-O + chemotherapy

• Pembrolizumab + chemotherapy6,7 • Atezolizumab + chemotherapy ± bevacizumab (NSQ only)8,10 • Cemiplimab + chemotherapy*9

I-O + I-O

• Nivolumab + ipilimumab*11

I-O + I-O + chemotherapy

• Nivolumab + ipilimumab + chemotherapy12 • Durvalumab + tremelimumab + chemotherapy13

Treatment-naïve NSCLC with targetable alterations (e.g., ROS1)

TKI

• Crizotinib14 • Entrectinib15 • Repotrectinib16 • Taletrectinib17 • NVL-52018

*Approvals/recommendations per PD-L1 status vary regionally.

I-O: immuno-oncology; NSCLC: non-small cell lung cancer; NSQ: non-squamous; PD-L1: programmed cell death ligand 1; TKI: tyrosine kinase inhibitor.

Immuno-oncology Plus Chemotherapy for First-Line Metastic Non-small Cell Lung Cancer

Turning to I-O plus chemotherapy combinations, Wolf discussed long-term readouts from the KEYNOTE-189 and KEYNOTE-407 trials, in which pembrolizumab plus chemotherapy was compared against placebo plus chemotherapy in patients with non-squamous and squamous mNSCLC, respectively. In both trials, patients who received pembrolizumab plus chemotherapy continued to demonstrate overall survival (OS) benefit over a median follow-up of approximately 5 years.6,7 A long-term survival benefit was also shown with atezolizumab plus chemotherapy versus chemotherapy alone in patients with non-squamous disease (IMpower130),8 and cemiplimab plus chemotherapy versus placebo plus chemotherapy (EMPOWER-Lung3).9 Additionally, in the IMpower150 trial, where

patients were treated with atezolizumab plus bevacizumab plus chemotherapy, or bevacizumab plus chemotherapy, the atezolizumab combination was favoured with regard to long-term survival following a minimum follow-up of 32.4 months.10 Wolf highlighted, however, that in the subpopulation of patients with PD-L1 <1%, these combinations did not confer the same longterm survival benefit as was observed in the overall trial populations. Similar 5-year landmark rates were observed with pembrolizumab plus chemotherapy and placebo plus chemotherapy.

Other I-O plus chemotherapy combinations had HR CIs that crossed unity, indicating that increased PD-L1 expression may be a potential enrichment factor for these regimens.6-10

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Immuno-oncology Plus Immunooncology With or Without Chemotherapy for First-Line Metastatic Non-small Cell Lung Cancer

Moving on to I-O plus I-O combinations, starting with the CheckMate 227 trial of nivolumab plus ipilimumab versus chemotherapy, Wolf explained that patients who received nivolumab plus ipilimumab continued to show a durable survival benefit after a median follow-up of 78.8 months, regardless of PD-L1 expression. Within the PD-L1 ≥1% population, the 6-year OS rate was 22% in the nivolumab plus ipilimumab arm compared with 13% in the chemotherapy arm. Similarly, in patients with PD-L1 <1%, 6-year OS rates were 16% in the nivolumab plus ipilimumab arm, and 5% in the chemotherapy arm.11 In addition to I-O plus I-O, the option of adding chemotherapy to this combination in the 1L setting has also been investigated in several studies. Wolf drew attention to the CheckMate 9LA study, in which nivolumab plus ipilimumab plus two cycles of chemotherapy was compared with four cycles of chemotherapy alone. Patients who received combination therapy demonstrated a durable survival benefit after a median follow-up of 54.5 months, regardless of PD-L1 expression. In patients with PD-L1 ≥1%, 4-year OS rates were 21% versus 16% for combination therapy versus chemotherapy alone. In patients with PD-L1 <1%, 4-year OS rates were 23% versus 13% for combination therapy versus chemotherapy alone, respectively.12

evolution of the treatment landscape, many patients still do not benefit from treatment with I-O or I-O combinations, and there remains a need for clinical trials that include tailored approaches and appropriate control arms to develop effective personalised treatment strategies for patients.

Clinical Developments in the ROS1+ Treatment Landscape

Switching to ROS1 TKIs, Wolf first highlighted that several therapies for ROS1+ NSCLC have been developed in recent years. He then examined the clinical efficacy of crizotinib and entrectinib in ROS1 TKI-naïve mNSCLC. Both treatments elicited high response rates, translating into a median progression-free survival (PFS) of 19.3 months with crizotinib (median follow-up: 62.6 months; PROFILE 1001 trial) and 15.7 months with entrectinib (median follow-up: 29.1 months; ALKA-372-001, STARTRK-1, and STARTRK-2 trials).14,15 He noted, however, that despite these data, patients are at risk of developing resistance mutations (e.g., the ROS1 G2032R mutation has been identified in patients who were treated with crizotinib or entrectinib), which lead to treatment failure and disease progression.19,20 This indicates an unmet need for patients for more durable activity with ROS1 TKIs. Wolf suggested that next-generation TKIs, such as repotrectinib, may help address this unmet need.

Additional data presented included those from the Phase III POSEIDON trial, in which durvalumab plus tremelimumab plus chemotherapy was compared against chemotherapy alone. Patients who received the combination therapy experienced a sustained survival benefit compared with those who received chemotherapy alone (HR: 0.75; 95% CI: 0.63–0.88) after a median follow-up of 46.5 months.13

Wolf presented data from the TRIDENT-1 trial of repotrectinib in TKI-naïve and pre-treated NSCLC. In the TKI-naïve setting, patients who were treated with repotrectinib achieved a median PFS of 35.7 months, and the median duration of response was 34.1 months (median follow-up: 24.0 months). In addition, treatment with repotrectinib led to an intracranial response rate of 89%. Importantly, no TKI-naïve patients who progressed on repotrectinib developed an on-target resistance mutation.16

Wolf closed this section on I-O combinations by highlighting that the observed safety profile across these trials was as expected, with treatments being generally well tolerated. He also mentioned that clinicians are increasingly able to address concerns about tolerability as they gain more experience with using these combinations.1-11 He concluded that despite the

In the TKI-pre-treated population, patients who received lorlatinib post-crizotinib achieved a median PFS of 8.5 months, while those who received repotrectinib post-ROS1 TKI had a median PFS of 9.0 months (median follow-up of 21.1 months and 24.0 months, respectively).16,22 Of note, Wolf highlighted that among the patients who were treated with lorlatinib, no response

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was observed in those with a ROS1 G2032R mutation, whereas responses were observed in 59% of patients who were treated with repotrectinib in the TRIDENT-1 trial.16,22 The safety profile of ROS1 TKIs was considered manageable, with <10% of patients experiencing adverse events leading to treatment discontinuation across trials.14–16,19–22 Looking toward the future, Wolf mentioned two additional treatments that are currently under investigation, taletrectinib and NVL-520.17,18 Wolf closed the section by thanking the researchers and patients who helped drive this evolution in the treatment landscape, emphasising the important role of patient advocacy groups in clinical research, adding: “We are now doing research not only for the patients, but with the patients.”

Multidisciplinary Approach to Managing the Expanding Options with Immuno-oncology in Non-metastatic Non-small Cell Lung Cancer Jose Luis Campo-Cañaveral de la Cruz introduced the session, switching focus from the metastatic to non-metastatic landscape, first drawing attention to the fact that 2- and 5-year survival rates correlate with disease stage, even when the disease is non-metastatic, where patients with Stage IA1 disease have the best outcomes.23 To address the issue of worsening outcomes across disease stage, it is necessary to focus on how patients with nonmetastatic NSCLC (nmNSCLC or resectable NSCLC) are treated, and how outcomes can be improved across the spectrum of Stage IA1–IIIC disease. He then shared an overview of the treatment landscape in resectable NSCLC, and the potential role of I-O in the neoadjuvant, perioperative, and adjuvant settings.

Latest Data on Immuno-oncology in the Neoadjuvant Setting

Campo-Cañaveral de la Cruz described the CheckMate 816 trial, highlighting that it is the first and only Phase III trial in which I-O (nivolumab) plus chemotherapy is being evaluated in the neoadjuvant setting. Patients with resectable Stage IB (≥4 cm)–IIIA NSCLC

were randomised to receive either nivolumab plus chemotherapy, or chemotherapy alone prior to surgery, which was followed by optional adjuvant chemotherapy with or without radiotherapy.24 Investigators reported a significant improvement in pathological complete response (pCR; OR: 13.94; 99% CI: 3.49–55.75; p<0.0001) and event-free survival (EFS) with nivolumab plus chemotherapy compared with chemotherapy alone (not reached [NR] versus 21.1 months; HR: 0.68; 95% CI: 0.49–0.93 at the first pre-specified analysis). Notably, patients who achieved a pCR with nivolumab plus chemotherapy experienced a long-term EFS benefit compared with those who did not (HR: 0.13; 95% CI: 0.05–0.37).24 Results from further subanalyses demonstrated that a greater magnitude of benefit was observed with nivolumab plus chemotherapy versus chemotherapy alone in patients with tumour PD-L1 ≥1% compared with those with tumour PD-L1 <1% (PD-L1 ≥1% EFS: HR: 0.41; 95% CI: 0.24–0.70; PD-L1 <1% EFS: HR: 0.85; 95% CI: 0.54–1.32). Campo-Cañaveral de la Cruz concluded that while OS data are not yet mature, there is a trend toward sustained OS improvement in patients who were treated with nivolumab plus chemotherapy compared with those treated with chemotherapy alone.24

The Surgeon’s Role in Resectable Non-small Cell Lung Cancer

Given the positive data on I-O in the neoadjuvant setting, Campo-Cañaveral de la Cruz switched his focus to the role of a surgeon throughout the patient journey, from diagnosis to post-surgical follow-up. He highlighted the key time points of pathological staging and treatment planning, as well as of the surgery itself, and mentioned the following key considerations for surgeons and the multidisciplinary team: • Resectability: Can the tumour be removed with a complete resection?

• Operability: Is the patient fit to undergo surgery?

• Surgical complexity: How difficult will the surgery be?

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• Patient preference: Is the patient willing to undergo surgery?

Campo-Cañaveral de la Cruz noted the importance of collaboration within the MDT, and working with pulmonologists and cardiologists to assess the complexity of the surgery, and how greatly it will impact the patient in terms of surgical recovery. He also emphasised how crucial it is to have proactive and open conversations with the patient, to ensure that they are involved in decision-making processes, and are aware of the potential risks and recovery associated with surgery.

Regarding factors that might impact the potential success of resection, Campo-Cañaveral de la Cruz highlighted that while the field is gradually moving toward a consensus on defining complexity in the neoadjuvant setting, it is still an ongoing process (Figure 2).25,26 He proceeded to revisit the CheckMate 816 trial, and discuss the impact of neoadjuvant nivolumab plus chemotherapy on resection as well.

In the CheckMate 816 trial, the addition of nivolumab to chemotherapy did not impede surgical feasibility.24 Among patients who received neoadjuvant nivolumab plus chemotherapy, 83% underwent surgical

Figure 2: Proposal for the definition of surgical complexity in the neoadjuvant setting.

Proposed scales

Characteristics

Level of surgical complexity

Proposed surgical complexity scale from NEOSTAR25

Complexity of tissue dissection

Easier than normal (tissues easily separate mostly with blunt dissection)

Normal (similar to routine anatomical lobectomy, blunt and sharp dissection used)

Difficult because of inflammation (tissue planes somewhat obliterated requiring mostly sharp dissection)

Proposed scales for intraoperative quantification of surgical complexity in early NSCLC after neoadjuvant I-O26

Peripheral fibrosis and/or perihilar/lobar or mediastinal adhesions

Mild fibrosis (no substantial impact on conduct of surgical resection)

Moderate fibrosis (requires increased effort and dissection during resection but otherwise does not severely impact the conduct of surgery)

Severe fibrosis Severe fibrosis (substantially resulting in impacts the unresectability conduct of the operation by increasing the duration of blood loss during the surgery, or requires converting minimally invasive to open surgery)

1 to <2 cm

2 to <3 cm

Lymphadenopathy <1 cm Tumour location

Central (inner two-thirds of lung)

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≥3 cm

Peripheral (outer two-thirds of lung)

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Very complex (tissue and anatomical planes completely obliterated similar to fibrosis or long-term postradiation effect)

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resection compared with 75% who received neoadjuvant chemotherapy alone.24 In addition, patients who received neoadjuvant nivolumab plus chemotherapy were more likely to receive a lobectomy and minimally invasive surgery, and less likely to receive a pneumectomy or thoracotomy or progress on their minimally invasive surgery to open, compared with those who received neoadjuvant chemotherapy alone.24 Overall, there were no differences between treatment groups in terms of the timing of surgery or length of hospital stay, and the safety profiles were manageable and similar.24

Latest Data on Immuno-oncology in the Adjuvant Setting

Switching from the neoadjuvant to adjuvant treatment setting, Tina Cascone provided an overview of the latest data from the IMpower010 and KEYNOTE-091 trials. In the IMpower010 trial, patients with Stage IB–IIIA NSCLC who had undergone a complete surgical resection, and subsequently received up to four cycles of chemotherapy, were randomised to receive atezolizumab monotherapy or best supportive care. The primary endpoint in the trial was disease-free survival (DFS);27 patients who received atezolizumab monotherapy experienced an improvement in DFS compared with those who received best supportive care, with the largest benefit being observed in the PD-L1 ≥50% population, excluding patients with known EGFR/ALK mutations (HR: 0.43; 95% CI: 0.26–0.71).27 In the KEYNOTE-091 trial, patients with Stage IB–IIIA NSCLC who had undergone a complete resection and subsequently received optional chemotherapy were randomised to receive pembrolizumab monotherapy or placebo. The primary endpoint in the trial was DFS.28 Patients who received pembrolizumab demonstrated a significant improvement in DFS compared with those who received placebo (median DFS: 53.6 months versus 42.0 months, respectively; HR: 0.76; 95% CI: 0.63–0.91; p=0.0014); however, this benefit was not observed in a subanalysis of the PD-L1 ≥50% population.28 Cascone highlighted that while this was an unexpected result for this subpopulation, the data are not yet mature, and future updates will be important.

The safety profiles were also similar across trials, with approximately 20% of patients in both

trials experiencing an adverse event, leading to treatment discontinuation.27,28

Utilising Immuno-oncology in the Peri-operative Setting

Moving on to a different treatment paradigm, Cascone discussed several trials in which I-O was utilised in the peri-operative setting: AEGEAN, KEYNOTE-671, and NEOTORCH. Each trial included patients with newly-diagnosed or previously untreated Stage II–III NSCLC.29–31 Patients in the AEGEAN trial were randomised to receive either durvalumab plus chemotherapy or placebo plus chemotherapy prior to surgical resection, followed by durvalumab monotherapy or placebo. The primary endpoints were pCR and EFS; patients who received durvalumabbased treatment demonstrated a significantly improvement in pCR rate (difference in pCR: 13.0%; 95% CI: 8.7–17.6; p=0.000036) and EFS versus those who received placebo (NR versus 25.9 months, respectively; HR: 0.68; 95% CI: 0.53–0.88; p=0.003902).29 Patients in the KEYNOTE-671 trial were randomised to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy prior to surgical resection, followed by pembrolizumab monotherapy or placebo. The primary endpoints were EFS and OS. Perioperative treatment with pembrolizumab significantly improved EFS (median EFS: NR versus 17.0 months; HR: 0.58; 95% CI: 0.46–0.72; p<0.00001) and OS (median OS: NR versus 45.5 months; HR: 0.73; 95% CI: 0.54–0.99; p=0.02124) in patients with resectable Stage II–IIIB (N2) NSCLC compared with those who received placebo.30 In the NEOTORCH trial, performed exclusively in China, patients were randomised to receive either toripalimab plus chemotherapy or placebo plus chemotherapy prior to surgical resection, followed by toripalimab plus chemotherapy, or placebo plus chemotherapy, for one cycle, and maintenance toripalimab or placebo for up to 13 cycles. The primary endpoints were EFS and major pathologic response (MPR). Peri-operative treatment with toripalimab plus chemotherapy significantly improved both MPR rate (difference in MPR rate: 40.2%; 95% CI: 32.2–48.1; p<0.0001) and EFS versus placebo plus chemotherapy

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(median EFS: NR versus 15.1 months; HR: 0.40; 95% CI: 0.28–0.57; p<0.0001).31 Cascone highlighted the importance of these data for patients with Stage III NSCLC as they may be at high risk of relapse. She also mentioned that as observed in the CheckMate 816 trial, patients with a pCR experienced a greater EFS benefit compared with those without a pCR in both the KEYNOTE-671 and NEOTORCH trials.24,30,31 It was noted that surgical outcomes and safety profiles were broadly similar to each other, and in line with expectations across the three trials.24,30,31 Cascone concluded this section by asking an open question: “How can we understand which patients may benefit from each treatment approach, and when should we consider management strategies such as switching, stopping, or amending the treatment regimen?”

Next, she focused on two trials of nivolumab, NADIM II and CheckMate 77T, where it was used in the peri-operative setting. In the Phase II NADIM II trial, patients with Stage III resectable NSCLC received neoadjuvant nivolumab plus chemotherapy followed by surgery. Patients in the nivolumab plus chemotherapy arm who underwent R0 resection subsequently received adjuvant nivolumab monotherapy for 6 months. The primary endpoint was pCR, and key secondary endpoints included PFS and OS at 24 months. Patients who were treated with nivolumab plus chemotherapy showed improvements in PFS (HR: 0.47; 95% CI: 0.25– 0.88) and OS (HR: 0.43; 95% CI: 0.19–0.98), compared with those who were treated with chemotherapy alone.32,33 In the Phase III CheckMate 77T trial, patients with previously untreated, resectable Stage II–IIIB NSCLC were randomised to receive either neoadjuvant nivolumab plus chemotherapy or placebo plus chemotherapy followed by surgery and adjuvant nivolumab monotherapy or

References 1.

2.

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Hendriks L et al. Non-oncogeneaddicted metastatic non-small cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):358-76.

Hendriks L et al. Oncogene-

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placebo. The primary endpoint was EFS, and a key secondary endpoint was pCR. Peri-operative treatment with nivolumab plus chemotherapy significantly improved EFS compared with chemotherapy alone (median EFS: NR versus 18.4 months, respectively; HR: 0.58; 97.36% CI: 0.42–0.81; p=0.00025). In addition, a higher proportion of patients experienced a pCR with nivolumab plus chemotherapy versus chemotherapy alone (25.3% versus 4.7%, respectively; OR: 6.64; 95% CI: 3.40–12.97).33 Cascone summarised these data by highlighting that CheckMate 77T is the first peri-operative study to build on neoadjuvant standard of care, and may be a future treatment option.

Key Considerations When Optimising Immuno-oncology Treatment for Non-small Cell Lung Cancer

Cascone closed the session by reviewing the evidence presented regarding the benefits of peri-operative treatment for patients with resectable NSCLC. Looking to the future, she highlighted a few key considerations to help guide the use of I-O in the neoadjuvant or adjuvant settings: Which patients would benefit from neoadjuvant or adjuvant I-O treatments?

Which patients would benefit from the addition of adjuvant I-O after receiving neoadjuvant I-O + chemotherapy? Which biomarker(s) can be used to reliably predict response to, or the long-term clinical benefits of, I-O treatments in the perioperative setting?

Closing with a final point on the role of the MDT in the management of patients with NSCLC, Cascone emphasised the importance of close collaboration and communication between healthcare providers that include, but are not limited to, surgeons, medical oncologists, and pulmonologists, to ensure that patients receive the optimal treatment at the right time to improve outcomes.

addicted metastatic non-small cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):339-57.

3.

Reck M et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-

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small cell lung cancer with PD-L1 tumor proportion score ≥50. J Clin Oncol. 2021;39(21):2339-49.

4.

Özgüroğlu M et al. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small cell lung

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cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, Phase 3 trial. Lancet Oncol.

2023;24(9):989-1001.

5.

6.

7.

8.

9.

Jassem J et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinumbased chemotherapy in treatmentnaive programmed death-ligand 1-selected NSCLC. J Thorac Oncol.

2021;16(11):1872-82.

Garassino M et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small cell lung cancer: 5-year outcomes from the Phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41(11):1992-98.

Novello S et al. Pembrolizumab plus chemotherapy in squamous non-small cell lung cancer: 5-year update of the Phase III KEYNOTE-407 study. J Clin Oncol.

2023;41(11):1999-2006.

West H et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small cell lung cancer (IMpower130): a multicentre, randomised, open-label, Phase 3 trial. Lancet Oncol.

2019;20(7):924-37.

Makharadze T et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: longer followup results from the Phase III EMPOWER-Lung 3 trial. Abstract 5O. European Lung Cancer Congress, 30 March, 2023.

10. Socinski MA et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021;16(11):190924.

11. Ramalingam S et al. Six-year survival and HRQoL outcomes with 1L nivolumab + ipilimumab in patients with metastatic NSCLC from CheckMate 227. Abstract OA14.03. World Conference on Lung Cancer, 9-12 September, 2023.

12. Carbone D et al. First-line (1L) nivolumab (N) + ipilimumab (I) + chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4‑y clinical update and outcomes by tumor histologic subtype (THS). Abstract LBA9023. American Society of Clinical Oncology Annual Meeting,

4 June, 2023.

13. Johnson ML et al. Durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in 1L metastatic (m) NSCLC: overall survival (OS) update from POSEIDON after median follow-up (mFU) of approximately 4 years (y). Abstract LBA59. European Society of Medical Oncology Congress, 11 September, 2022.

14. Shaw A et al. Crizotinib in ROS1rearranged advanced non-small cell lung cancer (NSCLC): Updated results, including overall survival, from PROFILE 1001. Ann Oncol.

2019;30(7):1121-26.

15. Drilon A et al. Long-term efficacy and safety of entrectinib in ROS1 fusion-positive NSCLC. JTO Clin Res Rep. 2022;3(6):100332.

16. Cho B et al. Repotrectinib in patients with ROS1 fusion-positive (ROS1+) NSCLC: update from the pivotal Phase 1/2 TRIDENT-1 trial. Abstract OA03.06. World Conference on Lung Cancer, 10 September, 2023.

17. Li W et al. Updated efficacy and safety of taletrectinib in patients (pts) with ROS1+ non-small cell lung cancer (NSCLC). Abstract 14MO. European Lung Cancer Congress, 31 March, 2023.

18. Drilon A et al. Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors.

Abstract 8. European Organisation for Research and Treatment of Cancer-National Cancer InstituteAmerican Association for Cancer Research Symposium, 28 October, 2022.

19. Gainor J et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive nonsmall cell lung cancer. JCO Precis Oncol. 2017;PO.17.00063.

20. Dziadziuszko R et al. Pre- and post-treatment blood-based genomic landscape of patients with ROS1 or NTRK fusionpositive solid tumours treated with entrectinib. Mol Oncol.

2022;16(10):2000-14.

21. Michels S et al. Safety and efficacy of crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): a European Phase II clinical trial. J Thorac Oncol.

2019;14(7):1266-76.

22. Shaw A et al. Lorlatinib in advanced ROS1-positive non-small cell lung cancer: a

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multicentre, open-label, singlearm, Phase 1–2 trial. Lancet Oncol.

2019;20(12):1691-1701.

23. Goldstraw P et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(1):39-51.

24. Forde P et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-85.

25. Sepesi B et al. Surgical outcomes after neoadjuvant nivolumab or nivolumab with ipilimumab in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg.

2022;164(5):1327-37.

26. Lee J et al. Important surgical and clinical end points in neoadjuvant immunotherapy trials in resectable NSCLC. JTO Clin Res Rep. 2021;2(10):100221.

27. Felip E et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected Stage IB–IIIA non-small cell lung cancer (IMpower010): a randomised, multicentre, openlabel, Phase 3 trial. Lancet.

2021;398(10308):1344-57.

28. O’Brien M et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected Stage IB–IIIA nonsmall cell lung cancer (PEARLS/ KEYNOTE-091): an interim analysis of a randomised, triple-blind, Phase 3 trial. Lancet Oncol.

2022;23(10):1274-86.

29. Heymach J et al. AEGEAN: a Phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Abstract CT005. American Association for Cancer Research Annual Meeting, 16 April, 2023.

30. Wakelee H et al. Perioperative pembrolizumab for early-stage non-small cell lung cancer. N Engl J Med. 2023;389(6):491-503.

31. Lu S et al. Perioperative toripalimab + platinum-doublet chemotherapy vs. chemotherapy in resectable Stage II/III non-small cell lung cancer (NSCLC): interim event-free survival (EFS) analysis of the Phase III NEOTORCH study.

Abstract 8501. American Society of Clinical Oncology, 3 June, 2023.

32. Provencio M et al. Perioperative nivolumab and chemotherapy in Stage III non-small cell lung cancer.

N Engl J Med. 2023;389(6):504– 13.

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33. Cascone T et al. CheckMate 77T: phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs.

neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable Stage II–IIIB

NSCLC. Abstract LBA1. European Society of Medical Oncology Congress, 21 October, 2023.

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Current and Upcoming Treatment Strategies After CDK4/6 Inhibitors for Patients With ER+/ HER2- Advanced Breast Cancer This industry symposium took place during the European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain, 20th–24th October 2023 Chairperson:

Antonio Llombart-Cussac1

Speakers:

Antonio Llombart-Cussac,1 Virginia Kaklamani,2 Volkmar Müller3 1. Arnau de Vilanova University Hospital, Valencia, Spain 2. UT Health San Antonio MD Anderson Cancer Center, Texas, USA 3. University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany

Disclosure:

Llombart-Cussac has received speaker honoraria and/or consultancy fees from AstraZeneca, Lilly, Merck Sharp & Dhome, Novartis, and Pfizer; travel support from AstraZeneca, Merck Sharp & Dhome, Pfizer, Roche, and Stemline Therapeutics; research support from Agendia, Daiichi Sankyo, Gilead, Lilly, Merck Sharp & Dhome, Novartis, Pfizer, and Roche; and has stocks or other ownership in Initia-Research and MAJ3 Capital. Kaklmani has received speaker honoraria and/or consultancy fees from AstraZeneca, Daiichi Sankayo, Gilead, Genetech, Lilly, Novartis, Pfizer, Puma, Seagen, Stemline Therapeutics, and Tersera; and research support from Eisai. Müller has received speaker honoraria and/or consultancy fees from Amgen, AstraZeneca, ClinSol, Daiichi Sankyo, Eisai, Gilead, high5 Oncology, Lilly, Medac, Medscape, MSD, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche, Sanofi, Seagen, and Stemline Therapeutics; research support from AstraZeneca, Genentech, Novartis, Roche, and Seagen; and travel support from Daiichi Sankyo, Gilead, Pfizer, and Roche.

Acknowledgements:

Writing assistance was provided by Nicola Humphry, Nottingham, UK.

Support:

The publication of this article was funded by Menarini Stemline. The views and opinions expressed are exclusively those of the speakers.

Keywords:

Breast cancer, ER+ HER2-, ESR1, elacestrant, metastatic, selective oestrogen receptor down-regulator (SERD).

Citation:

EMJ Oncol. 2023;11[1]:33-43.

DOI/10.33590/emjoncol/10303763. https://doi.org/10.33590/emjoncol/10303763.

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Meeting Summary This industry symposium took place during the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, with a goal of presenting the latest recommendations and upcoming treatment strategies for patients with oestrogen-receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer, who experience disease progression after cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

An expert panel of clinicians explained that most patients will eventually develop resistance to endocrine therapy during the metastatic setting, and there remains a considerable margin for improvement in the second-line (2L) treatment of these patients. Data for current therapeutic options in this patient population were presented, showing that patients who have previously received CDK4/6 inhibitor therapy are often resistant to many of the available 2L therapies, including combination therapies, and that resistance appears during first-line (1L) treatment, becoming particularly significant in tumours harbouring ERS1 mutations.

The recent approval of the oral selective oestrogen receptor degrader (SERD), elacestrant, was also discussed. The supporting data for this monotherapy at 2L was presented, along with changes made to the U.S. Food and Drug Administration (FDA) and European Union (EU) best practice recommendations to accommodate this therapeutic option. The panel stressed the importance of testing for ESR1 mutations at each progression during the metastatic treatment course, which is particularly relevant following the approval of elacestrant, for which ESR1 mutation is a predictive factor for efficacy.

Introduction Over 70% of breast cancers are ER+/HER2-, for which the backbone of treatment is endocrine therapy.1-3 Endocrine therapies for ER+/HER2advanced breast cancer at 1L include aromatase inhibitors, such as anastrozole, letrozole, and exemestane; selective oestrogen receptor modulators, such as tamoxifen; and SERDs, such as fulvestrant.4 Antonio Llombart-Cussac, Head of Medical Oncology at the Arnau de Vilanova Hospital in Valencia, Spain, emphasised that the addition of CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib to endocrine therapy represented a step-change in the treatment of ER+/HER2- breast cancer. CDK4/6 inhibitors provided benefits both in terms of progressionfree survival (PFS) and overall survival (OS), through the suppression of cell proliferation.3-6 Median duration of treatment with endocrine therapies plus CDK4/6 inhibitors is 15–24 months.7-10 This drug combination is the current standard of care (SoC) 1L therapy for patients

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with recurrent, unresectable, or advanced ER+/ HER2- breast cancer who are not at risk of imminent organ failure.1,11,12 However, Llombart-Cussac stressed that most patients will eventually develop resistance to endocrine therapy, and there remains a considerable margin for improvement in the 2L treatment of these patients.11 Resistance to endocrine therapy can be defined in terms of primary versus secondary clinical resistance, and de novo versus acquired molecular resistance.11 In the metastatic setting, primary resistance is defined as disease progression within the first 6 months of 1L endocrine therapy for advanced breast cancer, while secondary resistance is characterised as disease progression ≥6 months after initiating endocrine therapy in the same setting.11,13,14 Examples of de novo resistance include alterations to the PI3K/AKT/mTOR pathway, RB1 downregulation, or TP53 activation. Acquired resistance mechanisms occur after prior endocrine therapy in the metastatic setting.14,15

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A key mechanism of resistance to endocrine therapy is the emergence, during the treatment in the metastatic setting, of mutations in the ESR1 gene, which encodes the oestrogen receptor.16 Mutations that alter the ligand-binding domain of the oestrogen receptor can result in constitutive activation of the receptor and therefore oestrogen independence.15,17 LlombartCussac noted that ESR1 mutations can affect up to 40% of patients with ER+ advanced or metastatic breast cancer who have received endocrine therapy during 1L treatment.18

The Current and Future Treatment Landscape for ER+/HER2- Advanced Breast Cancer Virginia Kaklamani Best practice guidelines in Europe and the USA recommend that patients with ER+/ HER2- advanced breast cancer who experience disease progression on CDK4/6 inhibitors plus endocrine therapy should be treated with sequential endocrine therapy options.11,12 Virginia Kaklamani, Professor of Medicine in the Division of Hematology/Oncology, and leader of the Breast Cancer Program at the UT Health San Antonio MD Anderson Cancer Center, Texas, USA, explained that there are two options for treatment at this stage. The first is to consider endocrine monotherapy with aromatase inhibitors or fulvestrant (depending on the previous therapy), and the second is to consider endocrine therapy combinations, such as the addition of CDK4/6 inhibitors, or other agents that target the PI3K/AKT/mTOR pathway, such as everolimus, alpelisib, or capivasertib.11,12 However, Kaklamani stressed that there is room for improvement in the post-CDK4/6 inhibitor treatment landscape. She explained that monotherapy treatment options at this stage have a median PFS (mPFS) of 2–4 months.19-22 Fulvestrant, administered by intramuscular injection, is associated with injection site reactions, asthenia, nausea, and increased hepatic enzymes, though Kaklamani emphasised that its toxicity profile is generally favourable.23 Combination therapies with everolimus, alpelisib, or capivasertib can introduce additional adverse effects, such as rash, stomatitis, diarrhoea, and

hyperglycaemia.24,25 If an oncologist elects to rechallenge a patient with CDK4/6 inhibitors, then adverse effects, such as myelosuppression and diarrhoea, may occur.8,26,27 Discontinuation rates, particularly with PI3K/AKT/mTOR inhibitors, can be considerable, reaching up to 25%.24,25 The 2L treatment landscape for patients with ER+/HER2- advanced breast cancer is evolving.28 Each of the available treatments has a distinct mechanism of action, which is beneficial, because when one agent generates resistance in a tumour, using an agent with a different mechanism of action for subsequent therapy may overcome some of that resistance.

Efficacy of 2L+ Endocrine Therapy Regimens for ER+/HER2- Advanced Breast Cancer With No Prior CDK4/6 Inhibitor Therapy

In patients who relapsed on 1L therapy that did not include a CDK4/6 inhibitor, monotherapy with fulvestrant was associated with an mPFS of 4.8 months in the SoFEA trial (n=231; Figure 1).29 In comparison, combination therapies are associated with a longer mPFS: everolimus + exemestane had an mPFS of 11.0 months (n=485), which was superior to placebo + exemestane (hazard ratio [HR]: 0.38; p<0.0001) in the BOLERO-2 trial;30 and alpelisib + fulvestrant had an mPFS of 11.0 months (n=169), which was superior to placebo + fulvestrant (mPFS of 5.7 months; n=172), in a population with PIK3CA mutations in the SOLAR-1 trial (HR: 0.65; p<0.001).31 In the MONALEESA-3 trial, a CDK4/6 inhibitor + endocrine therapy in a population with early relapse, or receiving 2L therapy, was associated with an mPFS of 14.6 months (n=237).9 Capivasertib is an inhibitor of AKT, a key protein in the PI3K/AKT/mTOR pathway. This novel agent has been approved by the FDA as a combination therapy with intramuscular fulvestrant, for patients with advanced breast cancer with one or more biomarker alterations (PIK3CA, AKT1, or PTEN).37 Kaklamani explained data from the recent CAPItello-291 trial showed that capivasertib + fulvestrant (n=155) compared with placebo + fulvestrant (n=134), was associated with a significantly improved mPFS of 7.3 months versus 3.1 months, respectively (HR: 0.50; p<0.001); 29% of included patients had no prior CDK4/6 inhibitor exposure.22

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Figure 1: Efficacy of 2L+ ET regimens for ER+/HER2- advanced breast cancer with prior CDK4/6 inhibitor therapy and ESR1-mutation: indirect comparison of trial data.9,19,29-36

mPFS (months) Fulvestrant

1

2

3

1.9 mo EMERALD Ph3

Prior CDK4/6i ESR1-mut

Prior CDK4/6i

Everolimus + ET*

CDK4/6i + ET

4

Prior CDK4/6i ESR1-mut

Capivasertib + ET

8

9

10

11

2.8 mo TRINITI-1 Ph 1/2

4.3 mo RWE**

11.0 mo BOLERO-2 Ph3

ESR1-mut and prior CDK4/6i

Prior CDK4/6i

No prior CDK4/6i

12

13

14

15

Data for ESR1-mut are not reported

14.6 mo MONALEESA-3 Ph3

5.3 mo MAINTAIN Ph2 Prior CDK4/6i

Prior CDK4/6i PIK3CA-mut

Prior CDK4/6i

7

No prior CDK4/6i

ESR1-mut and prior CDK4/6i

Alpelisib + ET

6

4.8 mo SoFEA Ph3

3.0 mo MAINTAIN Ph2

Prior CDK4/6i ESR1-mut

5

No prior CDK4/6i

5.6 mo BYLieve Ph2

8.0 mo BYLieve Ph2

11. mo SOLAR-1 Ph3

ESR1-mut and prior CDK4/6i

Prior CDK4/6i

No prior CDK4/6i

5.5 mo CAPitello-291 Ph3 Prior CDK4/6i

*Plus ribociclib. **The RWE study of everolimus reported time to next treatment data, not mPFS. 2L: second-line; CDK4/6: cyclin-dependent kinase 4/6; CDK4/6i: CDK4/6 inhibitor; ER: oestrogen receptor; ET: endocrine therapy; HER2: human epidermal growth factor receptor 2; mo: months; mPFS: median progression-free survival; mut: mutation; RWE: real-world evidence.

Efficacy of 2L+ Endocrine Therapy Regimens for ER+/HER2- Advanced Breast Cancer With Prior CDK4/6 Inhibitor Therapy

Kaklamani stressed that outcomes in patients who experience disease progression on therapy that included a CDK4/6 inhibitor are generally poor (Figure 1). In this population, fulvestrant monotherapy was associated with an mPFS of 1.9 months in the VERONICA trial (n=52).20 In a realworld study, combination therapy with everolimus + exemestane was associated with a time to next treatment of 4.3 months (n=622),38 and the TRINITI-1 trial reported that triple combination therapy with everolimus + exemestane + ribociclib resulted in an mPFS of 5.7 months (n=95).32 In patients with a PIK3CA mutation, mPFS with alpelisib + fulvestrant was 8.0 months in the BYLieve trial (n=127).33 In the post-CDK4/6 inhibitor population, the CAPItello-291 trial showed that capivasertib was associated with an mPFS of 5.5 months in the AKT-altered population (n=289).22

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Several studies have investigated the efficacy of rechallenge with a CDK4/6 inhibitor in patients who have received prior CDK4/6 inhibitor therapy. In the MAINTAIN trial, ribociclib + endocrine therapy versus placebo + endocrine therapy was assessed in patients who had disease progression on a CDK4/6 inhibitor + endocrine therapy (86.5% with palbociclib included in the previous therapy).34 MAINTAIN reported an mPFS of 5.3 months in patients treated with ribociclib (n=60) versus 2.8 months in patients treated with placebo (n=59; HR: 0.57; p=0.006), indicating that rechallenge with a CDK4/6 inhibitor provided a benefit in this population. However, other trials failed to show a significant improvement in mPFS with CDK4/6 inhibitor rechallenge versus endocrine therapy alone, with the PACE trial reporting an HR for palbociclib + endocrine therapy after prior palbociclib + endocrine therapy of 1.11 (p=0.62; palbociclib + endocrine therapy: mPFS 4.6 months [n=111] versus endocrine monotherapy:

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mPFS 4.8 months [n=55]),40 and the PALMIRA trial reported an HR of 0.8 (p=0.206; palbociclib + endocrine therapy: mPFS 4.2 months [n=136] versus endocrine monotherapy: mPFS 3.6 months [n=62]).41 Adding the programmed death-ligand 1 inhibitor avelumab to palbociclib + endocrine therapy (n=54) showed a trend towards longer mPFS (compared with endocrine monotherapy [n=55]; 8.1 months versus 4.8 months, respectively) in the PACE trial, though the difference did not reach statistical significance (HR: 0.75; p=0.23).40

Efficacy of 2L+ Endocrine Therapy Regimens for ER+/HER2- Advanced Breast Cancer With No Prior CDK4/6 Inhibitor Therapy and ESR1 Mutation

Outcomes are particularly poor in patients who have received CDK4/6 inhibitor therapy and harbour an ESR1 mutation (Figure 1).

Kaklamani explained that in these patients, fulvestrant monotherapy was associated with an mPFS of 1.9 months in the EMERALD trial (n=165).19 In the MAINTAIN trial, rechallenge with a CDK4/6 inhibitor + endocrine therapy was associated with an mPFS of 3.0 months (n=18).34 Triple therapy with ribociclib + everolimus + endocrine therapy in the TRINITI-1 trial was associated with mPFS of 2.8 months (n=30).35 The BYLieve trial reported that alpelisib + fulvestrant was associated with an mPFS of 5.6 months in patients with a PIK3CA mutation (n=27).36 Capivasertib + fulvestrant data in patients with ESR1-mut tumours is not available.22 Kaklamani explained that, together, these data indicate that patients who have previously received CDK4/6 inhibitor therapy are more likely to have resistant disease to many of the available therapies, including combination therapies, than those who have not, and that resistance appears to be particularly substantial in tumours harbouring ERS1 mutations.

Oral Selective Oestrogen Receptor Down-Regulators

Oral SERDs have the potential to deliver a higher bioavailable dose than can be achieved with fulvestrant, a SERD administered through intramuscular injection. Kaklamani explained that this is an approach which is likely to be required

for the successful treatment of patients with ESR1 mutations. One oral SERD, elacestrant, has recently been approved as a 2L monotherapy for advanced breast cancer in the USA and EU.42,43 Phase II trials of oral SERDs, giredestrant, and amcenestrant, failed to show a significant PFS benefit at 2L in patients with ERS1 mutations.44,45 However, a Phase II trial of camizestrant versus fulvestrant demonstrated a trend towards improved mPFS in patients with an ESR1 mutation (camizestrant 75 mg [n=22] versus fulvestrant 500 mg [n=35]: 6.3 months versus 2.2 months; HR: 0.33). Of note, only 50% of the patients in this trial had prior exposure to CDK4/6 inhibitors.21 Kaklamani presented data from EMERALD, the first and only Phase III trial of an oral SERD to meet its primary endpoint.19 EMERALD enrolled patients with ER+/HER2- breast cancer who had received prior CDK4/6 inhibitor therapy, had ≤1 line of chemotherapy, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were randomised to receive either elacestrant 345 mg once daily (n=239), or the investigators’ choice of SoC endocrine therapy from fulvestrant, anastrozole, letrozole, or exemestane, depending on the prior endocrine therapy used (n=239). The two primary endpoints were PFS in patients with an ESR1 mutated tumour, and PFS in all patients. A tumour ESR1 mutation was detected in 47.8% of patients.

All patients had previously received a CDK4/6 inhibitor, and enrolment of patients with primary endocrine resistant breast cancer was allowed.

Results showed that elacestrant (n=115) provided a 45% reduction in risk of progression or death versus SoC (n=113) in patients with tumours with ESR1 mutations, with an mPFS of 3.8 versus 1.9 months (HR: 0.55; p=0.0005). A closer look at the Kaplan–Meier curves reveals an initial drop in both arms, which highlights primary endocrine resistance (present in almost 25% of the EMERALD patient population), but then it also shows a sustainable separation of the curves in the more endocrine-sensitive setting.

Since median PFS alone may not be enough to interpret results in this scenario, PFS landmark analyses were conducted at 6 and 12 months.19 The 6-month PFS rate reported in the EMERALD trial was 40.8% with elacestrant versus 19.1% with SoC, and the 12-month PFS rate was 26.8% versus 8.2%, respectively, demonstrating

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substantial and clinically meaningful improvements in PFS at these timepoints.

With the intention to identify tumours that remain endocrine sensitive despite an acquired resistance to aromatase inhibitors or fulvestrant, the impact of prior CDK4/6 inhibitor therapy duration for at least 6, 12, and 18 months on PFS in patients with ESR1-mutated tumours receiving elacestrant versus SoC endocrine therapy was examined. In patients with at least 6 months of prior CDK4/6 inhibitor duration, median PFS with elacestrant was 4.1 versus 1.9 months with SoC endocrine therapy (HR: 0.52). In patients with at least 12 months prior CDK4/6 inhibitor duration, median PFS with elacestrant increased to 8.6 versus 1.9 months with SoC (HR: 0.41).46 Results for patients with at least 18 months of CDK4/6 inhibitor duration are similar. These data indicate that elacestrant achieves the greatest benefit in patients with relative endocrine sensitivity leading to clinically meaningful benefit versus SoC. Elacestrant was well tolerated, with most adverse events (AE), including nausea, at Grade I or II in severity.46 The discontinuation rate due to an AE was 3.4% in the elacestrant arm and 0.9% in the SoC arm.46 The most common AEs were musculoskeletal pain, nausea, fatigue, and vomiting.19 Grade III nausea was reported in 2.5% of patients treated with elacestrant versus 0.9% of patients treated with SoC.19 A low percentage of patients received an antiemetic (8.0% with elacestrant, 10.3% with an aromatase inhibitor, and 3.7% with fulvestrant).46 Kaklamani concluded by emphasising the importance of delivering personalised care for patients with ER+/HER2- advanced breast cancer. When selecting 2L therapy, the relative benefit of combinations versus monotherapy and the increased prevalence of AEs with combination therapies must be considered.12 Since data suggest that greater PFS benefit is achieved with targeted agents than SoC in biomarker-selected patient subgroups,19,22,39 a biomarker-driven treatment algorithm is needed to ensure optimal treatment selection, especially for those patients whose tumours remain endocrine-sensitive (CDK4/6 inhibitor duration for at least 12 months).12,22,19,36

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Emerging Biomarkers in Breast Cancer: Implementing Liquid Biopsy ESR1 Mutation Testing Volkmar Müller Volkmar Müller, Professor of Medicine and Deputy Director at the Department of Obstetrics and University Breast Centre, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany, explained that the significance of ESR1 mutations in breast cancer was not fully appreciated until 2013, when a series of studies identified ESR1 mutations in 11–55% of advanced ER+ breast cancers with prior aromatase inhibitor exposure.47 Binding of oestrogen to the oestrogen receptor leads to conformational changes in the ligandbinding domain of the receptor, resulting in liganddependent activation, coactivator recruitment, downstream regulation of gene expression, which is associated with cancer growth.18 Mutations in ESR1 alter the ligand-binding domain of the oestrogen receptor, resulting in a ligandindependent, constitutively active conformation that enhances cancer growth, metastasis, and resistance.18 These mutations decrease the affinity of the oestrogen receptor for oestrogen, and for endocrine therapies such as fulvestrant that target the receptor.18 Combined data from clinical trials indicate that ESR1 mutations represent a negative prognostic marker in advanced breast cancer.48 Müller explained that there was little benefit to testing for this mutation until a clear advantage could be derived from selecting specific treatment approaches for patients harbouring these mutations. However, he emphasised that the recent clinical trial data described by Kaklamani indicate that patients with an ESR1 mutation derive greater benefit from elacestrant than from SoC therapies.19 Testing for ESR1 mutations is now recommended in patients with ER+/ HER2- metastatic breast cancer at progression, to ensure that they could receive appropriate treatment with elacestrant monotherapy, or another endocrine therapy either alone or in combination with targeted agents.49 Müller stressed that testing for ESR1 mutations should occur at each progression during the metastatic treatment course, unless detected previously.18-21 This is because the longer a

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tumour is exposed to endocrine therapy in the metastatic setting, the greater the chance of developing an ESR1 mutation (Figure 2). 18,19,50-55

Closing Remarks

ESR1 mutations can be identified in breast cancer through either liquid or tissue biopsy. However, Müller emphasised that liquid biopsy has several advantages compared with tissue biopsy: it is minimally invasive, can be repeated regularly without inconvenience and risk for patients, has high sensitivity, rapid sample acquisition, enables real-time monitoring, and reveals tumour heterogeneity.56,57 For these reasons, bloodbased circulating tumour DNA liquid biopsy is preferred owing to greater sensitivity in detecting ESR1 mutation status, as recommended

by ESMO, National Comprehensive Cancer Network (NCCN), and American Society of Clinical Oncology (ASCO) guidelines.49,57,58 Next generation sequencing-based assays are widely used to detect ESR1 mutations because of their broad dynamic range, though droplet digital PCR offers high sensitivity, economic feasibility, and highly readable and repeatable results.59,60 There is a strong concordance between ESR1 mutation allele frequency detected by droplet digital PCR and next generation sequencing.54

Llombart-Cussac presented two hypothetical case studies to emphasise the points made during the symposium.

Antonio Llombart-Cussac

Müller concluded that mutation of ESR1 is clinically relevant during endocrine treatment.13 ESR1 mutations are both prognostic, and predictive of response to elacestrant,13,14,57 and therefore, testing via liquid biopsy should occur at each progression during the metastatic treatment course, unless detected previously.50,51

Case 1 was a 60-year-old post-menopausal female with an initial diagnosis of ER+/HER2luminal A invasive duct carcinoma (T2N1M0).

She was treated with a left breast lumpectomy and axillary lymph node dissection. After 5 years of remission, she presented with a persistent cough, and supraclavicular lymph node and lung metastases were detected via CT scan.

Her ECOG PS was 0, and she was not in visceral crisis. During 1L treatment with endocrine therapy + CDK4/6 inhibitor, a routine followup CT at 24 months identified enlargement of existing lung lesions and a new 1.5 cm lesion in the left femur.

Following disease progression on endocrine therapy + CDK4/6 inhibitor, the ESMO guidelines recommend biomarker testing to guide the selection of appropriate 2L treatment for metastatic ER+/HER2- breast cancer (Figure 3).2 In this case, liquid biopsy detected an ESR1 mutation, with wild-type PIK3CA and BRCA1/2, and elacestrant was selected as 2L therapy.

Case 2 was a 57-year-old, post-menopausal female with de novo ER+/HER2- luminal A invasive ductal carcinoma (T2N1M1). She had

Figure 2: Longer exposure to endocrine therapy in 1L metastatic breast cancer increases the chance of developing ESR1 mutation.18,19,50-54

Early breast cancer

Advanced breast cancer

Adjuvant ET

1L ET Recurrence 0%

3L ET

2L ET Progression 5%

Progression up to 40%

33%

% ESR1-mut

1L: first-line; 2L: second-line; 3L: third-line; ET: endocrine therapy; mut: mutation.

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Figure 3: ESMO metastatic breast cancer treatment guideline.2

No imminent organ failure and prior ET + CDK4/6i in the metastatic setting

If no mutation detected

Everolimus + exemestane Or Everolimus + fulvestrant Or Switch ET + CDK4/6i Or Fulvestrant monotherapy

If PIK3CA-mut

If ESR1-mut

If BRCA1/2-mut

Fulvestrant + alpelisib

Elacestrant

PARP inhibitor

CDK4/6i: cyclin-dependent kinase 4/6 inhibitor; ER: oestrogen receptor; ESMO: European Society for Medical Oncology; ET: endocrine therapy; mut: mutation; PARP: poly (ADP-ribose) polymerase.

bone and liver metastases, with normal function and no organ failure at diagnosis, and an ECOG PS of 1. The patient was treated with abemaciclib and anastrozole at 1L. After 16 months, following reports of Grade II asthenia and back pain, a CT scan showed enlargement of existing liver lesions, with normal liver function, and two additional bone lesions.

Liquid biopsy revealed ESR1 and PIK3CA co-mutations. With no imminent organ failure, treatment recommendations for this patient include fulvestrant + alpelisib, and elacestrant.2 Llombart-Cussac noted that in a case like this one, it is important to consider factors such as the duration of exposure to CDK4/6 inhibitor therapy, which is indicative of a remaining endocrine sensitivity. He also pointed out that PIK3CA mutations are associated with de novo resistance to endocrine therapy, occurring prior to or early in endocrine therapy,11,14,62 whereas ESR1 mutations are a form of acquired resistance to endocrine therapy, which generally occur following exposure to endocrine therapy in the metastatic setting, often become the driver of the disease, and require a targeted therapy.11,18,57,62

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Llombart-Cussac concluded the symposium with six key points: •

CDK4/6 inhibitors are the SoC in 1L treatment of ER+/HER2- advanced breast cancer.4,5,12

•

2L treatment options include sequential endocrine monotherapies or combination therapies until exhaustion of endocrinetherapy-based regimens.11,16

•

Guidelines strongly recommend that 2L treatment decisions are based on mutation status.2,49,58

•

Longer prior duration of CDK4/6 inhibition in patients with ESR1 mutations is a predictive factor for response to elacestrant.18,19,61

•

In the presence of coexisting mutations, both PIK3CA and ESR1, data suggest that the endocrine pathway may be the driver of disease.32,35

•

ESR1 mutation testing is essential at each progression during the metastatic treatment course, to identify patients who are most likely to respond to targeted treatments.18,50-52

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Johnston S et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5.

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Hortobagyi GN et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptorpositive, HER2-negative advanced breast cancer. Ann Oncol.

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Tripathy D et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol.

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Finn RS et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/ human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2. Abstract LBA1003. ASCO Annual Meeting II, 3-7 June, 2022.

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Slamon DJ et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382:514-24.

10. Im SA et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381:307-16.

11. Gennari A et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol.

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12. Burstein HJ et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol. 2021;39(35):3959-77.

13. Patel R et al. An emerging generation of endocrine therapies in breast cancer: a clinical perspective. NPJ Breast Cancer.

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14. Rani A et al. Endocrine resistance in hormone receptor positive breast cancer-from mechanism to therapy. Front Endocrinol (Lausanne). 2019;10:245.

15. Xu X-Q et al. Intrinsic and acquired resistance to CDK4/6 inhibitors and potential overcoming strategies. Acta Pharmacol Sin. 2021;42(2):171-8.

16. Belachew EB, Sewaseq DT. Molecular mechanisms of endocrine resistance in estrogenreceptor-positive breast cancer.

Front Endocrinol. 2021;12:599586.

17. Lei JT et al. Endocrine therapy resistance: new insights. Breast.

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18. Brett JO et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptorpositive breast cancer. Breast Cancer Res. 2021;23(85).

19. Bidard F-C et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol.

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20. Lindeman GJ et al. VERONICA: randomized phase II study of fulvestrant and venetoclax in ERpositive metastatic breast cancer post-CDK4/6 inhibitors - efficacy, safety, and biomarker results. Clin Cancer Res. 2022;28(15):3256-811.

21. Oliveira M et al. Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2

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trial. Cancer Res. 2023;83(Suppl 5):GS3-02.

22. Turner NC et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-70.

23. European Medicines Agency (EMA). FASLODEX (fulvestrant) summary of product characteristics. 2022. Available at: https://www.ema.europa.eu/en/ documents/product-information/ faslodex-epar-productinformation_en.pdf. Last accessed: 25 October 2023.

24. US Food and Drug Administration (FDA). AFINITOR (everolimus) prescribing information. 2022.

Available at: https://www. accessdata.fda.gov/drugsatfda_ docs/label/2022/203985s023, 022334s051lbl.pdf. Last accessed: 25 October 2023.

25. Novartis. PIQRAY (alpelisib). FDA prescribing information. 2022.

Available at: https://www.novartis. com/us-en/sites/novartis_us/files/ piqray.pdf. Last accessed: 26 October 2023.

26. FDA. IBRANCE (palbociclib) prescribing information. 2022.

Available at: https://www. accessdata.fda.gov/drugsatfda_ docs/label/2022/207103s015lbl. pdf. Last accessed: 26 October 2023.

27. Novartis. KISQALI (ribociclib). FDA prescribing information. 2023.

Available at: https://www.novartis. com/us-en/sites/novartis_us/files/ kisqali.pdf. Last accessed: 26 October 2023.

28. Hanker AB et al. Overcoming endocrine resistance in breast cancer. Cancer Cell.

2020;37(4):496-513.

29. Johnston SR et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on nonsteroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol 2013;14(10):989-98.

30. Yardley DA et al. Everolimus plus exemestane in postmenopausal patients with hr+ breast cancer: BOLERO-2 final progressionfree survival analysis. Adv Ther.

2013;30(10):870-84.

31. André F et al. Alpelisib for PIK3CAmutated, hormone receptor–

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positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-40.

32. AstraZeneca. TRUQAP (capivasertib). FDA prescribing information. 2023. Available at: https://www.accessdata. fda.gov/drugsatfda_docs/ label/2023/218197s000lbl.pdf. Last accessed: 22 November 2023.

33. Rozenblit M et al. Patterns of treatment with everolimus exemestane in hormone receptorpositive HER2-negative metastatic breast cancer in the era of targeted therapy. Breast Cancer Res. 2021;23(1):14.

34. Bardia A et al. Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR+/ HER2- advanced breast cancer after progression on CDK4/6 inhibitors (TRINITI-1). Clin Cancer Res. 2021;27(15):4177-85.

35. Chia S et al. Alpelisib + endocrine therapy in patients with PIK3CAmutated, hormone receptor– positive, human epidermal growth factor receptor 2–negative, advanced breast cancer: analysis of all 3 cohorts of the BYLieve study. Abstract 1078. ASCO Annual Meeting, 2-3 June, 2023.

36. Kalinsky K et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN Trial. J Clin Oncol. 2023;41(24):4004-13.

37. Mayer EL et al. Palbociclib after CDK4/6i and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pretreated ER+/HER2- metastatic breast cancer. Cancer Res. 2023;83(Suppl 5):GS3-06.

38. Llombart-Cussac A et al. Secondline endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial. J Clin Oncol.

2023;41(Suppl 16):S1001.

39. Turner S et al. Impact of ESR1 mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptorpositive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC) who progressed on or after prior

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cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial. Cancer Res. 2022;82(Suppl 4):PD15-01.

40. Oliveira M et al. Capivasertib and fulvestrant for patients (pts) with aromatase inhibitor (AI)resistant HR+/HER2- advanced breast cancer (ABC): subgroup analyses from the Phase 3 CAPItello-291 trial. ESMO Open.

2023;8(1):101376.

41. Hurvitz SA et al. Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: final efficacy, safety, and biomarker results from TRINITI-1. Cancer Res. 2022;82(Suppl 4):PD13-03.

42. Stemline Therapeutics. Orserdu (elacestrant). Prescribing information. 2023. Available at: https://www.accessdata.fda. gov/drugsatfda_docslabel/2023/ 217639Orig1s000correctedlbl.pdf.

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43. European Medicines Agency (EMA). Orserdu (elacestrant) summary of product characteristics. 2023. Available at: https://www.ema.europa.eu/en/ medicines/human/EPAR/orserdu.

Last accessed: 26 October 2023.

44. Martin Jimenez M et al.

Giredestrant (GDC-9545) vs physician choice of endocrine monotherapy (PCET) in patients (pts) with ER+, HER2– locally advanced/metastatic breast cancer (LA/mBC): primary analysis of the phase II, randomised, openlabel acelERA BC study. Ann Onc. 2022;33:S633-4.

45. Tolaney SM et al. AMEERA-3: randomized phase II study of amcenestrant (oral selective estrogen receptor degrader) versus standard endocrine monotherapy in estrogen receptorpositive, human epidermal growth factor receptor 2-negative advanced breast cancer. J Clin Oncol. 2023;41(24):4014-24.

46. Bardia A et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/ HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting.

Cancer Res. 2023;83(Suppl 5):GS3-01.

47. Reinert T et al. Clinical implications of ESR1 mutations in hormone receptor-positive advanced breast cancer. Front Oncol. 2017;7:26.

48. Turner NC et al. ESR1 mutations

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and overall survival on fulvestrant versus exemestane in advanced hormone receptor–positive breast cancer: a combined analysis of the phase III SoFEA and EFECT trials. Clin Cancer Res. 2020;26(19):5172-7.

49. Burstein HJ et al. Testing for ESR1 mutations to guide therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2023;14(18):3423-5.

50. Jeselsohn R et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptorpositive breast cancer. Clin Cancer Res. 2014;20(7):1757-67.

51. Jeselsohn R et al. Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations. Cancer Cell.

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52. Allouchery V et al. Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients. Breast Cancer Res. 2018;20(1):40.

53. Schiavon G et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7(313):313ra182.

54. Callens C et al. Real-time detection of ESR1 mutation in blood by droplet digital PCR in the PADA1 trial: feasibility and crossvalidation with NGS. Anal Chem.

2022;94(16):6297-303.

55. Robinson DR et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446-51.

56. Lone SN et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer.

2022;21(1):79.

57. Pascual J et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol.

2022;33(8):750-68.

58. National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 2.2023: breast cancer.

2023. Available at: https://www. nccn.org/guidelines/guidelinesprocess/transparency-processand-recommendations/GetFileFro mFileManagerGuid?FileManagerGu

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idId=13b592d9-7493-48ac-b54de7f3b847d6b4. Last accessed: 30 October 2023.

59. Illumina. Introduction to NGS. Available at: https://emea.illumina. com/science/technology/nextgeneration-sequencing.html/. Last accessed: 30 October 2023.

60. Dustin D et al. ESR1 mutations in breast cancer. Cancer.

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61. Bardia A et al. EMERALD: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Future Oncol.

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62. Rasha F et al. Mechanisms of endocrine therapy resistance in breast cancer. Mol Cell Endocrinol.

2021;532.

FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Abstract Reviews Exploring the latest findings in the field of oncology from novel abstracts presented by experts from around the world at the Molecular Analysis for Precision Oncology (MAP) Congress 2023, in association with the European Society for Medical Oncology (ESMO).

Swiss-PO: A Web Tool for Personalised Oncology – Upcoming Updates Authors: Fanny S. Krebs,1 Shakiba Fadaei,1 Olivier Michielin,2,3 Vincent Zoete1,2 1. Computer-Aided Molecular Engineering, Department of Oncology, University of Lausanne, Epalinges, Switzerland 2. Modelling Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland 3. Département d’oncologie, Hôpitaux Universitaires de Genève (HUG), Switzerland *Correspondence to vincent.zoete@unil.ch Disclosure: The authors have declared no conflicts of interest.

Acknowledgements: The authors would like to thank the University of Lausanne, the Lausanne branch of the Ludwig Institute for Cancer Research, and the Swiss Institute of Bioinformatics, Lausanne, Switzerland, for their support.

Keywords: Cancer, modelling, mutation, webtool.

Citation: EMJ Oncol. 2023;11[1]:44-45.

DOI/10.33590/emjoncol/10306640. https://doi.org/10.33590/emjoncol/10306640.

INTRODUCTION Next-generation sequencing techniques enable rapid detection of mutations present in a patient’s tumour. The next step is to define which mutations may contribute to the cell’s malignant transformation or to resistance to a treatment.

In some cases, this information is available in databases. Very often, however, the variants

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detected are uncharacterised, and predicting their potential effect requires bioinformatics analysis, such as molecular modelling. This task can be complicated by a wide dispersion of relevant information. Based on the authors’ experience as molecular experts and active participants of the Molecular Tumor Board of the Réseau Romand d’Oncologie, they have developed Swiss-PO1 to help non-specialists in molecular modelling tackle questions regarding uncharacterised mutations detected in patients with cancer.

DISCUSSION To meet growing demand and adapt to the new next-generation sequencing panels used in hospitals, the authors have updated the oncodriver gene list from 50 to >900, covering among others the FoundationOne®CDx gene panel (Foundation Medicine, Cambridge, Massachusetts, USA). Soon, a new structurebased scoring function to predict potentially damaging mutations in kinases will be added, one capitalising on known structures extracted from the Protein Data Bank (RCSB, Rutgers, The State University of New Jersey, Piscataway, USA).

Among others, a prediction tool for BRAF mutation class will be introduced, and a new section dedicated to kinases will be proposed, with useful information concerning the kinase inhibitors, families, and mutations.2 The authors can also mention the addition of new 3D structures, including predicted models for domains not covered by experimental structures (PDB3 [RCSB], AlphaFold4 [DeepMind, London, UK], and SWISSMODEL5 [ExPASy, Geneva, Switzerland]), leading to a total of >15,000 curated structures, >700 uncharacterised mutations manually analysed by molecular modelling, sequence alignments of

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Abstract

human proteins, orthologous organisms, and paralogous to analyse amino acid conservation, etc.

Reduced Diversity of HLA Class I Alleles May Contribute to the Early Manifestation of Breast Cancer in Carriers of the BRCA1 Mutation Authors: *Ekaterina Kuligina,1 Alexandr Romanko,1,2 Alexandr Martianov,1,2 Juliy Gorgul,1 Aniruddh Kashyap,3 Cezary Cybulski,3 Jan Lubinski,3 Dmitry Trofimov,4 Tatjana Jankevic,4 Evgeny Imyanitov1,2 1. N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg, Russia 2. Saint Petersburg Pediatric Medical University, Russia 3. International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland 4. DNA-Technology LLC, Moscow, Russia *Correspondence to kate.kuligina@gmail.com Disclosure: This work has been supported by the RSF grant #22-15-00278. The authors have declared no conflicts of interest.

Keywords: BRCA1, breast cancer (BC), cancer risk, germline mutations, human leukocyte antigen (HLA), penetrance.

Citation: EMJ Oncol. 2023;11[1]:45-46.

DOI/10.33590/emjoncol/10300645. https://doi.org/10.33590/emjoncol/10300645.

ESMO 2023

References 1.

Krebs FS et al. A new tool to analyze the impact of mutations on protein three-dimensional structures for precision oncology. NPJ Precis Oncol. 2021;5(1):19.

2.

Krebs FS et al. Structure-based prediction of BRAF mutation classes using machine-learning approaches. Sci Rep. 2022;12(1):12528.

3.

Berman HM et al. The protein data bank. Nucleic Acids Res. 2000;28(1):235-42.

4.

Jumper J et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583-9.

5.

Waterhouse A et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296-303.

CONCLUSION The authors are convinced that the expert curation of data available in Swiss-PO, the additional tools to come, and its user-friendliness will make it a crucial web tool for the analysis of newly discovered and uncharacterised mutations, particularly during tumour boards. ●

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BACKGROUND AND AIMS Most female carriers of germline BRCA1 mutations develop breast and/or ovarian cancer.

However, the penetrance of BRCA1 pathogenic variants does not reach 100%, and the age at onset for BRCA1-associated breast cancer (BC) is a subject of variation.1 This study aimed to evaluate whether the age-related likelihood of developing BC in carriers of the BRCA1 mutation is influenced by inherited variations in the host immune system, namely, human leukocyte antigen (HLA) Classes I and II genes polymorphism. The search for modifiers of BRCA1 penetrance is complicated by the need to identify a large number of healthy individuals who remain cancer-free in late adulthood despite carrying a pathogenic variant. Here, the authors utilised a different approach, where they included in the study only patients with BRCA1-driven BC, and compared the distribution of HLA genotypes in young-onset versus late-onset cases. The authors reasoned that young-onset patients are likely to be enriched by genetic variants, which increase the penetrance of BRCA1 pathogenic alleles.

MATERIALS AND METHODS Next-generation sequencing was utilised for genotyping of HLA Class I and II genes (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5) in Slavic patients with BRCA1-associated BC with early (≤38 years; n=215) and late (≥58 years; n=108) age at

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onset. The age thresholds corresponding to the youngest and oldest quartiles of females were determined by analysing the age distribution in 771 consecutive female patients with BC carrying BRCA1 mutations.

these genotypes were diagnosed with BC before the age of 39 years (OR: 6.97; 95% CI: 0.39–125.01; p=0.187).

RESULTS

This study demonstrates that HLA

The HLA-DQB1*06:03P prevalence was higher in the late-onset group due to the excess of allele carriers (25/108 [23.1%] versus 22/215 [10.2%]; adjusted odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.58–5.56; p<0.001) and homozygous genotypes (3/108 [2.8%] versus 0/215 [0.0%]; OR: 14.30; 95% CI: 0.73–279.27; p=0.08). For all HLA-I loci, there was a trend toward an increase in the number of homozygous genotypes in the early-onset group. For the HLA-A locus this prevalence was significant (14.4% versus 6.5%; p=0.037; OR: 2.4; 95% CI: 1.03–5.72; p=0.042). The frequencies of HLA-DPB1, HLA-DQB1, and HLA-DRB3/4/5 homozygous genotypes did not differ between patients with young-onset and late-onset BC. There was a trend towards the increased frequency of DRB1 homozygotes in the young versus senior patients (11.7% versus 6.5%; p=0.144). The maximum degree of homozygosity detected in this study was six out of seven HLA Class I/II loci; all six female carriers of

Precision MedicineBased Platform to Guide the Treatment of EML4ALK Lung Cancers and Other Non-Small Cell Lung Cancers Authors: Nathan Merrill,1 Aaron Udager,1 Angel Qin,1 Kiran Lagisetty,1 Marisa Aikins,1 Liwei Bao,1 Xu Cheng,1 Laura Goo,1 Varun Kathawate,1 Bryce Vandenburg,1 Peter Ulintz,1 Zhaoping Qin,1 Chia-Jen Liu,1 Habib Serhan,1 Sunitha Nagrath,1 Peggy Hsu,1 Matthew Soellner,1 *Sofia Merajver1

CONCLUSION polymorphism may play a role in modifying the penetrance of BRCA1 pathogenic variants.

The authors revealed that HLA-DQB1*06:03P is overrepresented in patients with late-onset versus young-onset BRCA1 heterozygous BC, suggesting that this allele has a protective role.

In addition, the authors observed a trend towards the role of the reduced HLA genotype diversity (homozygosity) in modifying age-related BRCA1 penetrance. Genetic variations in the immune system were not previously considered in studies of BRCA1/2-associated cancer risks. The obtained data warrant international multicentre studies aimed to test whether particular HLA alleles or HLA homozygosity, or variations in some other immune-related genes, may increase the risk of cancer disease in carriers of the BRCA1/2 mutation. ●

References 1.

Kuchenbaecker KB et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-16.

Disclosure: All authors report support from the Judy Tam ALK Lung Cancer Initiative. A. Qin also reports payments to their institution from Merck, Clovis, AstraZeneca, Genentech, Janssen, and Xencor; and serves on the advisory board of Amgen.

Acknowledgements: The authors would like to thank the Judy Tam Research Initiative for funding to complete this work.

Keywords: Anaplastic lymphoma kinase, EML4-ALK fusion, lung cancer (LC), next-generation sequencing, non-small cell lung cancer (NSCLC), patient-derived organoids, precision medicine, precision medicinebased platform (PMP), resistance, tyrosine kinase inhibitors (TKI).

Citation: EMJ Oncol. 2023;11[1]:46-48.

DOI/10.33590/emjoncol/10309598. https://doi.org/10.33590/emjoncol/10309598.

1. University of Michigan, Ann Arbor, USA *Correspondence to smerajve@med.umich.edu

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Figure 1: Schema for the precision medicine-based platform.

Mice

Patient tumour

DMSO Cmax

Real-time drug testing patient-derived organoids (7–10 days)

10,000 nM

Relative viability

Drug response

Clinical history and genomic sequencing profile (10–14 days)

Drug A

Drug B

Drug C

Drug D

PDX 3

PDX 4

OR

PDX 1

PDX 2

PDX clinical trials

Drug 1

100

Drug 2

50

0 -12

-10

-8

-6

-4

Logarithm

Patient tissue is brought into the lab following normally scheduled clinical procedures, and after obtaining informed consent. Material is utilised to obtain drug response information in real-time (7–10 days). Results are integrated with clinical history and molecular characterisation. When material is sufficient, renewable models like PDXs are developed for additional precision medicine studies.

Cmax: maximum plasma concentration; DMSO: dimethyl sulfoxide; PDX: patient-derived xenograft.

BACKGROUND AND AIMS

MATERIALS AND METHODS

Lung cancer (LC) remains the top cause of cancer-associated mortality worldwide, with a 10year overall survival rate of only 5%.1 While most LCs are smoking-related, 25% of non-small cell LC (NSCLC) are diagnosed in patients with little or no smoking history.2 Fusions involving anaplastic lymphoma kinase (ALK) are the oncogenic driver in approximately 3–7% of NSCLC.3 While tyrosine kinase inhibitors (TKI) targeting the kinase domain of ALK have proven extremely effective, inevitably, resistance develops with limited effective treatment options.4

The authors developed a precision medicinebased platform (PMP) to screen patient-derived material (PDM) directly from the operating room, with curated panels of drugs. PDM collected during clinically indicated procedures was plated in culture to generate patient-derived organoids, and screened with drugs curated to each tumour type. Patient-derived organoids are screened at therapeutically relevant doses, drawing from pharmacokinetic data for each drug, when available, in the authors’ previously published 3D assay.5 The authors have optimised

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an assay to rapidly screen for EML4-ALK fusions, and can perform next-generation DNA and RNA sequencing in real time (approximately 7 days) to integrate with drug screening results.

RESULTS To date, the authors have screened 51 cases of NSCLC, including seven cases of ALK-positive NSCLC. Screening of EML4-ALK tumours, which have progressed to second- or higher line TKI, demonstrates sensitivity to earlier generation ALK TKIs, a known phenomenon in the literature. The authors’ results recapitulate known resistance in samples previously exposed to therapy, demonstrating a strong negative predictive value. Longitudinal assessment will be required to robustly assess positive predictive value. In one case of EML4-ALK NSCLC, the authors were able to collect PDM from two distinct regions (pleural effusion and paracentesis), and screen with the same panel of drugs, highlighting the reproducibility and consistency of their assay.

Programmed DeathLigand 1 Expression and its Relation to EML4-ALK Gene Variants in Metastatic Lung Adenocarcinoma: A Single Centre Real-World Experience Authors: *Santhosh Meedimale,1 S.S. Panda,1 L. Moharana,1 S. Mohanty,1 L. Samantaray,1 S.P. Vankina,2 S. Devaraj,1 A. Tiwari,1 Y.S. Kumar,1 A. Sanyal,1 G. Biswas3 1. Department of Medical Oncology, Institute of Medical Sciences (IMS) and Sum Hospital, Bhubaneswar, India

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CONCLUSION The authors’ PMP captures robust and reproducible results that are consistent with known clinical pathogenesis. Moving forward, they are collecting longitudinal data from enrolled patients in parallel with clinical trials, to demonstrate positive predictive value of their PMP. They additionally strive to demonstrate reproducibility to obtain Clinical Laboratory Improvement Amendments (CLIA) approval, and to deliver results to patients and physicians to help guide clinical care. ●

References 1.

Barta JA et al. Global epidemiology of lung cancer. Ann Glob Health. 2019;85(1):8.

2.

Dubin S, Griffin D. Lung cancer in non-smokers. Mo Med. 2020;117(4):375-9.

3.

Vašíková A. [EML4-ALK fusion gene in patients with lung carcinoma: biology, diagnostics and targeted therapy].

Klin Onkol. 2012;25(6):434-9. (In Czech).

4.

Tabbò F et al. Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won.

Transl Lung Cancer Res. 2020;9(6):2545-56.

5.

Merrill NM et al. MEK is a promising target in the basal subtype of bladder cancer. Oncotarget.

2020;11(44):3921-32.

2. Radiation Oncology Department, Cachar Cancer Hospital and Research Centre (CCHRC), Silchar, India 3. Medical Oncology, Sparsh Hospitals & Critical Care, Bhubaneswar, India *Correspondence to docsanu@gmail.com Disclosure: The authors have declared no conflicts of interest.

Keywords: Adenocarcinoma, EML4-ALK, gene variants, programmed death-ligand 1 (PDL1).

Citation: EMJ Oncol. 2023;11[1]:48-49.

DOI/10.33590/emjoncol/10307634. https://doi.org/10.33590/emjoncol/10307634.

BACKGROUND AND AIMS Targeted therapy and immunotherapy have revolutionised the treatment of metastatic non-small cell lung cancer, particularly adenocarcinoma.1 Among non-small cell lung cancer cases, around 8–10% are ALK-positive,2

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Table 1: Metastatic sites and their incidence for ALK-mutated non-small cell lung cancer.

Metastatic sites

Frequency

Malignant pleural effusion

70.5%

Brain metastasis

35.2%

Bone metastasis

35.2%

Contralateral lung involvement

23.5%

Liver metastasis

11.7%

with the majority involving EML4-ALK gene variants.3 This study aimed to explore the connection between ALK gene variants and programmed death-ligand 1 (PDL1) expression in patients with metastatic lung adenocarcinoma, focusing on relevant clinical parameters, as there is limited data from the Indian cohort on this subject.

metastases were more frequent in the PDL1negative cohort (35.2%), and bone metastases and malignant pleural effusions were more common in V1 compared with V2 and V3. ALK positivity was observed in various metastatic sites with varying frequencies (Table 1).

MATERIALS AND METHODS

The study concludes that V1 and V3 EML4-ALK gene variants are prevalent in patients with metastatic lung adenocarcinoma. It reveals a significant association between PDL1 expression and specific ALK variants, with V1 being more frequently associated with PDL1 negativity, and V3 with PDL1 positivity. Additionally, the V1 and V3 variants were more commonly found in female patients, and were associated with brain metastases and malignant pleural effusions.

This real-world experience contributes valuable insights into treatment responses in this specific patient population. ●

A retrospective analysis was conducted on data collected from 17 patients with advanced lung adenocarcinoma with ALK gene mutations.

The anaplastic lymphoma kinase protein variants were determined through nextgeneration sequencing, while PDL1 expression was assessed using immunohistochemistry with the sP263 antibody. These findings were then correlated with relevant clinical parameters.

RESULTS The median age of the patient cohort was 46 years (range: 28–65). Among 17 of the patients who were ALK-positive, the majority had EML4ALK gene fusions, with V1 (47.05%), V3 (35.20%), and V2 (11.70%) being the most common variants. V1 was more prevalent in females (87.5%) than males (12.5%). PDL1 negativity was observed in 64.7% of patients, while 35.2% were PDL1-positive. Specifically, PDL1 negativity was more common in the V1 variant, whereas PDL1 positivity was associated with V3. Brain

CONCLUSION

References 1.

Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5(3):288-300.

2.

He Y et al. The prevalence of EML4-ALK variants in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Biomark Med. 2019;13(12):1035-44.

3.

Camidge DR et al. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non–small cell lung cancer in the global phase III ALEX study.

J Thorac Oncol. 2019;14(7):1233-43.

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Abstract Highlights

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Abstract Highlights The following highlights spotlight selected abstracts presented at the European Society for Medical Oncology (ESMO) Annual Congress 2023. They cover key topics, including the importance of nutrients in lung cancer survival rates; a new, minimally invasive therapy which targets endometrial cancer stem cells; and new potential for identifying bladder cancer using genomic sequencing.

EMJ Oncol. 2023;11[1]:50-56. DOI/10.33590/emjoncol/10308059. https://doi.org/10.33590/emjoncol/10308059.

Citation:

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Alternative to Chemotherapy for Locally Advanced Metastatic Urothelial Carcinoma FOR the first time, there is an alternative to chemotherapy for patients with advanced or metastatic urothelial carcinoma. The results of a randomised Phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) compared to chemotherapy for the treatment of locally advanced metastatic urothelial carcinoma (la/mUC) received a standing ovation at the ESMO Congress 2023. Platinum-based chemotherapy is the standard of care for la/mUC, but long-term outcomes are poor.

The global, Phase III, open-label, randomised study evaluated EV+P in patients with previously untreated la/mUC who were eligible for cisplatin or carboplatin-containing chemotherapy. The participants were randomised 1:1 to receive 3-week cycles of EV (1.25 mg/kg intravenously) on Days 1 and 8, and P (200 mg; IV) on Day 1, or gemcitabine with cisplatin or carboplatin. Primary endpoints investigated were progression-free survival and overall survival, while secondary endpoints included overall response rate and safety.

Overall, 886 participants were included in the study with a median follow-up of 17.2 months.

Progression-free survival was significantly higher in the EV+P group, yielding median values of 12.5 months compared to 6.3 months in the

chemotherapy group (hazard ratio: 0.45; 95% confidence interval: 0.38–0.54; P<0.00001), thus reducing the risk of progression or death by 55%.

Overall survival was also significantly prolonged, increasing from 16.1 months in the chemotherapy group to 31.5 months in the EV+P group (hazard ratio: 0.47; 95% CI: 0.38–0.58; P<0.00001), with the risk of death reducing by 53%. Furthermore, confirmed objective response rate was 67.7% and 44.4% in the EV+P and chemo arms, respectively (P<0.00001).

"The results of a randomised Phase III study received a standing ovation at ESMO 2023."

Overall, the research team report significantly improved outcomes in participants with previously untreated la/mUC receiving EV+P, with progression-free survival and overall survival significantly increasing in these treatment groups, compared to those receiving chemotherapy. Furthermore, the safety profile was generally manageable, with no new safety signals reported. ●

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Improving Nutritional Interventions Could Increase Lung Cancer Survival Rates IDENTIFYING an early food consumption deficit may improve preservation of muscle mass in patients with lung cancer, as low muscle mass is often associated with this disease, according to new research presented at the ESMO Annual Congress 2023, held from 20th–24th October in Madrid, Spain.

The provision of nutrients in an adequate quantity and of a suitable quality is essential in treating low muscle mass. In a prospective, observational study, carried out by Imanuely Borchardt, Universidade Federal do Rio de Janeiro, Brazil, and colleagues, data were collected at the first nutritional consultation of patients with cancer between January– December 2019. Patients’ height, body weight, weight loss, calf circumference, and handgrip strength were measured in order to estimate average food and macronutrient intake. Survival curves to analyse the association between caloric and protein intake and 3-year mortality were created.

In total, 50 patients with lung cancer were included in the study, 62% of whom were female, 94% elderly, 88% diagnosed with non-

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small cell lung cancer, 88% diagnosed with disease Stages III and IV, and 64% were smokers.

The weight-adjusted mean daily intake of energy was 18.6 kcal/kg/day, while for protein it was 0.94 g/kg/day. The results showed that those with a consumption greater than 1 g/kg/day had a significantly longer overall survival rate than those with consumption lower than the recommended amount for patients with cancer (35.2 months versus 21.9 months, respectively; p=0.03). The differences in caloric intake of the patients showed no significant difference in length of survival (p=0.2).

The team concluded that lower protein intake was associated with shorter survival time in patients with lung cancer. They added that nutritional interventions would be low-cost, and would not be difficult to implement as a strategy to improve the survival rates for these patients. ●

"Provision of nutrients in an adequate quantity is essential in treating low muscle mass."

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Photodynamic Therapy Strategy to Target Endometrial Cancer Stem Cells A MINIMALLY invasive anticancer strategy, photodynamic therapy, is a promising targeted therapy for cancer stem cells in endometrial cancer, according to new research presented at the ESMO Congress 2023. Researchers from Portugal aimed to investigate photodynamic therapy through 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine-fused chlorins, which were modulated to target cancer stem cells in endometrial cancer by incorporating aldehyde substituents.

The researchers synthesised a mono-aldehyde derivative of a 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine-fused chlorin (A-PX) by mixing a monoester/mono-alcohol derivative chlorin with a Dess–Martin periodinane and dichloromethane solution. Proton nuclear magnetic resonance confirmed the presence of aldehyde. Aldehyde dehydrogenase 1A1 oxidation of the A-PX was followed by reverse-phase high-performance liquid chromatography through a reaction, which was stopped every 30’ with acetonitrile. The researchers performed a resazurin assay to evaluate A-PX-based photodynamic therapy.

The results show a A-PX proton nuclear magnetic resonance peak of 10.28 ppm with the aldehyde. Furthermore, overexpression of aldehyde dehydrogenase is associated with

cancer stem cells in endometrial cancer. The high-performance liquid chromatography and the kinetics of the enzymatic reaction illustrated a decreased relative area of the aldehyde peak, which was paralleled with the increase of carboxylic acid, which was formed by aldehyde dehydrogenase 1A1-promoted oxidation.

A-PX did not show toxicity, according to the preliminary results, and the A-PX cytotoxicity on cancer stem cells in endometrial cancer showed a decreased proliferation.

"Overexpression of aldehyde dehydrogenase is associated with cancer stem cells."

The researchers concluded that it is possible to create chlorins that can interact with aldehyde dehydrogenase 1A1, which allows for the modification of the hydrophilicity of the photosensitiser in situ. Therefore, A-PX appears to be effective in treating cancer stem cells in endometrial cancer. However promising these results, more studies are needed to confirm this. ●

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Bladder Cancer: Could Genomic Sequencing of Urine Aid Diagnosis and Identify Treatment Targets?

"TP53 and ERBB2 mutations were found to be significantly higher in those with MIBC compared to those with NMIBC."

NEXT-GENERATION sequencing (NGS) assays have the potential to identify tumour-derived variants of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) to aid diagnosis, and identify targets for personalised treatment, according to novel research presented at the ESMO Annual Congress 2023.

Researchers from Renji Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, and Hui (Shanghai) Medical Technology Company Ltd, Shanghai, China, performed a prospective study to determine whether evaluation of urinary tumour DNA led to identification of actionable mutations.

The study included 154 patients, some of whom were treatment naïve, and others had received treatment and were at risk of recurrence. Of the total cohort, 65 had a diagnosis of NMIBC and 89 had a diagnosis of MIBC. Using the PredicineCARE™ (Hayward, California, USA) NGS liquid biopsy assay, urine samples from each patient were analysed for somatic mutations in urinary tumour DNA. In patients with MIBC, 485 somatic mutations and 43 copy number variants were identified, and the genes most frequently mutated were

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TP53 (57%), TERT (39%), ERBB2 (24%), ARID1A (20%), and PIK3CA (20%). For those with NMIBC, 368 somatic mutations and 14 copy number variants were identified, and the most frequently mutated genes were TP53 (38%), TERT (37%), ARID1A (22%), and BRCA2 (20%).

TP53 and ERBB2 mutations were found to be significantly higher in those with MIBC compared to those with NMIBC (TP53: 51/89 versus 25/65, respectively; p<0.05; and ERBB2: 21/89 versus 4/65, respectively; p<0.01). In contrast, there was significantly higher prevalence (p<0.05) of RARA variations in those with NMIBC (5/65) than those with MIBC (0/89). The authors additionally found that FGFR2/3 variations were prevalent in 13% and 15% of all patients with MIBC and NMBIC, respectively. However, when looking at only patients who were treatment-naïve, the prevalence of FGFR2/3 variations was 26.3% for MIBC and 38.5% for NMIBC. From these findings, the authors were able to discuss the identified mutational landscape of MIBC and NMIBC by performing NGS of urine samples in a real-world setting. They concluded that their study highlights the potential use for urine-based NGS assays in bladder cancer diagnosis and personalised treatment. ●

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Does Analgesia Affect Survival in Patients with Lung Cancer Receiving Immune Checkpoint Inhibitors?

CANCER-RELATED pain, when unrelieved, is associated with worse survival, and non-opioid analgesics are frequently used to manage pain in patients with cancer. New research presented at the ESMO Annual Congress 2023, in Madrid, Spain, explored whether non-opioid analgesics affect survival in patients with lung cancer who receive immune checkpoint inhibitor (ICI) therapy.

"This cohort of patients had shorter survival than their counterparts who did not use non-opioid analgesics."

Sichao Wang, The University of Hong Kong – Li Ka Shing Faculty of Medicine, Hong Kong, and colleagues, reviewed the records of 910 patients with lung cancer who had a minimum of two cycles of ICI prescription±non-opioid analgesic prescription between 2018–2020. Data were obtained from the Clinical Data Analysis and Reporting System of Hong Kong, and patients were followed up for a median duration of 35.9 months.

Using Kaplan–Meier curves and Cox proportional hazards regression analysis, the team compared the overall survival of patients with lung cancer receiving ICI with (n=765) and without (145) nonopioid analgesics.

The findings showed that overall survival was significantly shorter in patients with lung cancer receiving ICI who had records of non-opioid analgesic prescriptions (13.4 months), when compared to those without (40.5 months; p<0.0001). Significantly worse prognosis was also seen in patients with lung cancer receiving ICI and non-opioid analgesic prescriptions upon the Cox regression analysis (hazard ratio: 2.42; 95% confidence interval: 1.86–3.10; p<0.001).

Wang and colleagues concluded that patients with lung cancer receiving ICI and using nonopioids are likely to have suboptimal tumour control and cancer-related pain, which were associated with poorer prognosis, and that overall, this cohort of patients had shorter survival than their counterparts who did not use non-opioid analgesics. ●

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Does BMI Influence Breast Cancer Survival Outcomes?

PREVIOUSLY, the relationship between BMI and survival outcomes had not been investigated in patients with breast cancer who have undergone adjuvant chemotherapy. Researchers set out to investigate the effect of baseline BMI, BMI after adjuvant therapy, and change in BMI from baseline to post-adjuvant chemotherapy on disease-free survival (DFS) and overall survival (OS). Their findings were presented at the ESMO Congress 2023, held in October in Madrid, Spain.

Data were collected from 2,394 patients who had taken part in two randomised Phase III clinical trials that investigated adjuvant chemotherapy in breast cancer, accessed through Project Data Sphere. Restricted cubic splines, adjusting for confounding factors, were used to examine potential non-linear associations between BMI value and survival. Stratified analyses involved chemotherapy regimens used.

Results showed that patients who were severely obese (BMI ≥40.0 kg/m2 at baseline) were associated with poorer DFS (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.02–2.16; p=0.04) and OS (HR: 1.79; 95% CI: 1.17–2.74; p=0.007) when compared with those who had a normal BMI (≤24.9 kg/m2). Adverse OS was also

associated with a BMI loss of more than 10% (HR: 2.14; 95% CI: 1.17–3.93; p=0.014).

When taking into account chemotherapy regimens, multivariate analysis showed that severe obesity had detrimental effects on DFS (HR: 2.38; 95% CI: 1.26–4.34; p=0.007) and OS (HR: 2.90; 95% CI: 1.46–5.76; p=0.002) in the docetaxel group. This was not observed in the non-docetaxel group. Restricted cubic splines demonstrated an association between baseline BMI and risk of recurrence (p for non-linearity: 0.111) or all-cause death (p for non-linearity: 0.008). This was more pronounced in the docetaxel-based group for DFS (p for non-linearity: 0.011) and OS (p for nonlinearity: <0.001).

Overall, baseline severe obesity was associated with worse DFS and OS in patients with breast cancer treated with adjuvant chemotherapy.

Significant BMI loss (>10%) from baseline to post-adjuvant chemotherapy was also associated with poorer OS. Lastly, the diagnostic ability of BMI may be altered depending on chemotherapy regimens, as observed in the docetaxel-based and non-docetaxel-groups. ●

"Data were collected from 2,394 patients who had taken part in two randomised Phase III clinical trials."

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In house podcast advert

EMJ Podcasts The EMJ Podcast aims to provoke conversations around the latest trends and innovations in healthcare, provide engaging and educational content for healthcare professionals, and hosts conversations with physician entrepreneur, Jonathan Sackier.

Listen today www.emjreviews.com Creative Commons Attribution-Non Commercial 4.0

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Interview

Interviews This year, EMJ has the pleasure of introducing key opinion leaders Karen Canfell and John Marshall, whose interviews shed light not only on their impressive careers, but on important topics in oncology today, from screening for cervical cancer in low-income countries to the growing need to understand the causes behind gastrointestinal cancers.

Featuring: Karen Canfell and John Marshall

Karen Canfell Professor and Director of the Daffodil Centre, University of Sydney, A Joint Venture with Cancer Council NSW, Australia EMJ Oncol. 2023; DOI/10.33590/emjoncol/10302304. https://doi.org/10.33590/emjoncol/10302304.

Citation:

Q1

What initially attracted you to the specialism of population health and in particular population health in oncology?

My entry point was through a field that I now still spend a lot of time in, which is cervical cancer control, particularly cervical cancer prevention. I originally trained as an engineer, and I worked in biomedical technology many years ago. Through that route and via working in the medical technology space, I became very interested in the role of technology in health, as well as understanding the role of human papillomavirus (HPV) in cervical cancer, and what that meant in terms of technology development. I decided to do a PhD in epidemiology to build on that understanding, as I was very inspired by the events of that time in terms of the development of a prophylactic HPV vaccine. I was lucky enough to meet Ian Frazer at that time, who was one of the co-inventors of the vaccine and an

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leader in the field, and he was very supportive of my ideas and ambitions to contribute to the public health understanding of the role of vaccines. While I saw a public health challenge, I also saw a public health opportunity around the better integration of the new prophylactic vaccines with existing cervical screening programmes, and the potential to change and adapt screening programmes to be better optimised in relation to HPV vaccination.

Q2

You are the inaugural director of the Daffodil Centre, a flagship centre at the University of Sydney, Australia. Can you tell our readers a little about the aims of this organisation and the work you do as director?

The Daffodil Centre is a very exciting and relatively young research centre. The centre specialises in cancer control through aiding

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Interview

decision-making and integration of research insights into policy and practice. We try to reflect a wider vision about understanding and anticipating technology and other developments in terms of what they might mean for population health or health services. We further try to understand, anticipate, and help policymakers and others work through the implications in terms of what the combined effects of new interventions might look like, what the economic impacts might be, and what the best decisions might be in cancer control to take that forward in the interests of the population and of cancer patients. One of the aspects that is special about the Daffodil Centre is that it is a joint venture between the University of Sydney and Cancer Council, which is a not-for-profit civil society organisation - so we have an academic environment and expertise, rigour, and resources to draw upon as well as a strong connection to the community. The idea is that we bring

together the best of all worlds in our endeavours to improve cancer control and improve outcomes for people in our own local setting, but also in Australia as a country, and globally, through our work supporting the World Health Organization (WHO) and other international stakeholders.

Q3

Your work was instrumental in transforming the National Cervical Screening Program (NCSP) in Australia from Papanicolaou (Pap) tests to HPV DNA testing. Please could you expand on why this change was necessary and the journey to achieving this?

Australia has been a very interesting environment in which to work in terms of cervical cancer control, because it really has been a leader in the space since the early 2000s. By then, we had an established national

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cervical screening programme based on Pap tests, as many other high-income countries had. This was a successful programme, as it had reduced rates of cervical cancer incidence and mortality by about half, but the impact had also plateaued. In the early 2000s, the programme had reached its maximum effectiveness with the Pap test, which relies on frequent testing. In Australia, we recommended 2-yearly Pap tests from the age of 18–69 years. This involves many tests in a lifetime, which posed many challenges in reaching every female or person with a cervix so frequently, particularly in rural and regional areas. In Aboriginal Australians and Torres Strait Islander groups, in culturally and linguistically diverse communities, in LGBTQ and intersex people, and in other groups such as those living with disability, the programme was not fully serving their needs, and so it was very difficult to reach the maximum potential of cervical screening. The introduction of prophylactic HPV vaccines was a large-scale disrupter, and Australia was one of the first countries to roll those out in 2006–2007. The combination of the HPV vaccine and the emergent evidence on HPV testing were really the key elements to this change. We needed to adapt the screening programme in the post-vaccination era to improve outcomes, which also opened up new possibilities for expanded access through, for example, the possibility of self-collection of the sample which can be done with HPV screening. For all those reasons, I think it was a very important transition. The journey was essentially around building the evidence to show that transition would be appropriate and safe, and lead to better outcomes for females.

Australia was not quite the first, but it was one of the first countries to transition, and I think it has been an important aspect of why Australia has been well positioned to eliminate cervical cancer over the next decade or so.

Q4

In 2022 you co-authored a paper entitled, ‘Health impacts of COVID-19 disruptions to primary cervical screening by time since last screen: A model-based analysis for current and future disruptions’. Can you speak about the impact of the pandemic on cancer screening programmes and the effect this will have on future cancer incidence?

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This work is one of the outputs of a major consortium, which is now called the International Partnership for Resilience in Cancer Systems (I-PARCS). This was a global group that formed in the immediate aftermath of the onset of the pandemic in early 2020. Our aim was to understand and quantify the effects of COVID-19 on cancer outcomes, and to work towards supporting evidence for best practice mitigation.

In the cancer screening space, we have worked across screening modalities, particularly in cervical and colorectal cancer screening. We were able to bring together some of the leading modelling groups in those two spaces to do a comparative modelling analysis of the impact of disruptions and best practice mitigation. We were able to quantify the impact of the disruptions

"In Australia, we recommended 2-yearly Pap tests from the age of 18–69 years." on cancer outcomes longer term and to show, in the context of both types of screening, what mitigation strategies should be prioritised.

Our main message was that catch-up screening is incredibly important. If it can be done, it actually mitigates much of the disruption impact going forward. In a sense that seems quite obvious, but we were able to quantify the impact and the effect of mitigation so that programme managers, and other stakeholders involved in screening programmes, could understand the importance of investing in mitigation.

I-PARCS has been an absolutely wonderful experience, because researchers, programme managers, and others around the world just volunteered their time for this. There was institutional involvement from the Daffodil Centre as well as the International Agency for Research on Cancer (IARC), and other important partners.

However, one of our struggles has been finding data on what exactly did happen in health systems. Having timely access to information about the nature of the disruptions has been quite difficult, even in many high-income countries. One of the important insights was that the crisis exposes existing weaknesses in health systems, highlighting the need for timely access to integrated data from health ssytems.

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Q5

Can you tell our readers a little more about the work your team has undertaken with WHO to develop clinical management guidelines for cervical screening in low-income countries?

The original work we did with WHO was in 2018–2019, and was to support the strategic plan for cervical cancer elimination. A consortium was formed, called the Cervical Cancer Elimination Modelling Consortium, and we were one of three groups that supported WHO. We were modelling the impact of scaling up across the three pillars of elimination across low- and middle-income countries. The three pillars are 90% vaccination coverage; 70% access to screening, with HPV testing; and 90% access to precancer and cervical cancer treatments. This work supported the estimates for how many lives could be saved by implementation of those goals and targets by 2030, and helped to underpin the impact, cost effectiveness, and investment case for elimination, for low- and middle-income countries.

The next important step was to provide countries and stakeholders with more detailed guidelines for how to how to implement primary HPVbased screening. The WHO had previously put out recommendations for cervical screening in 2013–2014, but a great deal has changed in terms of the evidence. In the meantime, high-income countries like Australia and the Netherlands had implemented the transition to HPV screening for the evidence-based reasons around its greater effectiveness. The WHO conducted a major review of their cervical screening guidelines, which incorporated an updated review of the evidence on HPV screening and triaging approach for HPV-positive women Our team at the Daffodil Centre used this updated evidence to inform the modelling piece, which involved looking at the different screening available approaches, which are cytology or Pap test screening, and visual inspection with acetic acid, and comparing them to HPV screening, and how that would play out in terms of the benefits, harms, and cost effectiveness in a low-and-middle-income context. We did a very extensive piece of modelling to support these new global screening guidelines, both in the general population of females and females living with HIV. Countries can really look at what approaches to HPV screening and triaging might

work nationally, or even sub-nationally, and how those models can be tailored. That has been a really important development. The WHO cervical screening guidelines are now moving into a living framework where the evidence is continually evaluated as we go forward.

Q6

As a public health researcher, what interests you looking forward and where can we expect to see your focus lie in the coming years?

For HPV, I think the main challenges are around effective implementation for one-dose HPV vaccination and for HPV screening approaches incorporating self-collection, and point-ofcare options. Moving forward, we need to understand the longer term performance of HPV screening in an HPV-vaccinated population, and a major trial we are performing in Australia called Compass, which is due to report main outcomes in 2025-6, will be very informative in this space. To strengthen health systems in cancer control, there is a potential role for new technology, for example, effective therapeutic HPV vaccines, which could be very exciting and could complement prophylactic HPV vaccination and cervical screening and treatment. So, I think there are some wonderful prospects there. I am also very excited about, hopefully, playing a part in building the evidence in some of those spaces. More broadly, one of the biggest areas of interest that my team and I have is the potential in cancer prevention, screening, and early detection, because those are very effective levers for saving many lives.

We need to make those types of programmes more effective, to tailor them more to individuallevel risk, and to expand effective screening approaches to other cancer sites. There is a lot of talk about risk-based screening or tailored or personalised screening using new technologies.

We aim to support building the evidence for better tailored approaches to screening, including breast and colorectal cancer screening.

The challenges lie in new lung screening programmes and what is called multi-cancer early detection technologies, which are looking to screen for many cancers at once. We hope to assist decision-makers in understanding the relative benefits, harms and cost-effectiveness of promising new approaches. ●

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John Marshall Physician Executive Director, Medstar Washington D.C. Integrated Hematology Oncology Division; Director, The Ruesch Center for the Cure of GI Cancers, Washington, D.C., USA EMJ Oncol. 2023; DOI/10.33590/emjoncol/10308998. https://doi.org/10.33590/emjoncol/10308998.

Citation:

Q1

You have always been very passionate about gastrointestinal (GI) cancers, and advocating for their treatment. Where did the interest in GI cancers come from initially?

You have to remember that I am a very old oncologist. So, when I first started, there was almost nothing in the world of GI cancer. I was very interested in new drug development, early Phase I and Phase II clinical trials, but less interested in large randomised clinical studies.

GI cancer was a huge unmet need, and huge opportunity for new drug development; I was just drawn to the disease group.

Q2

Can you tell our readers a little about the aims of the Otto J. Ruesch Center [for the Cure of GI Cancers] at Medstar Georgetown University Hospital in Washington, D.C., and the work you do there?

One thing that is important to note is that I was raised in a cancer centre that was famous for breast cancer, and so lots of resources and energy was spent on breast cancer research, recruitment, and studies, etc. I was trying to take care of patients with GI cancer, which represents the most common and most fatal group of cancers on our planet. And yet, there was this disconnect of prioritisation. I am lucky enough to have met Otto J. Ruesch, unfortunately because he had pancreas cancer. He and his wife, Jeanne Ruesch, were determined to try and level the playing field by helping to support the effort. The concept of the Ruesch Center was to emphasise all of the work that needed to be done to draw attention to the huge gaps that exist in focus and resources for GI cancers.

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We started the programme in 2009. At the beginning, we had a big debate about whether ‘cure’ should be in our title; should we just make a much lower goal than cure? I felt very strongly that it needed to be there. This is what our patients are seeking. This is what the objective of cancer research is. Sure, survival is important.

Sure, quality of life matters to people; but what they're seeking, and what we are all seeking, is a way to get rid of these diseases. And so, I thought that was an important element for our overall goals.

We have made some progress in this space: not so much in pancreatic cancer, although some, but a lot of progress in colorectal cancers, liver cancers, and gastric cancers. However, we have miles to go.

Q3

You mentioned the lack of awareness and advocacy surrounding GI cancer.

Do you think there is still a lack of awareness, and what are the disadvantages of this?

The second most important cancer, if you measure it by money investment and awareness, is actually something called the Leukemia & Lymphoma Society (LLS). Number one is breast cancer. The number two, LLS, is a collection of more than 200 different kinds of cancers; the society has come together to increase awareness, advocacy, and research in that group

"When I first started, there was almost nothing in the world of GI cancer."

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as a collective. One of the things we've really tried to do in the Ruesch Center is to bring that together. One of the areas we're most proud of is the formation of something called the GI Cancer Alliance, which, I believe, now has as many as 80 different advocacy groups from the various GI cancers working together.

Now, to your question, we have miles to go.

In Western society, colon cancer is our most common cancer from the GI tract. We've made some good progress in that space with awareness and advocacy. But sadly, one of the reasons why that's become more successful is because young people are starting to get the disease. We don't know why 20-year-olds, 30-year-olds, and 40-year-olds are suddenly getting colon cancer when they didn't at the beginning of my career. But this phenomenon has further shone light on the problem of, specifically, colon cancer. Pancreas cancer has very strong advocacy and awareness, but honestly, without major impact in understanding what makes this cancer tick, if you will, so that we can improve things there. And then you get to cancers like liver cancer, stomach cancer; some of these are bad behaviour cancers. They're associated with choices, life choices, whereas pancreas cancer and colon cancer are not so much. So, we have to make sure that we are bringing everyone along in this. The more we divide into the different cancers, and then into their different molecular subgroups, the smaller the clubs are, and therefore, the smaller the voice is. So, on some level, we need to make sure that while it's important to have our individual voices, we must come together and speak as one when that's appropriate.

Q4

The Ruesch Center has recently decided to focus on increasing access to cancer care for all patients. Please tell us more about the ways in which you plan to do this.

I spent the middle part of my career thinking more globally. It was really my Don Quixote period, where I was trying to take whatever influence I could bring along with me to try and level the access problem on a global scale. We know that only about one in seven people on our planet has access to cancer care the way I get to deliver it, for example. And so I was trying as best I could to globalise the access.

And I realised that that was crazy, after a while, because cancer care is so complicated, and so expensive, quite honestly, that for most of the planet, it is not even on their radar, when water and food is the primary goal.

And so, in the last portion of my career, I have decided to look at that not on a global scale, but just in my own backyard. I now oversee cancer care in two hospitals here in Washington, D.C. The reality is that the two hospitals are 3 miles apart, but there is a 1-year difference in the survival of colon cancer between those two hospitals. That's not the problem of resources; these are insured people. This is a problem of health literacy, of socioeconomic barriers on the patient side. How does one consume cancer care? How do you use your resources to the greatest benefit? On one side of town, I've got a very educated, driven patient population that wants to get everything they can out of our system, whereas on the other side of town, it's hard for them just to take time off work to go and get treatment. So, what we're trying to do now is level that playing field, just the local one, to try and close that simple 1-year gap, with a strategy to intervene on behalf of the healthcare system and the community to provide those bridging

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resources. Our hope is that we will demonstrate that this model works, and is translatable, not just to GI cancers, but to all different types of cancer, and cities around the world.

Q5

Have you begun to see any change in outcomes amongst patients who now have increased access to care that they may have previously struggled to receive?

No. And the main reason is that we are still in the collection phase. So, we're proving that all of the things I just said to you are true, with the 1-year difference in the metrics. The plan is to begin the intervention this fall.

Q6

Do you think that once you start interventions, based on your results in the community, that those interventions can be applied on a national, or international, scale?

They’re very basic endpoints: did the patient get started on treatment in time, and did they get the recommended treatment, pure and simple?

Secondly, was the proper molecular testing done, and are they in the right subgroup? And thirdly, were they offered a clinical trial, or at least an opportunity to be part of the future of cancer care? We think that if those three metrics are equal, then survival will be equal.

Q7

Having had the personal experience of being a caregiver to a cancer patient, when your wife was diagnosed with breast cancer a few years ago, do you think this experience has been influential in your approach to medicine and patient interactions since?

Totally. I then saw what it was to be on the other side of the room. And I thought, I was pretty good at this before, but until you experience it, you really can't understand the emotions and the complexity of receiving cancer care. My wife got care at our centre. It was a very familiar world that I was in, whereas most patients don't have that. And so, as Director of the centre, I became driven to try and provide that level of care that we received to everyone we could. This actually resulted in mostly frustration, realising that, no matter how hard we worked, there was no way

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we could provide that level of oversight and care to all of our patients. That ended up being something that actually resulted in my burning out from being an oncologist. The emotional cost, the wear and tear of taking care of very sick patients, got to me. In the end, we lived for 4 or 5 months in Oxford, and were able to write our story about it into a book, called Off Our Chests, which was quite therapeutic as well. But the arc of that story is that it had a dramatic impact to a point of recognising our shortcomings, which I think also brings back around this attempt to just try and help those who are socioeconomically challenged to receive cancer care, a little bit closer.

The healthcare team is a very complicated, large network of people, all pointing to that one person trying to take care of that one person; it's not just the physician, it's all the people around that person. It's our team, and there has to be a team on the other side, too. It's not just an individual; it's their family, maybe spouse, maybe sick child, and their friends and family who are helping to support them. The importance of engaging that whole team became very, very critical to me.

Q8

The 14th Annual Ruesch Center Symposium is approaching; what topics do you think are going to be of particular interest this year in the field of GI cancers?

We have decided to dedicate the entire weekend to young people with GI cancers. So firstly, what do we know? Why is this happening? To help increase our knowledge, we've invited a select group of scientists to attend the day before, in what we're calling a thinktank around this, to try and just understand the current knowledge; not only the background as to why this is happening, and the specific interventions that are needed, but also the psychosocial impact of this. It's one thing to have a bad cancer and be 75-years-old; it is another thing to have a bad cancer and be 45-years-old, or 35-years-old with kids around the house. So, we're trying to better understand that. Many of our speakers from the thinktank are also then carrying forward discussions around what we know, the impact, and where we need to go. As part of this, we always have a patient portion, which will be focusing on subjects related to this that are important to the patient community. ●

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Isolated Tumour Cells in Early Endometrial Carcinomas: A New Concept With Controversial Therapeutic and Prognostic Impact Authors:

Youbi Zakaria Ahmed1 1. University Hospital Centre of Montreal (CHUM), Quebec, Canada *Correspondence to zakaria.youbi@gmail.com

Disclosure:

Zakaria Ahmed has declared no conflicts of interest.

Received:

05.06.23

Accepted:

01.11.23

Keywords:

Early, endometrial cancer, isolated tumour cells (ITC).

Citation:

EMJ Oncol. 2023;11[1]:65-67.

DOI/10.33590/emjoncol/10309935. https://doi.org/10.33590/emjoncol/10309935.

Endometrial cancer is the most common gynaecologic malignancy in highincome countries due to increased life expectancy. Approximately 8,100 endometrial cancer cases were reported in Canada in 2022, and almost 1,500 of these will die from this disease.1 Due to the significant morbidity and mortality of endometrial cancer, several studies are underway, taking into account technological advances in molecular biology and therapeutics.

The Cancer Genome Atlas (TCGA) identified four subgroups with different prognoses (POLE hyper-mutated, mismatch repair deficient, p53 abnormal, and non-specific molecular profile), which require treatment regimens to be adapted.2 Node mapping is an important step that conditions the treatment, and consequently the overall survival.3 It is essentially surgical, with pelvic and para-aortic selective lymph node dissection. Lymph node involvement is a proven factor of poor prognosis, and, therefore, finding out its status is an essential step during staging surgery, because it conditions, with other risk factors, the utility of adjuvant treatments by radiation therapy and/or chemotherapy.4,5 However, a lymph node dissection is often

responsible for infections, haemorrhages, and especially compressive complications due to the lymphoceles.6 To remedy this considerable morbidity, several randomised trials and meta-analyses have been performed, and demonstrated the benefit of the sentinel node biopsy technique (SLN) in early endometrial cancer.7,8 Better sensitivity was attributed to this new technique, and negative predictive value and false negatives were lower.9 In the multicentre trial by Rossi et al.,9 SLN followed by pelvic+/-para-aortic lymphadenectomy had only 3% false negatives, with fewer post-operative complications.

Currently, SLN is considered a validated option for surgical treatment of endometrial cancer recommended by most scientific societies, including the European Society of Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN), the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP).10-12

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The concept of isolated tumour cells (ITC) has appeared since the validation of the sentinel biopsy as an alternative to pelvic lymph node dissection in early endometrial cancer treatment.

The American Joint Committee on Cancer (AJCC) defined it, for the first time, in 2002.13 It is present in approximately 5.9% of endometrial and serous subtypes, according to the largest published cohort.13 The Memorial Sloan Kettering Cancer Center (MSKCC), New York City, USA, established its own definition, which is the presence of a small volume metastatic lymph node (size: ≤0.2 mm), different from micrometastatic involvement (size: >0.2–≤2.0 mm).13 Several studies have shown that ultra-staging has increased the detection of lymph node volume between 20–65%.14 To pathologically detect the cancer, haematoxylin and eosin staining and cytokeratin AE1/AE3 staining are used on two 5 µm sections.9,13,14 Two instances of ITCs can be individualised: a single cluster of cells or several clusters sized ≤0.2 mm, the prognostic significance of which is still not elucidated.

The risk of lymph node involvement is estimated to be less than 5% in Stage I. Adjuvant treatment with chemotherapy and/or radiotherapy did not improve locoregional or overall recurrence-free survival according to the PORTEC and GOG trials. 15-16 Several retrospective studies have evaluated the therapeutic and prognostic value of this concept, but no Phase III study has been performed to date. Its impact in the choice of adjuvant treatment remains controversial. In the MSKCC study, published by St Clair et al.,14 of 844 patients, 23 had ITC (2.7%) in SLN, 21 had micro-metastasis (2.5%), and 47 had macrometastasis (5.6%). Adjuvant chemotherapy was administered to 19 out of 23 patients (83.0%) with ITCs, and two patients (8.7%) had pelvic radiotherapy. Recurrence-free survival at 3 years was 90% (±1.5) for patients who were node negative, 86% (±9.4) for ITCs, 86% (±9.7) for micro-metastatic, and 71% (±7.2) for macrometastasis (p<0.001). These results show a better survival rate with ITCs, and allowed the investigators to question the use of adjuvant treatment in this subgroup of patients.14 Another large study, published by Plante et al.,17 evaluated the role of adjuvant treatment in the management of 519 patients with early

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endometrial cancer, 31 of whom had ITCs positively identified by SLN. Of these, 11 received adjuvant chemotherapy with or without whole pelvic radiotherapy, 10 patients received whole pelvic radiotherapy, and 10 others received no adjuvant therapy or vaginal brachytherapy only.

To note, ITCs are not retained as node positive in this study. After 29 months of median follow-up, the 3-year progression-free survival was similar for the patients with ITCs (95.5%), who were node negative (87.6%), and had micro-metastasis (85.5%), but statistically better than patients with macro-metastasis (58.5%; p=0.0012). Only one patient with ITC recurred (stage IB, 7 cm carcinosarcoma), despite adjuvant treatment, while none with endometrioid histology recurred (0 out of 28), and none of the patients with ITC who did not receive adjuvant treatment or vaginal brachytherapy recurred (0 out of 10).

The conclusion of this prospective trial affirms the better outcome of patients with positive SLN-ITCs. However, the indication for adjuvant treatment must take into account other high-risk uterine factors, as well as the histological type of endometrial cancer, and not just the presence of ITCs. Thus, patients in this group probably derive little benefit from the addition of adjuvant therapies.7 Ghoniem et al.18 had demonstrated in its multiinstitutional study that patients with Grade I endometrioid carcinoma without lympho-vascular extension, or of unknown status, and with a low-volume metastasis on the SLN, had a better prognosis even without adjuvant treatment.18 To date, no randomised trial has been published demonstrating the benefit in local control or overall survival of adjuvant treatment with pelvic radiotherapy. The discussion of all cases on a tumour board is essential, and strongly recommended, and other risk factors of recurrence should be integrated, particularly myometrial invasion and lympho-vascular space infiltration, which indicate vaginal brachytherapy and/or post-operative pelvic radiotherapy. The proposed treatment, according to the experts, for endometrioid carcinomas Grade I Stage IA without myometrial invasion and without lymphovascular extension, or with focal extension, is observation, but some centres continue to irradiate the pelvis in view of the paucity of the literature.

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At the author’s centre, all observations of endometrial cancer are presented to a tumour board, and the centre has retained a local consensus that pelvic radiotherapy should be used if there are ITCs on several clusters, but they should always have a volume of <0.2 mm. In the presence of a single cluster, simple observation is necessary in the absence of other high-risk factors, and adjuvant pelvic radiotherapy is necessary when there are high-risk factors.

References 1.

2.

Canadian Cancer Society; Statistics Canada; Public Health Agency of Canada. Canadian cancer statistics: a 2022 special report on cancer prevalence.

2022. Available at: https://cdn. cancer.ca/-/media/files/research/ cancer-statistics/2022-statistics/2022-special-report/2022_ prevalence_report_final_en.pdf?rev=7755f9f350e845d58e268a59e3be608e&hash=3F3F30CADD8CAF0049636B5A41EDBB13&_ gl=1*17gdykb*_gcl_au*MTkxMzY1MjE2Ny4xNjk5MDAxMTA0.

Last accessed: 5 June 2023.

Levine D. Integrated genomic characterization of endometrial carcinoma. Nature.

2013;497(7447):67-73.

3.

Kitchener H et al. Efficacy of systemic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet.

2009;373(9658):125-36.

4.

Mueller JJ et al. Incidence of pelvic lymph node metastasis using modern FIGO staging and sentinel lymph node mapping with ultra-staging in surgically staged patients with endometrioid and serous endometrial carcinoma.

Gynecol Oncol. 2020;157(3):61923.

5.

Benedetti Panici P et al. Systematic pelvic lymphadenectomy vs.

Therefore, several questions need to be answered, and randomised trials should be conducted to evaluate lymph node dissection or pelvic irradiation in case of single ITCs or multiple, in order to identify the risks of lymph node recurrence, loco-regional recurrence, and overall survival. Its integration with the new molecular classification: POLE mutated, mismatch repair deficient, p53 abnormal, and non-specific molecular profile, remains to be demonstrated for a better management of this patient entity.

no lymphadenectomy in earlystage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100(23):1707-16.

6.

Yost KJ et. al. Lymphedema after surgery for endometrial cancer: prevalence, risk factors, and quality of life. Obstet Gynecol.

2014;124(2):307-15.

7.

Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Cancer Netw. 2014;12(2):288-97.

8.

Bodurtha Smith AJ et al. Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis. Am J Obstet Gynecol. 2016;216(5):45976.e10.

9.

Rossi EC et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol.

2017;18(3):384-92.

10. Oaknin A et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol.

2013;24(Suppl 6):vi33-8.

11. Abu-Rustum NR et al. Updates in Version 1.2024 of the NCCN Guidelines for Uterine Neoplasms from Version 2.2023. Version 1.2024. J Natl Compr Cancer Netw.

2023;21(2):181-209.

12. Imboden SB et al. Implementation of the 2021 molecular ESGO/ ESTRO/ESP risk groups in endometrial cancer. Gynecol Oncol. 2021;162(2):394-400.

13. Greene FL et al. AJCC Cancer Staging Manual (2002) 6th edition, Philadelphia: Springer.

14. St Clair CM et al. Low-volume lymph node metastasis discovered during sentinel lymph node mapping for endometrial carcinoma. Ann Surg Oncol.

2016;23(5):1653-9.

15. Creutzberg CL et al. Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Rad Onc Biol Phy. 2011;81(4):631-8.

16. Latif NA et al. Adjuvant therapy in early-stage endometrial cancer: a systematic review of the evidence, guidelines, and clinical practice in the U.S. Oncologist.

2014;19(6):645-53.

17. Plante M et al. Isolated tumor cells identified by sentinel lymph node mapping in endometrial cancer: doses adjuvant treatment matter?

Gynecol Oncol. 2017;146(2):240-6.

18. Ghoniem K et al. Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: an international multiinstitutional study. Gynecol Oncol.

2021;162(3):590-8.

FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Improving Inclusivity, Equity, and Diversity in Oncology Clinical Trials: A European Perspective Editor's Pick

My Editor’s Pick for this edition of EMJ Oncology is a fascinating review article, in which the authors analyse the lack of representation of diverse populations in oncology clinical trials. Michie et al. look at how this discrepancy may affect medication efficacy and toxicity. The authors describe how making clinical trials more inclusive may help us to improve our knowledge of disease in various groups.

Ahmad Awada Head of the Oncology Medicine Department, Jules Bordet Cancer Institute, Brussels, Belgium Authors:

Benjamin Langley,1 Sophie Talas,1 Karim Hussien El-Shakankery,1 *Caroline Michie1 1. Department of Medical Oncology, Edinburgh Cancer Centre, UK *Correspondence to Caroline.Michie@nhslothian.scot.nhs.uk

Disclosure:

The authors declare no conflicts of interest. Langley and Talas contributed equally to this work.

Received:

29.06.23

Accepted:

06.11.23

Keywords:

Cancer, clinical trials, diversity, equality, health literacy, INCLUDE, socioeconomic status.

Citation:

EMJ Oncol. 2023;11[1]:68-80. DOI/10.33590/emjoncol/10303428. https://doi.org/10.33590/emjoncol/10303428.

Corrigendum:

This article was first published on 5th December 2023. Since then, a corrigendum was made. The corrigendum can be seen here.

Abstract Historically, clinical trials in cancer medicine are, unfortunately, often poorly representative of the diverse populations who ultimately receive the intervention in realworld settings. This discrepancy could relate to age, extent of comorbidity, ethnicity, socioeconomic status (SES), and/or disability. This is particularly important, as medication efficacy and/or toxicity are known to be influenced by such variables. Many cancers also disproportionately affect individuals in underserved communities. If a highly selected cohort of individuals are recruited to a trial, theoretically, the findings should only be translated to equivalent cohorts in the community. Therefore, the more representative a trial cohort is of the target population, the more generalisable and applicable findings will be. If we aim to lessen disparities and improve equity, clinical trials must strive to become more inclusive, improving our knowledge of disease in these underserved groups, and therefore improving the care we provide to them in wider clinical practice.

This review summarises the current European perspective on this topical issue, suggesting potential strategies to proactively improve inclusivity and diversity in cancer trials, by encouraging enthusiastic collaboration between the pharmaceutical industry, healthcare authorities, study sponsors, research networks, and clinicians.

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Key Points 1. Clinical trials in cancer medicine have been criticised as, historically, trial populations have often not truly reflected real-world patient populations, with a significant number of underrepresented groups with respect to, for example, age, ethnicity, disability, socioeconomic status, or patients with sociolinguistic barriers. This limits the generalisability of the data, and creates an inequality for patients who could benefit from inclusion in clinical research.

2. This review summarises the current European perspective on this important and topical issue, suggesting potential strategies to improve inclusivity and diversity in cancer trials, drawing on evidence to date from other countries.

3. To improve diversity in clinical trials, a proactive approach, with collaboration between the pharmaceutical industry, healthcare authorities, study sponsors, research networks, and clinicians, will be required. Only when these inequalities have been properly addressed, can we say that clinical trials are truly representative of the populations they serve.

BACKGROUND Although clinical trials form the backbone of evidence-based medicine, cohorts participating in clinical trials are often poorly representative of the diverse populations who ultimately receive the intervention in real-world settings.

This discrepancy may relate to age, extent of comorbidity, ethnicity, socioeconomic status (SES), and/or disability.1 This is particularly important, considering the medical literature tells us that medication efficacy and/or toxicity can be influenced by age, sex, ethnicity, and other variables.2 We also know that many cancers disproportionately affect individuals in underserved communities.3,4 If a highly selected cohort of individuals are recruited to a trial, theoretically, the findings should only be translated to equivalent cohorts in the community. Therefore, the more representative a trial cohort is of the target population, the more generalisable and applicable findings will be.5 If we aim to lessen disparities and improve equity, clinical trials must strive to become more inclusive, improving our knowledge of disease in these underserved groups, and therefore improving the care we provide to them.5 Prior to discussing this further, the authors define diversity, inclusivity, and equity below in Table 1.1,6 In 2022, the U.S. Food and Drug Administration (FDA) issued guidance on improving trial racial inclusivity, including a requirement for all trial sponsors in the USA to formally submit a

‘Race and Ethnicity Diversity Plan’. The plan should highlight any existing evidence as to whether efficacy of the trial intervention/ agent is influenced by race and/or ethnicity, alongside listing ‘goals and plans for enrolment of underrepresented racial and ethnic participants’.7 Supporting this, the United States Congress’ end-of-year budget allocated funding to develop interventions that improve trial diversity.8 Presently, no such requirements exist for other underrepresented groups.

This review explores the challenges that underserved groups face regarding clinical trial involvement. With the USA taking proactive steps to counteract such issues, the authors consider what Europe and its leading organisations are doing to improve trial inclusivity, alongside discussing various innovative solutions aimed to improve recruitment and the representation of underrepresented parties. In writing this review, for each key inequality challenge, a separate search was undertaken using the individual challenge as a search term, together with “clinical trials,” in order to select appropriate literature. The authors focus here on bringing together a European perspective.

CHALLENGES Ethnicity

An ethnic group is defined as a large collection of ‘people classed according to common racial, national, tribal, religious, linguistic, or cultural

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Table 1: Key terminology and definitions.

Terminology and definitions Diversity

Refers to the variety of characteristics, personalities, and behaviours of individuals.

Inclusivity

Encompasses actions that ensure all people are respected, appreciated, and valued, permitting diversity to prosper.

Equity

Ensures all individuals have fair opportunities to access resources and achieve their best health, regardless of their characteristics or background. Equity involves distributing resources based on need, rather than equally between all individuals/groups.

origin or background’, while an ethnic minority group describes those ‘living in a country where most people are from a different ethnic group’. In contrast, race is defined as a group in which people belong, classified by physical characteristics one perceives them to share; although the definition shares similarities with ethnicity/ethnic groups, the terms should not be used interchangeably.9-11 In 2022, the National Institute for Health and Care Research (NIHR) reported that only 60% of 148 UK randomised controlled trials (RCT) provided data on participant ethnicity.12 Furthermore, in trials that do report ethnicity, underrepresentation is often apparent. For example, Smith et al.13 analysed data from 943 RCTs crucial to medication authorisation by the European Commission (EC), showing that Black and Asian populations were underrepresented in almost 50% of trials. The review highlights the abundance of literature discussing trial ethnic diversity stemming from the USA, relative to European counterparts; this is perhaps driven by a combination of historical and attitudinal differences.13 Despite knowing that ethnic minorities in Europe also face disparities in cancer care, one must consider whether European research is comparably as committed to prioritising equity for these groups.14,15 Aimed at enhancing trial ethnic diversity, Schwartz et al.16 state three key goals: building trust, promoting equity, and increasing biomedical knowledge. Described in American literature, distrust of the medical profession draws on historical abuses and modern-day inequalities.17,18 However, European literature on this subject is lacking, so whether the reasons underpinning American distrust translate to

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this population is difficult to say. Secondly, equity recognises that potential benefits of trial participation should be made accessible to all, regardless of background and characteristics.

This benefit comes not only from the trial intervention, but also from participation in general; inequity limits access to groups that may need it most.19-22 Such benefits include dedicated support by a trials team, enhancing continuity of care, and increased (and often quicker) access to investigations, blood tests, and appointments with a healthcare professional.19,20,23 Finally, biomedical knowledge is gained through diversity, because cohorts highly representative of the diverse target population increase the generalisability of results. Pharmaco-ethnicity considers ethnicity-dependent variations in treatment response and toxicity,24 and though individual trials are usually underpowered to robustly identify these differences, it emphasises why inclusivity makes for more applicable data.16 Indeed, achieving equity may not mean proportional representation with regard to the general population, but representation weighted to reflect that some cancers affect certain ethnicities to a greater degree. For example, mortality incidence in African American patients with triple negative breast cancer (TNBC) is almost twice that of White counterparts.25,26 Nevertheless, social factors may play a significant role in TNBC survival in this group, which may also form barriers to trial participation, widening inequity.26 However, the pressing need to improve care for this subgroup is not reflected in clinical trial recruitment. For example, in one of the most recent practice-changing studies in TNBC, ethnicity data were not reported until recently, where <5% were Black or African American.27,28

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We must also recognise that ethnicity intersects with socioeconomic, educational, language, and geographical factors, all of which may contribute. The term ‘ethnic minority’ refers not to a homogenous population, but describes diverse peoples with different cultures, history, and genetics. Moreover, Europe is a diverse continent, with variation between countries not only in ethnic and linguistic makeup, but in healthcare access, resources, governing bodies, historical tensions, politics, migration, and attitudes towards equality. Therefore, inclusion strategies must be both multifaceted, and regionally tailored.

Language and Health Literacy

Language is a well-recognised barrier to trial inclusion.29-35 For an individual to provide capacitous consent, they must be able to understand, retain, weigh up, and communicate their decision.36 The Centers for Disease Control and Prevention (CDC) defines health literacy as the ability of individuals to "find, understand, and use information and services to inform healthrelated decisions and actions for themselves and others."37 Alongside verbal explanations, trials also involve significant volumes of written information and paperwork, including written consent. It may not always be immediately evident that a language barrier exists. For example, someone with good conversational English may have difficulties with written language, and/or be unfamiliar with medical jargon. National Health Service (NHS) England’s Increasing Diversity In Research Participation guide recognises further language-related barriers, like poor health literacy, culturally inappropriate explanations, use of acronyms, and poor access to quality translation.29 A 2020 study objectively assessing the readability of patient information documents from 154 different UK clinical trials found that not one met the recommended mean reading age of <12 years, recommended by the American Medical Association (AMA).38 Consideration should also be applied to communication needs in populations prone to language barriers, including visually/hearing impaired, cognitively impaired, learning disability groups, and groups for whom the trial participant’s first language differs from the primary language used in the country that the trial is based.30,39-41

Sociolinguistic Disabilities

Communication of trial information can be equally difficult for sociolinguistic minorities, such as those with impaired hearing or vision.

Without adequate accessibility and support for these patients, lower involvement in clinical trials is inevitable. Deaf patients are particularly prone to lower levels of health literacy, and may also have unique reservations with regard to research participation, such as fears of confidentiality breaches via translators likely to be within the same social circles as themselves.41

Rural Communities

Several studies, primarily conducted in the USA, have demonstrated that people from rural communities may have a shorter life expectancy,42 present with more advanced cancers,43,44 and are less likely to participate in clinical trials.42,45,46 Possible reasons for this are numerous, including lower education and SES in rurality,37 patient perception that healthcare is less accessible,39 fear of associated costs,41 and poor trial recruitment effort rurally.47 To some degree, many of these likely translate to corresponding European populations.

Individuals living in remote areas are considered an underserved group by the NIHR Innovations in Clinical Trial Design and Delivery for the Under-served (INCLUDE) project.34 Regarding healthcare distributions, Europe has a distinct rural-urban divide, concentrating workforces in urban populations.35 A 2020 UK-based YouGov poll of clinical trials participants found that those in urban regions travelled 10–20 miles on average for cancer care, while rural participants travelled an average of 20–50 miles.48 Additionally, despite modern solutions to increase digital presence, and minimise face-to-face contact for participants, rural communities may still find themselves digitally isolated.30

Socioeconomic Status

Cancer incidence is known to vary according to SES, with cancers such as cervical and lung more common in those of low SES living in incomedeprived areas.49 Despite those from deprived areas representing a significant proportion of the general cancer population, most individuals enrolling in clinical trials tend to be affluent, limiting generalisability of the data to real-world

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settings.8,50,51 Created by the UK government, the Index of Multiple Deprivation (IMD) score is a measure of socioeconomic deprivation, summarising how deprived individuals living within a geographical area are; it is often considered deeply related to socio-economic status.52,53 Supporting the above, Noor et al.54 observed that patients with an IMD score of 5 (most deprived quintile) were significantly less likely to be referred for early Phase (Phase I) trials in an England-based cancer centre (odds ratio: 0.53; 95% confidence interval: 0.38–0.74).

Potential barriers have been postulated that may prevent deprived individuals from accessing trials, including lower health-seeking behaviours, distrust, lack of awareness/understanding, and language/cultural barriers.55-58 Furthermore, in those showing interest, associated costs may also limit engagement. These include expenses for more frequent travel, commonly to trial centres further away than their local hospital, secondary to additional appointments, and more frequent imaging.59,60 Time away from their employment and/or other caring responsibilities may also deter individuals from lower SES more than those who are affluent. Furthermore, poor retention in clinical trials has commonly been attributed to financial, time, or other practical reasons.61 With research highlighting a clear relationship between SES and physical health, those of lower SES may also be disproportionately excluded from trials via eligibility criteria that include various comorbidities and lower performance statuses. Several factors may result in worse physical health in those of lower SES, including housing conditions, nutritional status, income, and the likelihood to undertake manual labour work.62,63

Elderly Populations

Considering older individuals are more likely to be frail and/or comorbid, alongside being more susceptible to treatment toxicities, it is perhaps easier to understand the reduced representation of elderly patients in clinical trials involving potentially harmful interventions. Additionally, they may have different perspectives on quality versus quantity of life. However, despite these factors undoubtedly influencing patient eligibility, evidence suggests older patients are no less

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willing to participate in research. As 42% of the cancer population are >70 years, their participation is valuable. Despite this, only 10% of this cohort are involved in National Cancer Institute (NCI)-sponsored clinical trials.64,65 Therefore, one must consider if unnecessary barriers are preventing involvement.

In particular, we understand that there are notable biological differences in the handling of medications by the elderly. These include changes in gastric acid production and gut transit time (influencing absorption and peak drug concentration), declining serum albumin, impaired hepatic and renal drug clearance, and differences in body composition.66 These may serve to alter the therapeutic benefits or possible side effects of medications, and the overall effect of a particular drug in this population will only be truly established when opportunities are provided to test them. Indeed, any appropriate dose adjustments could be best defined prior to a treatment going to market.

Alongside drug metabolism concerns, a 2021 systematic review identified several other barriers at both care provider and patient levels.64 These included strict eligibility criteria, choice of language in consenting, reluctance from healthcare professionals secondary to fears of toxicity or comorbidities, poor awareness of available trials, and even general concerns solely around the patient’s age. Finally, patients themselves may lack comprehensive understanding of what trials entail, and/or may worry about logistical implications, such as reliance on family members for travel, and time commitments.

There has, however, been some progress, with the European Organisation for the Research and Treatment of Cancer (EORTC) Elderly Task Force initiating an Older Adult Council thinktank to ‘actively promote clinical and translational research in older adults over 70’. Several of their tumour subgroups have collaborated with this taskforce to initiate a number of trials dedicated to elderly populations.67 Furthermore, geriatric oncology is also now a specialist field in its own right, promoted and supported by the International Society of Geriatric Oncology (Société Internationale d’Oncologie Gériatrique [SIOG] in French). This was set up in 2000 in Europe as a multidisciplinary network, and

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presently boasts members from >80 countries worldwide. Research and education are two of its main strategic priorities.68

POSSIBLE SOLUTIONS Reasons for underrepresentation of the above groups are both numerous and broad. Though some innovative ideas may benefit more than one population, no one-size-fits-all solution exists; each group should be considered in turn to optimise outcomes.

The INCLUDE Framework

Several European groups have been working to improve inclusivity of underserved groups, including the NIHR and their INCLUDE framework, which considers several underserved populations, including those listed in Table 2. The guidance encourages research teams to carefully consider their target/study population, specifically highlighting relevant underserved groups, and any potential barriers to participation. Through helpful definitions, examples, and questions, the framework prompts researchers to reflect on the inclusivity of their work.34 In considering inclusion and exclusion criteria, research teams are strongly encouraged to justify why such criteria are merited if they are likely to prevent underserved groups from being eligible to participate.34

Possible Solutions: Ethnicity

To generate solutions, one must first consider the many postulated barriers to participation faced by ethnic minorities. These include distrust in medical communities;17,29-33,69 lacking knowledge around trials;30 financial worries;29,30,32,34 associated logistical issues, such as transport, or care responsibilities;30,31 cultural barriers, including stigmas about disease;29-34 language barriers;29-35 and excessive exclusion criteria.30-34 Multiple studies suggest that ethnic minorities are no less willing to participate than their counterparts, and so the discrepancy cannot be dismissed as purely attitudinal.70,71 Of the numerous proposed and tested strategies, the most notable include: cultural competency training, where trial staff are educated in respecting, understanding, and communicating appropriately with patients from different cultures;29,30,72,73 video education interventions that provide simple, culturally-sensitive explanations of trials;34,73 community-based approaches, e.g., partnership with community organisations and leaders, alongside involving them in study design/implementation;30-32 and use of trusted or respected medical professionals.32 Non-discriminatory and carefully selected exclusion criteria also consider that certain comorbidities, for example, are more prevalent amongst particular minority groups, and may not truly need to be excluded.30,33,34 However, strategies must avoid becoming coercive, or paint an unbalanced view of trial involvement.

Table 2: Underserved groups highlighted within the National Institute for Health and Care Research (NIHR) INCLUDE project.

Demographic Factors

Social and Economic Factors

Health Status Factors

Disease-Specific Factors

Age, ethnicity, sexual orientation, educational disadvantage.

Residing in deprived areas, full-time employment, living remotely, carers for family and/or friends, language barriers, stigmatised groups.

Mental health conditions, those lacking capacity, learning disabilities, cognitive impairment, physical disability, pregnant females, comorbidities, visually/ hearing impaired, smokers, obesity.

Rare cancer subtypes, patients with brain metastases.

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Looking forward, the INCLUDE project has produced a catalogue of available multimedia resources and an ethnicity framework,74 amongst other resources, which challenge teams to evaluate their trial design. Similarly, the UK Engineering and Physical Science Research Council (EPSRC) has produced an Equality, Diversity, and Inclusivity (EDI) strategy, encompassing a variety of themes, from good recruitment practices to accessible environments, as well as diversity of study recruitment.75 This effectively demonstrates that EDI should permeate all aspects of research, and that inclusive trials should be the fruit of inclusive organisations. Furthermore, ‘Increasing Diversity in Research Participation’, a good practice guide from NHS England, proposes and categorises practical recommendations into pre-research planning, involvement, and respect during research, and post-research feedback and improvement.29 As one of its key targets within the 2021-22 Clinical Research Delivery Implementation plan, the UK government has also published several recommendations, with the intention of working with the NIHR to make research ‘more diverse and more relevant to the whole UK’.76 Outside of government-led organisations, Egality are a startup agency with the goal of improving clinical trial diversity by facilitating the engagement of researchers with diverse communities.77 Through these relationships and practical experience, they have generated recommendations targeted at the national, organisational, and individual level, to encourage the first steps towards improvement.77 Meanwhile, the European Medicines Agency (EMA) stress the importance of diversity in several of their International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, emphasising representative participant selection.78,79 The Medicines and Healthcare products Regulatory Agency (MHRA) are also set to release a new framework that contains guidance on improving diversity in trials.80 However, despite the above concerted efforts, there remains no requirement for trial publications to report ethnicity data (unlike examples in the USA),81 and no standardised way of recording this.12 In the meantime, it remains to be seen whether European nations value

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inclusive trials, and are making meaningful steps forward.

Possible Solutions: Language and Sociolinguistic Minorities

Considering language and its associated barriers, multiple solutions exist. Using bilingual staff has been shown to be effective, as has access to professional interpreters.30 Written material available in the participant’s preferred language can be helpful,30,31 but straightforward translation of documents may not give much benefit, and a more tailored approach is needed;32,82 these include pitching writing at an appropriate literacy and cultural level, creating simpler and more concise documents, and making use of multimedia materials.29-31,72,82 Non-written patient education materials, such as videos, pictographs, and audiotapes, have been shown to increase patient understanding,83 and trial information videos with sign language would further facilitate participation of deaf patients.34,84 It is also important to recognise not only the huge volumes of languages widely spoken in diverse European countries, but also the nuances of different languages. One example of this is Gujarati, which is predominantly a spoken language, making written translations largely redundant.32 Additionally, the language does not have a word for cancer, so much care has to be taken to communicate concepts effectively.32 This highlights the importance of cultural competency alongside language tools, seeking to ensure communication is not only effective, but considerate and informed.72

Possible Solutions: Rural

Proposed strategies for reducing inequalities for rural patients in clinical trials include employing technology for virtual appointments;85 reimbursing expenses;4,46,85 providing transport;86,87 and using satellite sites for clinics, appointments, scans, and/or treatments.88 Improving physician education around the challenges for rural populations will also be imperative.45,46,87 One organisation actively addressing the urban-rural divide is the International Institute for Rural Health (LIIRH), based in Lincoln, UK.89 In particular, they hope to use the European Code of Cancer Practice, which summarises the pillars of a quality cancer service, to evaluate rural cancer care.90 The

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current paucity of research into rural population involvement in European clinical trials means these communities are likely to remain underserved.

Possible Solutions: Socioeconomic Status

Despite disparity in oncology trial participation having always been present, only now is there a slowly growing body of research attempting to address it. The NIHR-INCLUDE guidance contains a ‘Socioeconomic Disadvantage Framework’,34,91 which specifically seeks to increase participation of poorer patient groups.

The framework also encourages research teams to ensure trial outcomes are relevant to the broader population, and not just the typically over-represented affluent trial participants. Four key questions are proposed to encourage trial organisers to optimise inclusion of those of lower SES: 1. Are people from different socioeconomic backgrounds likely to respond to the intervention in different ways?

2. Will my trial intervention and/or comparator make it harder for people from different socioeconomic backgrounds to take part in the trial?

3. Will the way I have planned and designed my trial make it harder for people from different socioeconomic backgrounds to take part in the trial?

4. What factors might affect the reporting and dissemination of trial results?

Patients of lower SES are more vulnerable to the financial stressors of trial participation, including travel and childcare costs. To improve recruitment and retention, trial sponsors must consider compensating for such expenses, and addressing concerns of potential trial participants.

Possible Solutions: Elderly Patients

Reassuringly, more seems to have been actioned at a legislative level with regard to elderly involvement in trials.

The guideline ICH E7, initially published in 1994, laid out the fundamental principle that "drugs should be studied in all age groups, including the elderly, for which they will have significant utility."92 Their guidance made specific requirements for adequate representation of elderly patients, with at least 100 older patients included in trials where the disease is not unique to the elderly. They clearly state that upper age limits should be avoided, as should excluding patients with comorbidities, where possible.

The guideline also highlighted the importance of pharmacokinetic and pharmacodynamic studies in this population, alongside research into novel drug-drug interactions. A decade later, the World Health Organization (WHO) encouraged the development of laws and guidelines that would obligate the inclusion of the elderly in clinical trials, stating that these patients were ‘unjustifiably excluded’.93 They advocated for tailored formulations of drugs for the elderly, to maximise adherence, and recommended thorough monitoring for adverse reactions.

In 2006, the EMA reviewed 10 dossiers of recently approved medications to assess their compliance with ICH E7, which, on the whole, showed good compliance.94 They also made recommendations for how they believed ICH E7 could be improved upon, such as necessitating the involvement of both the elderly and very elderly participants as discreet subgroups in the clinical testing of medications.

While guidelines have laid groundwork for better inclusion of the elderly, barriers preventing optimal patient involvement still remain. One proposed solution is ‘geriatrising’ trial design;64 this includes trying to use standardised measures of frailty, and choosing appropriate endpoints, such as active life expectancy, as well as specifically designing studies that investigate dosing, tolerability, benefits, and toxicities in the elderly.95 Indeed, these measures will require widespread support alongside commitment of dedicated funds and resources for success.

Easing logistical barriers through telehealth appointments, or assisting with travel and/ or lodging, may also encourage enrolment.64,96 Furthermore, improving communication and providing information tailored to elderly patients is another important step in aiding accessibility and understanding. Finally, psychosocial barriers, such as physician bias, must be tackled; in part,

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this may be addressed through availability of high-quality data and literature, aiding clinicians to make evidence-based decisions.96

PHARMA PERSPECTIVE Data from the EMA suggest that of approximately 2,800 clinical trials authorised each year for human medicines, 60% of these are commercially funded. Hence, the pharmaceutical industry must show active engagement in processes to improve diversity, and enact meaningful change.97 Since the COVID-19 pandemic, improving diversity has become a hot topic of discussion. Literature stemming from several companies highlights trial diversity as an area of unmet need.98-102 Companies are already starting to implement many of the solutions discussed above; notable examples include community engagement and advocacy groups,98,99,102 diversity-specific staff training, increased recruitment of female and minority ethnic trial investigators,99 increased ethnic minority representation within pharmaceutical organisations alongside gender parity,98 and dedicated/ringfenced funding to ensure equity and diversity commitments are upheld within organisations and trials.98 Other companies are also setting their own in-house targets, aiming for >75% of trials to have an outlined participant demographic plan, specifically and appropriately aligned with the epidemiology of the disease being studied; this was achieved in 100% of their Phase III studies in 2022.102 Aiming to build trust, work is also underway to improve access to patient-facing materials, such as videos to explain trials in multiple languages, and patient testimonies of trial involvement, especially from participants of underserved groups (unpublished correspondence). It should be highlighted, however, that these resources should be treated the same as any patient information correspondence, and therefore will be subject to the same regulatory and ethical restrictions, incurring cost and time. It is imperative that any digital communications are used as explanatory aids, and not as an ‘advert’.

Furthermore, confidentiality, and the ability to easily share digital resources further than their intended population, is also a risk that must be balanced (unpublished correspondence).

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FUTURE DIRECTIONS AND STRATEGIES Though many solutions show great potential, ensuring these are implemented in practice remains challenging. Although progress is being made, more is required. Previous research, primarily from the USA and the FDA, has demonstrated that legislation and recommendations from official public bodies, with associated accountability for actions, does translate to effective outcomes.8 At present, no such legal requirements have been proposed by European organisations.

In a similar vein, the Fair Inclusion Score (FIS) for clinical trial diversity has been developed, generating an index/score based on trial participant sex, age, and ethnicity.8,103 The score, intended to be publicly visible alongside published research, considers transparency of demographic data in published trials, alongside demographic representations in those that do present this data, compared to official demographics of the relevant target population.

The score can be utilised on any published RCT, providing a diversity ‘quality measure’ that can be considered overall, or split into female, age, and ethnicity subgroup scores. Scores may then be compared to an acceptable ‘benchmark’, or directly compared with other trials and/ or organisations, highlighting the efforts that organisations are, or are not, making to ensure their clinical trials are generalisable. As part of its development, retrospective application of the FIS on 69 RCTs (leading to FDA approval of 59 novel therapeutics between 2012–2017) showed that trials often displayed good transparency (mostly age and gender, with fewer studies noting ethnicities), but poor demographic representation, consistent with previous findings.

Although the score highlights and considers diversity of trial populations after publication, this is performed retrospectively, and does not play a role in improving inclusivity prospectively.8,103 Similarly, organisations in the USA, such as the National Academies of Sciences, Engineering, and Medicine, are calling on journal editors and publishers to consider trial representation and inclusivity in all submissions.1 However, changes must be considered far earlier than this, hence the proposal of a Diversity, Equity and Inclusion Clinical Trial Life Cycle (DEICTLC), produced

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by Versavel et al.1 Somewhat similar to the NIHR-INCLUDE project, the DEICTLC outlines each stage of trials from planning to close, with a useful checklist of actions that can be undertaken at each stage to maximise inclusion of underserved groups. Though the DEICTLC is in its infancy, and more evidence around its use in real-world practice is required, it shows great potential as an aid for study sponsors. In the UK specifically, organisations such as MedCity have themselves released guidance on trial inclusivity, with recommendations largely echoing those previously noted above. They also call for official UK organisations such as the Association of the British Pharmaceutical Industry (ABPI) and the Prescription Medicines Code of Practice Authority (PMCPA) to formulate code of

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The Plate Matters: Exploring the Intersection of Food Insecurity in Patients with Cancer Authors:

Andrés Noyola Pérez,1 Emily H. Wood,2 *Manali I. Patel2,3 1. Facultad de Medicina, Universidad Autónoma de Nuevo León, Mexico 2. Stanford University School of Medicine, California, USA 3. VA Palo Alto Health Care System (VAPAHCS), California, USA *Correspondence to manalip@stanford.edu

Disclosure:

The authors declare no competing financial or non-financial interests that could be perceived as influencing the research presented in this paper.

Received:

27.07.23

Accepted:

23.10.23

Keywords:

Cancer care, food insecurity, health disparities, nutritional status, systemic issues, treatment outcomes.

Citation:

EMJ Oncol. 2023; DOI/10.33590/emjoncol/10306925. https://doi.org/10.33590/emjoncol/10306925.

Abstract This paper explores the overlooked influence of food insecurity on cancer care, its correlation with malnutrition and poor patient outcomes, and potential strategies for intervention. Food insecurity, the inconsistent access to nutritionally adequate food, significantly impacts up to 55% of patients with cancer, particularly among minority populations, and those of lower socioeconomic status. This multidimensional issue contributes to malnutrition, impairs treatment adherence, and increases mortality rates among patients with cancer. It also exacerbates health disparities, and is intricately tied to systemic factors, such as poverty, discrimination, unemployment, and chronic health conditions. The authors’ review elucidates the negative impact of food insecurity on cancer treatment outcomes, and highlights the need for holistic interventions, including on-site, community, and federal initiatives. Addressing food insecurity within cancer care requires comprehensive, multilevel collaborations to improve nutritional status and health outcomes for patients with cancer. Despite growing awareness of food insecurity among patients with cancer, significant gaps remain in intervention development, access, and effectiveness. Existing clinical trials are limited, underscoring a lack of understanding of food insecurity's impact on cancer care. Within cancer care, we need improved food insecurity screening, more collaborations across sectors, and rigorous research to evaluate intervention impacts. These steps, while potentially lacking immediate impact, are essential for sustainable health improvement and long-term food insecurity reduction. The intricate link between food insecurity and adverse cancer outcomes calls for comprehensive strategies, going beyond food provision, to address systemic issues of racism and poverty.

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Key Points 1. The intersection of food insecurity and cancer: Patients with cancer face extensive medical demands that overshadow the vital role of nutrition in cancer care. Food insecurity, defined as inconsistent access to nutritious food, is a health-related social and medical need. Racial and ethnic minoritised groups, and other populations with limited socioeconomic status, are far more likely to be impacted by food insecurity during cancer care, and worse cancer outcomes.

2. Financial toxicity exacerbates nutritional challenges: The economic implications of a cancer diagnosis are profound. Beyond medical bills, many face reduced income, leading to significant financial hardships. Such constraints amplify food insecurity, with patients resorting to cheaper, low-nutrient foods, which negatively impact their treatment outcomes, and heightens the risk of complications.

3. Multilevel solutions: The solution is not just to provide food access, but rather understanding and addressing the deeper social and economic determinants of health that underlie food insecurity.

Successful interventions demand collaborations across sectors, and a focus on both immediate relief and long-term systemic changes that promote equity. Early identification of food and nutrition insecurity in patients with cancer is crucial for impactful interventions, and improved outcomes.

INTRODUCTION Cancer is an imposing condition that impacts individuals and their loved ones in multiple ways.

Over the past 250 years, extensive research has begun to unravel cancer’s biological and organic causes.1 While there have been some critical milestones in cancer research, the focus on merely biological perspectives has inadvertently overlooked a crucial component of cancer care: addressing the multiple needs of patients that extend beyond medical treatment. This paper underscores one such overlooked aspect: the role and implications of food insecurity on cancer care.

When diagnosed with cancer, individuals often experience various physical and emotional changes that can be overwhelming, and difficult to navigate.2 Whether coping with the side effects of treatment,3,4 managing stress and anxiety,5 or financial toxicity,6 facing cancer can be an intimidating experience. Amidst this overwhelming state of medical demands and complicated and intensive cancer treatments, nutrition tends to be sidelined.7 However, nutrition is not a secondary concern, but a fundamental piece of cancer care.8 In this context, the intersecting issue of food insecurity becomes crucial to cancer care. A structured overview of the intersection between food insecurity and cancer care is depicted in Figure 1.

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Food insecurity is the lack of consistent access to safe, nutritious, and adequate food to maintain an active and healthy lifestyle.9 The contributions to food insecurity cannot be attributed to one factor alone, but rather systemic issues, including poverty, discrimination, unemployment, and chronic health conditions.10-12 The prevalence and impact of food insecurity are far from uniform, varying based on sociodemographic characteristics, with some groups disproportionately affected, including individuals who self-identify as Black and Hispanic, and who are from low-income households.13 These disparities are often the result of broader systemic issues, such as poverty and the social determinants of health.14 Such patterns are interconnected with historical and systemic biases, which influence economic opportunities and outcomes over time.15 Food insecurity presents a major barrier to optimal receipt of cancer care. Studies estimate that up to 55% of patients with cancer experience food insecurity.16 This issue becomes more pronounced in low-income and medically underserved patients with cancer.17 Research conducted in Iran revealed that nearly 80% of patients undergoing cancer treatment struggle with food insecurity, with half of all patients with cancer suffering from hidden hunger.18 Similarly, a study on children with cancer in South Africa reported that 30% of these children were at high risk of poverty, highlighting a correlation

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Figure 1: A structured overview of the intersection between food insecurity and cancer care.

Aetiology

Systemic issues: • Racism • Poverty • Discrimination • Unemployment • Chronic health conditions

• Malnutrition • Increased risk of mortality • Treatment and screening lack of adherence

Future Recommendations

Interventions

Current Challenges

• On-site food banks • Community initiatives • Government assistance programmes • NGO support

• Limited clinical trials • Inadequate screening and awareness • Insufficient resources • Eligibility limitations in federal programmes

Impact

• Increased screening and awareness in clinics • Multilevel collaboration • Increase research from LMICs • Holistic approaches considering SDoH

LMIC: low- and middle-income countries; NGO: non-governmental organisation; SDoH: social determinants of health.

between food insecurity and malnutrition, which subsequently negatively impacted their treatment outcomes.19 Despite the increasing evidence of the importance of nutrition among patients with cancer, a staggering 10–20% are estimated to die from nutrition-related issues.20 This review contains the latest research on how food insecurity impacts patients with cancer, the significance of addressing this issue in cancer care, and interventions to combat this growing problem.

IMPACT OF FOOD INSECURITY ON NUTRITIONAL STATUS AND TREATMENT OUTCOMES Maintaining a healthy and well-balanced diet that includes sufficient proteins, vitamins, and minerals is essential for humans to reach optimal energy levels, and reduce the risk of developing chronic diseases or infections.21 For patients with cancer, a healthy diet is critical for optimal outcomes.8 This section will highlight the existing nutritional challenges patients with cancer experience, and the burden of food insecurity.

Cancer-related malnutrition, present in around 75% of patients with cancer,22 significantly contributes to multiple adverse treatmentrelated outcomes, and accounts for up to 20%20 of all cancer deaths. Cancer and its associated treatments introduce multiple nutritional challenges, including alterations in taste, gastrointestinal challenges, and psychological or psychosocial strain, impacting a patient’s appetite, and their ability to digest food effectively. Consequently, many patients with cancer may not be able to consume a sufficient quantity of healthy and necessary foods, which can lead to malnutrition, loss of muscle and bone mass, and decreased functional status.23 Malnutrition can have several consequences, including extended hospital stays, increased treatment-related toxicity, reduced healthrelated quality of life, and mortality.24-26 Furthermore, the nutritional status of a patient with cancer also plays a role in increasing the tolerability and effectiveness of some anticancer drugs.8 Due to the multiple nutritional challenges patients with cancer face, food serves as more than just fuel for the body. Unfortunately, these dietary

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demands are further intensified when patients with cancer experience an additional burden of food insecurity. The economic implications of a cancer diagnosis are profound. Not only do patients experience significantly expensive medical bills, but many experience loss of income after the diagnosis, due to the inability to work, or the need for assistance from a caregiver.27 Patients and their families struggling with financial toxicity are often forced to choose between meeting vital needs, such as rent, childcare, medications, nutritious food, and/or transportation. Such economic limitations further amplify food insecurity, as household finances become concerning to manage when expenses increase, income decreases, and priorities shift. Consequently, patients with cancer who experience food insecurity consume lower cost foods, which are less varied, poorer quality, and are lacking in essential nutrients, such as from vegetables, fruits, and dairy.

This further worsens cancer-related malnutrition, and increases susceptibility to treatment complications.28 Correlations are prevalent between the populations burdened by cancer and those experiencing food insecurity. Socioeconomic status, race and ethnicity, cultural barriers, and educational attainment influence the prevalence and impact of food insecurity in patients with cancer.29 For example, low-income, immigrant, and minority populations with cancer experience elevated risk for financial hardship and food insecurity.17 Such elevated risk among these populations remains prevalent among patients who have completed treatment. For example, cancer survivors who are Black, Hispanic, or Latinx are twice as likely to experience food insecurity than cancer survivors who are White.30,31 Food insecurity also directly impacts patients’ ability to adhere to recommended treatment, and ultimately impacts cancer outcomes. For example, persistently food-insecure survivors of cancer are significantly more prone to skip medications and cancer-related treatment.32 Moreover, food insecurity among patients with cancer has been shown to impact adherence to colon, breast, and prostate cancer screening, as compared to patients without food insecurity.33,34

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Patients with cancer who experience food insecurity also face a higher risk of mortality.

This risk increases based on the severity of food insecurity, and any non-medical financial worries they may also experience. For example, patients with moderate and severe food insecurity are 53–69% more susceptible to mortality.35,36 Similarly, high levels of food insecurity are associated with greater incidence and mortality from cancer, specifically lung and colorectal cancer.37 A recent study among patients with gastrointestinal cancer with food insecurity showed 22% greater overall mortality among those with food insecurity than those without.38 Given the impact of food insecurity on patients with cancer, exploration of exacerbating barriers that may impede cancer care is crucial; for example, the lack of vehicle ownership restricts their ability to travel to areas with better food access.39 This situation is linked with the concept of food deserts, which are areas that have limited access to nutritious food due to socioeconomic and geographic limitations to food access.39 A recent study, which analysed how transportation barriers affect survivors of cancer, found that patients with cancer who faced such barriers were also three-times more likely to suffer from food insecurity than their counterparts, and to experience greater delays in their cancer care compared to those without transportation barriers.40 Such intersectional needs are important to address holistically, given that they are often co-occurring, and exacerbate the impact of food insecurity.

In essence, the additional burden that food insecurity poses on patients with cancer and their clinical outcomes is significant, particularly among minority populations, and those with socioeconomic disadvantages.19,41

APPROACHES TO MITIGATE FOOD INSECURITY IN CANCER CARE Addressing food insecurity requires comprehensive and extensive multilevel collaborations to successfully mitigate the impact. Targeted interventions are essential for improving nutritional status and treatment outcomes among patients with cancer. These interventions can be broadly categorised into on-site (at the clinic), community, and federal

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programmes. Yet, gaps remain in understanding the feasibility, accessibility, and effectiveness of such programmes among patients with cancer.

In low- and middle-income countries, nongovernmental organisations play a significant role in financing and providing healthcare services, including food and financial support, to patients with cancer. These interventions provide ease of access, particularly in socioculturally diverse areas that are often fraught with economic and social barriers to high quality medical care.42

On-Site Programmes

On-site programmes that provide patients with food at the clinic where they receive care is one approach to improving food insecurity.

Food banks and food pantries can assist in obtaining food, and distributing food to patients with food insecurity, in the clinic setting. Such options are especially important for patients who may be at risk of treatment delay, or who may forego treatment due to cost.43 Food banks and food pantries are often non-profit groups that gather food from various sources, such as grocery stores and restaurants with extensive storage facilities, and distribute it to the community, or directly to individuals in need.44 Clinic- and hospital-based pantries have a positive impact on patient-reported wellbeing, with patients reporting comfort and satisfaction with food options. These clinic- and hospitalbased programmes have resulted in increased consumption of food and vegetables among patients overall.45 Other programmes, such as Feed1st, expanded distribution during the COVID-19 pandemic by eliminating identification or other restrictions to food access for patients, hospital visitors, and staff. Such programmes have resulted in increased distribution by maximising open access to food, and thereby removing the stigma.46 To date, many of these on-site programmes have not been specifically tailored to patients with cancer, but rather for patients generally in the primary care setting.43 The few examples of cancer-tailored, on-site food pantries include Food to Overcome Outcome Disparities (FOOD) in New York, USA,43 and the Legacy of Hope initiative in Philadelphia, Pennsylvania, USA.47 The FOOD programme tailors its services to the needs of patients with cancer by providing healthy meals that are low in sodium and sugar.

Beyond merely providing food, it further offers bilingual (English and Spanish) nutritional education programmes for these patients.

Moreover, the programme also provides a unique training course for healthcare providers, differentiating it from traditional food banks that primarily focus on broad food distribution.43 Limitations of on-site programmes apply to food pantries in general, in which the food may not alleviate all aspects of food security, such as providing a balanced diet, or meeting high demand. In addition, these programmes are limited in availability, as they are only within, or linked to, specific clinical settings. Such clinic-based programmes are frequently limited by insufficient resources, such as inadequate staffing, insufficient training, and restricted operating hours. As a result, these on-site food pantries have yet to meet the food security needs of their communities.45 Moreover, food pantries rely heavily on donations, which limits the availability and quality of food, and are usually stocked with unhealthy items. They can also evoke stigma and embarrassment, especially when restrictions for access are imparted.48 Innovative programmes and policies are needed to optimise food access.

Community and Home-Based Programmes

Community programmes offer both informal and formal strategies to support those who are food insecure. Informal approaches include seeking support from friends and family, who may provide food or money to address food insecurity. On the other hand, formal systems are more structured, and typically involve food banks or pantries, as discussed above.49 These community programmes operate at a local level, employing community gardens, meal delivery services, and the distribution of food, or grocery gift cards. While local community food pantries rely on volunteers and donations to provide necessary food, and programmes for those in the community that are in need, they differ from the on-site food banks, where patients receive the food directly within the clinic, eliminating the need for an extra trip. The primary difference between these two approaches lies in their operational structure and target population.

Community pantries focus on serving the broader community, while on-site food banks

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within clinics primarily serve the nutritional needs of patients who are already accessing healthcare services.

Home-based programmes vary, and include home-delivered tailored meals. These meals are fully prepared, nutritionally tailored, and generally healthy for individuals living with advanced and costly diet-sensitive illnesses.

One study shows that such meals can prevent approximately 1.6 million hospitalisations, and save up to 13.6 billion USD in costs annually.50 One randomised controlled trial, which included patients with metastatic lung and non-colorectal gastrointestinal cancers, demonstrated improved nutrition, independence, and reduced fatigue.51 Community gardens are also another approach associated with improved health and wellbeing.

These gardens are open spaces where community members can collectively cultivate plants or flowers. While the evidence supporting community gardens is limited,52 there are some studies showing associated cancer risk reduction,53 and increased intake of fruits and vegetables among people with cancer.54 To date, there are no studies that evaluate the impact of community gardens on food insecurity among patients with cancer, however.

Food or grocery vouchers are also important interventions, and are designed to support patients by providing additional funds for their food budget.49 This may include debit cards that patients receive, with a prespecified amount of money, which are specifically created for the programme. These programmes are associated with higher levels of fruit and vegetable consumption among patients with cancer than the national average.55 These are also shown to increase the amount of household budget spent on healthy food items, and reduce the amount that patients with cancer spend on sweetened beverages and unhealthy foods.55 In addition, food vouchers have been shown to increase treatment completion rate among underserved patients with cancer,56 which may indirectly lead to improved survival, and decreased recurrence risk.

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Federal Nutrition Programmes

Various federal agencies run Federal Nutrition Programs (FNP), which aim to provide nutritious food to low-income individuals and their families, pregnant people, infants, and children. To date, the government of the USA has implemented 16 FNPs to help address the growing problem of food costs, and help to stretch food budgets.57 The Supplemental Nutrition Assistance Program (SNAP), operated by the U.S. Department of Agriculture, and the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), are two of the largest federallyfunded programmes that address food insecurity among low-income households.

The SNAP programme, formerly known as food stamps, is the largest FNP in the USA that helps with food costs among low-income families, including those with children, seniors, and people with disabilities. SNAP improves food access and reduces food insecurity by 30%,58,59 and is associated with decreased poverty among eligible low-income households, and improved health outcomes.49 To qualify for the programme, individuals must meet three requirements: a gross monthly household income that is below 130% of the poverty line, a net household income below the poverty line, and a household asset limit.60 Populations not meeting these criteria, and undocumented migrants, are not eligible for such programmes. In the state of California, such programmes were also ineligible for people who were receiving Supplemental Security Income (SSI) benefits, until policy changes in June 2019, which expanded the programme among these populations as well.61 The WIC programme is another federally-funded programme. WIC is a short-term federal grant intervention programme for states, which aims to provide supplemental foods, healthcare referrals, and nutrition education to low-income females who are pregnant and postpartum, infants, and children up to age 5 years, who are at nutritional risk. To qualify for the programmes, applicants must have an annual household income below 185% of the USA’s poverty income guidelines, or be enrolled in the Temporary Assistance for Needy Families (TANF), SNAP, or Medicaid.62 Unlike SNAP, undocumented migrants are eligible for WIC benefits. Such programmes are associated with improvements in health outcomes, including longer pregnancies, fewer

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premature births, lower incidence of moderately low and very low birthweight infants, fewer infant deaths, and a greater likelihood of receiving prenatal care.63,64 Although FNPs like SNAP and WIC provide assistance to low-income individuals and families, they may not provide the nutritional support that many patients with cancer may need, and often do not meet the needs of underserved, immigrant, and limited Englishproficient populations.43 Specifically, among patients with cancer who received SNAP benefits, 70% remained food insecure, and stayed at significant risk for the negativeassociated outcomes of food insecurity.65 Furthermore, these programmes do not comprehensively address food insecurity, as many patients with cancer may be above the income eligibility cutoff, or cannot meet other criteria, such as immigration status eligibility.

Such deficits are important to recognise, as food insecurity is often concentrated in minority and immigrant populations. Thus, programmes aiming to address food insecurity should comprehensively address the needs of patients with cancer and their households, who are most at risk for burden.

CHALLENGES AND FUTURE DIRECTIONS Over the past decade, there has been much more attention on the growing problem of food insecurity, and the unique nutritional requirements of patients with cancer.7 Yet, gaps remain regarding interventions and their feasibility, accessibility, and effectiveness, that can overcome this critical problem. Currently, there are 106 clinical trials registered in the International Clinical Trials Registry Platform (ICTRP) for the term “food insecurity,” and 125 in the National Clinical Trials (NCT) registry.

Nonetheless, when searching for trials related to both food insecurity and cancer, the numbers significantly drop to four on the ICTRP, and two on the NCT registry.

Adolescents and young adults (AYA; 15–39 years), a subset of survivors of cancer, face distinctive challenges, which are less characterised. Although AYA populations are often grouped with either children or adults, AYA

populations face quite distinct developmental, psychosocial, and pathophysiological differences.66 These include the long-term effects of anticancer treatments, such as cardiovascular and bone diseases, and altered taste perceptions, leading to nutritional deficiencies. Such populations need further research to understand and overcome their specific needs.

The limited number of intervention trials indicates the first major challenge: a gap in our understanding of food insecurity’s impact on cancer care, and how to best address it. Most of the existing literature on food insecurity in patients with cancer, and survivors of cancer, is based on observational studies that aim to describe its prevalence and risk factors.67 Although the existing evidence is valuable, this limited view of the problem, which is often focused on an individual’s immediate needs, and not on the broader social determinants that are the root causes of the problem, provides shortterm relief, and perpetuates this growing issue.

Multiple challenges arise when addressing food insecurity, as the solutions often require multilevel interventions, ranging from immediate food assistance programs to broad policy interventions that aim at systemic change. Such broader interventions must involve and address the non-medical, social, and economic factors that influence health and outcomes.29 These include addressing community-wide conditions, addressing systemic racism, and addressing policies that can sustain interventions, rather than focusing on the immediate social needs of the individual, such as providing transportation, food, or housing. Given that emergency food resources only provide immediate relief for 29% of households in the USA which are suffering from food insecurity, interventions must address the root causes of food insecurity and poverty to eliminate this issue. Hence, systemic changes are required to ensure long-term solutions.43 Specifically, as related to patients with cancer, addressing food insecurity requires support throughout stages of treatment.16 First, awareness and screening of food insecurity is a fundamental first step in addressing this problem.

To date, few oncology clinics have embedded Registered Dietitian Nutritionists, and even among those that do, few clinicians ask patients

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with cancer about their ability to afford or obtain food. This is despite the growing recognition that food insecurity can impact patient outcomes.68 Targeted education and training to improve the screening and management of food insecurity is the first step in addressing such problems.

Programmes such as the World Cancer Research Fund (WCRF), the American Institute for Cancer Research (AICR), and the Continuous Update Project (CUP) offer key resources. The AICR provides tools for dietary needs and health, while the CUP shares updated research on nutrition’s impact on cancer. Second, collaborations across multilevels should engage patients, caregivers, clinicians, community-based organisations, patient advocacy groups, policymakers, and other researchers, to invest in the codevelopment of both immediate interventions and long-term systemic changes at a community level. While the impact of these efforts may not be immediately evident, they are essential to promoting sustainable health improvement, and reducing food insecurity in the long term.69 Finally, rigorous research to evaluate the impact of interventions on food insecurity among patients with cancer is needed to demonstrate the clinical benefit, and the return on investment to support policy implications. This research should entail more randomised controlled trials investigating the effectiveness, and should align household, community, and policy-level interventions to comprehensively tackle food insecurity.49

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CONCLUSION The complex and unexplored relationship between food insecurity and adverse cancer outcomes, particularly among low-income and minority populations, demands a multifaceted approach that extends beyond merely providing food to patients with cancer. Interventions must address the more profound social and economic causes, including systemic issues of racism and poverty. In high-income countries, collaborations between hospitals and on-site food distribution programmes could be enhanced, and widely adopted. In contrast, in low- and middle-income countries, where infrastructure and resources may be limited, non-governmental organisations can play a vital role by providing food aid and educational resources, and bridging the gap between patients and available government programmes. To mitigate food insecurity, comprehensive, multilevel collaborations encompassing patient and clinician education, broader policy interventions, and rigorous research are needed to ensure immediate relief, but with long-term, sustainable, and systemic changes. Incorporating screening for food and nutrition insecurity can significantly improve patient outcomes. Early identification of these health-related social needs will allow for timely interventions that can improve patient outcomes.

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Case Report

The Role of Radical Radiotherapy in Sinonasal Myopericytoma: A Case Report and Literature Overview Authors:

Anna Merlotti,1 *Stefania Martini,1 Riccardo Vigna Taglianti,1 Alessia Reali,2 Giuseppe Signorini,3 Silvana Parisi,4 Francesca De Felice5 1. Department of Radiation Oncology, S. Croce and Carle Teaching Hospital, Cuneo, Italy 2. Department of Radiation Oncology, Michele and Pietro Ferrero Hospital, Verduno, Italy 3. Department of Maxillo-Facial and Plastic Reconstructive Surgery, E.O. Ospedali Galliera, Genoa, Italy 4. Department of Biomedical, Dental Science and Morphological and Functional Images, Radiation Oncology Unit, University of Messina, Italy 5. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Italy *Correspondence to martini.st@ospedale.cuneo.it

Disclosure:

The authors have declared no conflicts of interest. Written informed consent of the patient to use the data was obtained.

Received:

18.02.22

Accepted:

18.11.22

Keywords:

Haemangiopericytoma, head and neck region, maxillary sinus, myopericytoma (MPC), paranasal sinus, radiation therapy, radical radiotherapy, radiotherapy.

Citation:

EMJ Oncology. 2023; DOI/10.33590/emjoncol/10049168. https://doi.org/10.33590/emjoncol/10049168.

Abstract Myopericytoma (previously defined haemangiopericytoma) is a rare vascular tumour originating from extracapillary cells called pericytes and rarely occurs in paranasal sinuses. Surgical wide resection is the treatment of choice. Postoperative radiotherapy is usually used in the case of incomplete resection. The current study reports a case of a 38-year-old male with an extended maxillary sinus myopericytoma, who developed an early bulky recurrence 3 months after surgical excision. The relapse was treated using salvage radiation therapy with radical purpose. Radiotherapy was completed 52 months ago, at the time of writing, and the patient is alive and disease-free. Although literature data report radioresistance as an important obstacle for management of this tumour, it could be important to start considering myopericytoma as a heterogeneous entity, with different underlying molecular mechanisms, growth kinetics, and response to treatments.

High-dose ‘modern radiotherapy’ with radical purpose represents a reliable treatment strategy in cases with no surgical option. Furthermore, given the paucity of data available in the literature regarding this clinical setting, the authors conducted an overview on the topic.

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Key Points 1. Sinonasal myopericytoma is an uncommon neoplasm derived from pericytes surrounding the blood vessels and, due to its rarity, there are no standardised treatments.

2. Clinical data regarding the use of definitive radiotherapy as primary treatment modality in sinonasal myopericytoma are scarce.

3. High-dose definitive radiotherapy using a modern technique should be considered for sinonasal myopericytoma cases where the tumours are unresectable or the patient is unfit for surgery.

INTRODUCTION Myopericytoma (MPC) is a term used to describe a continuum of mesenchymal tumours with elevated cellularity found in bone and soft tissue. Previously called haemangiopericytoma, MPC is an uncommon neoplasm derived from pericytes surrounding the blood vessels and rarely arises in the nasal cavity and paranasal sinuses, accounting <0.5% of all neoplasms.1 MPC has been reported at all ages, but there appears to be an incidence peak in the fifth and sixth decades of life. Spontaneous or induced bleeding and nasal obstruction are the main complaints in MPC of the nose and paranasal sinuses. Pain can occur when lesions invade surrounding tissues or are confined in unyielding spaces such as the paranasal sinuses. MPC typically presents as a slow-growing, solitary mass exhibiting low malignant potential. Although many reports describe this tumour as indolent, its potential for local invasion and destruction of adjacent structures as well as for metastatic spread has been reported.2 Aggressive behaviour predictors include tumour size of >5 cm, bone invasion, profound nuclear pleomorphism, increased mitotic activity (>4/10 high power fields), presence of immature tumour cells, necrosis, foci of haemorrhage, and a proliferation index of >10%.1 However, relapse and metastases can occur even in cases of more favourable histological appearances.3 Scientific literature on sinonasal MPC is scant, and it consists primarily of small case series and case reports. Due to its rarity, there are no standardised treatments. Radical surgery (performing en bloc resection with wide margins) is considered the standard of care.2,4 Pre-operative embolisation is often employed to reduce intra-operative blood loss. Adjuvant

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treatment remains largely empiric. Because there is a risk of relapse of up to 30% after surgery, some chemotherapy regimens, including anthracycline and ifosfamide agents, as well as post-operative radiotherapy (RT) have been proposed.5 Traditionally, MPC is considered intrinsically resistant to systemic therapy and with low radiosensitivity. However, several adverse features such as high mitotic activity, high proliferation index, and rich vascularisation could potentially overcome its radioresistence.

In this context, the role of definitive RT as primary modality remains unclear. Definitive RT has been explored in a small number of sinonasal MPC cases, but outdated RT techniques and improper low total doses were used.4 Probably, ‘modern RT’ can play a role in this oncological scenario, assuring higher lethal dose to the target volume, meanwhile preserving surrounding normal tissues.

In this article, the authors report a case of bulky recurrent MPC in the left maxillary sinus successfully treated with radical RT and review the limited literature on the role of primary RT in sinonasal MPC management. The workflow included literature research of all index reports written in English. The search was based on the following combination of keywords: “haemangiopericytoma,” “myopericytoma,” “paranasal sinus,” “maxillary,” “head and neck region,” and “radiotherapy.” The last search data was 14th January 2022.

CASE DESCRIPTION A 38-year-old male was evaluated due to a 3-month history of post-traumatic left maxillary haematoma and oral bleeding. The

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patient presented significant volume increase on the left maxillary bone region, with painful sensibility when palpated. A CT scan showed a left maxillary necrotic mass with erosion of all the bony walls of the sinus. The infiltrative mass anteriorly eroded the anterior wall of the maxillary sinus, occupying the buccal space with the swelling of the subcutaneous soft tissues and the thickening of the buccinator muscle.

Below, it eroded the alveolar process with an extrinsication in the soft palate; posteriorly, it infiltrated the medial pterygoid muscle, reaching the parapharyngeal mucosa; laterally, it infiltrated the retromaxillary adipose tissue; and superiorly, it involved the pterygopalatine fossa.

As a part of the staging procedure, an incisional oral biopsy was performed. Histological analysis revealed a sinonasal haemangiopericytoma-like tumour/MPC. Microscopic examination showed an inhomogeneous cell density consisting of spindle and oval elements with a hyperdense nucleus. The neoformation was characterised by a rich vascular network of various calibre, myopericytomatosis/haemangiopercytomasis (cluster of differentiation 31-positive and cluster of differentiation 34-positive), mitotic index of 28x10 high-power field, and a Ki-67 proliferation index of 30%. Functional imaging carried out with 18-fluoro-2-deoxy-glucose PET scans confirmed the left maxillary cancer and excluded nodal or distant metastases.

To control intra-operative tumour bleeding, the patient underwent pre-surgical endovascular embolisation of left external carotid artery terminal branches. A left orbital-maxillary resection surgery was performed, with plastic reconstruction by left fibula flap, and a custom-made plate orbital grid in titanium.

The histological examination of surgical specimen confirmed the finding of the biopsy.

Microscopically positive margins were found (the neoplasm reached the margins of the maxillary tuberosity, the pterygoid muscle, and the resection margin of the nasal flap). In the immediate post-operative period, blood transfusions were required. The patient was afebrile, and the vital signs were normal and stable during the entire postsurgical phase.

A control CT scan 2 months after surgery showed a mass occupying the masticatory space, with longitudinal extension from the

pterygoid processes to a plane passing through the uvula, with peripheral contrast enhancement and hypodense content. On physical examination, a trismus (interincisal distance at a maximum mouth opening was 10 mm) and an oral ulcer located in the hard palate were found. The patient was referred to the authors’ department (the Department of Radiation Oncology, S. Croce and Carle Teaching Hospital, Cuneo, Italy) 3 months after surgery. A repeat CT scan, performed 4 months after the initial CT scan, documented a bulky recurrence of the disease that occupied the entire maxillary sinus and emerged in the oral cavity (70 mm diameter [Figure 1A]). Due to the complexity of a new surgical procedure, and the patient’s desire, a RT treatment was proposed. The patient had a CT simulation procedure in a supine position and was immobilised with thermoplastic mask. The simulation non-contrast CT scan was performed with 3 mm slice thickness axial images acquired from the vertex to the jugular notch.

An isocentre was determined within the left maxillary lesion and marked on the mask under laser guidance for daily set-up. Using a dedicated tool, diagnostic images were fused to the simulation non-contrast simulation CT scan to help delineate target volume and organs at risk. Gross tumour volume was comprised of macroscopic disease, and it was defined based on diagnostic CT information. Gross tumour volume was expanded isotropically by 5 mm to obtain subsequent clinical target volume (CTV).

The latter was optimised to include flaps and reconstructive plates, and to avoid organs at risk.

The planning target volume (PTV) was defined by 3 mm isotropic expansion around CTV. The prescribed dose to the disease was 67.5 Gy/30 fractions. RT was administrated daily, on 5 consecutive days per week. To reduce the dose to critical structures, an intensity-modulated RT with volumetric-modulated arc therapy approach was performed. Dose-volume constraints for normal tissues and PTV dose coverage were reported in Table 1.

To verify daily set-up and inter-fraction organ motion, image-guided RT was employed, with an automatic matching of cone-beam CT images acquired prior to each fraction delivery and reference planning CT (Figure 2). The treatment was delivered on a TrueBeam machine (Varian Medical Systems, Palo Alto, California, USA),

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Figure 1: A) Contrast-enhanced CT scan of bulky recurrence of myopericytoma that occupied the entire maxillary sinus and emerged in the oral cavity; and B) contrast-enhanced CT scan after 3 months from the end of radiotherapy, showing the absence of disease.

A

B

using a multi-leaf collimator with 60 leave pairs.

The patient experienced acute Grade (G) 2 skin toxicity and G1 oral mucositis, according to the Common Terminology Criteria for Adverse Events, version 5 classification.6 During follow-up, a CT scan acquired at 1 month after the end of RT showed a residual tissue without contrast enhancement. The next CT scan 3 months after the end of the treatment confirmed the absence of disease (Figure 1B). The tissue defect, caused by the disease response, formed a fistula between the oral cavity and maxillary sinus. It was not possible to treat the fistula by the placement of an obturator prosthesis due to the pre-existing trismus, which further worsened after RT (the interincisal distance was 3 mm). Residual left maxillary region alterations were treated with lipofilling procedures with aesthetic purposes. Long-term toxicities, identified 5 years after the end of radiotherapy, were trismus G3, dysgeusia G2, dysphagia G2, dry mouth G1, skin induration G2

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(according to the Common Terminology Criteria for Adverse Events, version 5 classification).6 Currently, patient is disease-free; however, their quality of speech is reduced. Through the extraction of some teeth (teeth numbered 23, 24, 25, 33, and 34 were removed), soft oral feeding is allowed. The skin above the titanium plates remains thin but trophic.

DISCUSSION In the case presented by the authors, the patient with bulky recurrent sinonasal MPC achieved a persistent complete response after definitive RT. The patient is still alive and recurrence-free 54 months from the start of treatment. Overall, RT was well tolerated, with high compliance and mild sequelae. Given the speed of growth, a moderately hypo-fractionated RT schedule was chosen, employing 2.25 Gy per fraction to a total dose of 67.5 Gy. The treatment

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Table 1: Dose-volume constraints for normal tissues and planning target volume dose coverage.

Temporal lobe

D max: <68 Gy, 1 cc <58 Gy

Normal brain

Whole organ D max: 60 Gy

Brainstem

Whole organ D max: <54 Gy

Chiasm, optic nerve

Whole organ D max: <55 Gy

Lens

D max: <7–10 Gy

Retina

D max: <45 Gy

Eyeball

D mean: ≤35 Gy

Pituitary

D max: <50 Gy

Spinal cord

Partial organ D max: <50 Gy

Cochlea

Whole organ D mean: ≤45 Gy

Parotid

Bilateral whole parotid glands D mean: <25 Gy Unilateral whole parotid gland, contra, D mean: <20 Gy

Oral cavity

Uninvolved D mean: <40 Gy D max: <55 Gy

Mandible

D max: <65 Gy V55: <20% D mean: ≤60–63 Gy D 1%: ≤70 Gy

Temporomandibular joint

D 1%: ≤70 Gy D mean: ≤60–63 Gy

Pharynx

Whole organ D mean: <50 Gy

Larynx

Whole organ V50: <27% Partial organ D mean: <44 Gy

Thyroid

V45: <50% V30: <50%

Oesophagus

Whole organ D mean: <34 Gy Whole organ V35: <50% Whole organ V50: <40% Whole organ V70: <20% D max: <45 Gy

PTV

≥95% of the PTV should receive at least of 95% of the prescription D ≤2% of the PTV should not exceed of 107% of the prescription D

D: dose; max: maximum; PTV: planning target volume; V: volume

volume included the relapse site, flaps, and reconstructive plates. For the complexity of the volume and the proximity to some critical structures (orbit, optic nerve, temporomandibular joint, masticatory space, and skull base), an intensity-modulated RT-image-guided RT technique was chosen to minimise the CTV-PTV expansion margins at 3 mm.

Clinical data regarding the use of definitive RT as primary treatment modality in sinonasal MPC are scarce. A comprehensive and evidencebased analysis is difficult. In fact, to the best of the authors’ knowledge, only one other case of MPC was successfully treated in recent years with primary RT and has been described in the literature.7 In that clinical case, a 78-yearold female presented with an enlarged MPC in the soft palate. The patient refused surgical

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Figure 2: Intensity modulated radiotherapy planning of sinonasal myopericytoma.

approach and, thus, RT was proposed. A total dose of 66 Gy in daily fractions of 2 Gy was prescribed. A remarkable tumour regression was recorded and there was no sign of tumour growth 4 months after treatment.

While the role of primary RT is pending, several studies addressed the role of adjuvant RT.2,810 For sure, surgery with wide margins is the standard of care for patients with MPC. A systematic review of individual cases of sinonasal MPC, including 97 articles published between 1950–2009, pointed out a complete excision is essential to minimise tumour recurrence, and RT may increase the diseasefree survival and decrease the rate of recurrence when complete resection is not possible.2 Recently, a retrospective study investigated the role of RT to reduce the risk of recurrence after surgery in the framework of the Rare Cancer Network (RCN), in a cohort of patients diagnosed with extracranial MPC. The median RT dose was 60.0 Gy (range: 45.0–68.4 Gy) in 1.6–2.2 Gy fractions. An improvement of prognosis in terms of local control rates and disease-free survival was observed, especially in patients with extremities/superficial trunk tumour locations.9 Lastly, a multi-institutional retrospective study (KROG 18-11) evaluated the role of postoperative RT in 133 patients with histologically confirmed

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intracranial solitary fibrous tumours/MPC.10 The study supported the role of post-operative RT in disease control of intracranial MPC, irrespective of the surgical extent and G. For local control, post-operative RT needs to enclose the residual tumour or surgical cavity with sufficient margin for the target volume.

On the other hand, registry analysis and retrospective series supported the absence of clinical benefit of adjuvant RT in patients with MPS. A Surveillance, Epidemiology, and End Results (SEER) registry population-based analysis of 1,243 patients with MPC, treated from 1975–2016, highlighted that surgery remains the standard of care to assure significant overall survival and cancer-free survival rates.11 Surgery plus adjuvant RT had a similar survival effect compared with surgery alone (overall survival: p=0.900; cancer-free survival: p=0.156).

Likewise, a systematic review of sinonasal MPC management (128 cases collected from 56 articles, consisting of case reports and series) confirmed surgical excision as mainstay of treatment, limiting the role of RT both in primary and adjuvant setting.8 In their meta-analysis of 116 primary head and neck MPC cases, Wushou et al.12 confirmed that surgery plus adjuvant RT was not superior to surgery alone, and concluded that surgical resection should

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be the first step in MPC management. It is tempting to consider that RT has a marginal role, but important limitations may have led to underestimations in the clinical efficacy of RT. All studies are retrospective and the lack of tumourand RT-related details such as body site of origin and RT protocols and technique, which may produce inconsistent conclusions.

At this point, classification of MPC radiosensitivity remains the principal question.

Although it is traditionally believed that MPC is resistant to ionising radiation, its radiosensitivity has been somewhat controversial. Several reports have shown the presence of tumour features that may confer sensitive response to radiation. High cellular metabolism, rapid cellular growth, and increased or unstable vascularity are recognised predictors of a good response to radiation; however, other factors such as the presence of necrosis and host immune responses are not.13 At present, there are no known biomarkers predictive of radiosensitivity.

A dose-response relationship has been reported for MPC in older series.4,14 Mira et al.4 published a study with the purpose to analyse the response of MPC to RT in 11 patients with MPC treated

References 1.

Thompson LDR et al, “Borderline and low malignant potential tumours of soft tissues,” Barnes L et al. (eds), Pathology and Genetics of Head and Neck Tumours, WHO Classification of Tumours (2005) 3rd Edition, Volume 9, Lyon: IARC Press, pp.44.

2.

Duval M et al. Systematic review of treatment and prognosis of sinonasal hemangiopericytoma.

Head Neck. 2013;35(8):1205-10.

3.

Thompson LDR et al. Sinonasaltype hemangiopericytoma: a clinicopathologic and immunophenotypic analysis of 104 cases showing perivascular myoid differentiation. Am J Surg Pathol.

2003;27(6):737-49.

4.

5.

Mira JG et al. The role of radiotherapy in the management of malignant hemangiopericytoma: report of eleven new cases and review of the literature. Cancer.

1977;39(3):1254-9.

Delgado M et al. Anti-

at Memorial Hospital (Memorial Sloan-Kettering Cancer Center [MSKCC], New York City, New York, USA). Dose and tumour size were found to be the main factors influencing response.4 This was consistent with a report by Staples et al.14 who showed that a total dose greater than 55 Gy improved local control in patients with MPC. Overall, literature data are extremely poor to provide any firm recommendation. In the absence of robust evidence and guidelines, each MPC case should be discussed in a multidisciplinary tumour board. High-dose definitive RT should be considered for those sinonasal MPC cases unresectable or unfit for surgery.

CONCLUSION The role of definitive RT in sinonasal MPC remains largely unknown. This case report clearly indicates the value of high-dose definitive RT using modern technique in the management of patients with MPC. The authors suggest a multiinstitutional registry for this rare entity to help guide treatment.

angiogenic treatment (sunitinib) for disseminated malignant haemangiopericytoma: a case study and review of the literature.

Case Rep Onc. 2011;4(1):55-9.

6.

U.S. Department of Health and Human Services (HHS); National Institutes of Health (NIH); National Cancer Institute (NCI). Common terminology criteria for adverse events (CTCAE). Version 5.0.

2017. Available at: https://ctep. cancer.gov/protocoldevelopment/ electronic_applications/docs/ ctcae_v5_quick_reference_5x7.pdf.

Last accessed: 3 December 2022.

7.

Hiraumi H et al. Radiosensitive hemangiopericytoma in the soft palate. Auris Nasus Laryn.

2002;29:95-7.

8.

Dahodwala MQ et al. Management of sinonasal hemangiopericytomas: a systematic review. Int Forum Allergy Rhinol. 2013;3(7):581-7.

9.

Krengli M et al. Radiotherapy in the treatment of extracranial hemangiopericytoma/solitary fibrous tumor: study from the Rare

Cancer Network. Radiother Oncol.

2020;144:114-20.

10. Lee JH et al. The role of postoperative radiotherapy in intracranial solitary fibrous tumor/ hemangiopericytoma: a multiinstitutional retrospective study (KROG 18-11). Cancer Res Treat.

2022;54(1):65-74.

11. Wang K. Hemangiopericytoma: incidence, treatment, and prognosis analysis based on SEER database. Biomed Res Int. 2020:2468320.

12. Wushou A et al. Treatment outcome and prognostic factors of head and neck hemangiopericytoma: meta-analysis. Head Neck.

2015;37(11):1685-90.

13. Ewing J. Radiosensitivity.

Radiology. 1929;13(4):313-8.

14. Staples JJ et al.

Hemangiopericytoma -- the role of radiotherapy. Int J Radiat Oncol Biol Phys. 1990;19(2):445-51.

FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Synergistic Immune-Mediated Anti-tumour Effect of Dostarlimab and Radiotherapy in the Management of MSI-H/dMMR Endometrial Cancer: A Case Report Authors:

Giuseppa Scandurra,1 *Valentina Lombardo,1 Francesco Marletta,2 Giulia Marletta,3 Emanuele Buffettino,3 Milena Tomaselli,3 Placido Lanza,3 Gabriele Corsale,4 Giacomo Calcara,5 Domenico Patanè,5 Paolo Scollo,6 Basilio Pecorino6,7 1. U.O.C. Oncologia Medica, Azienda Ospedaliera per l’Emergenza Cannizzaro, Catania, Italy 2. U.O.C. Radioterapia, Azienda Ospedaliera per l’Emergenza Cannizzaro, Catania, Italy 3. Scuola di Specializzazione in Radioterapia, Università degli Studi di Messina, Italy 4. U.O.C. Neuroradiologia, Azienda Ospedaliera per l’Emergenza Cannizzaro, Catania, Italy 5. U.O.C di Diagnostica per Immagini, Azienda Ospedaliera per l’Emergenza Cannizzaro, Catania, Italy 6. U.O.C. Ginecologia ed Ostetricia, Azienda Ospedaliera per l’Emergenza Cannizzaro, Catania, Italy 7. Università degli Studi di Enna “Kore”, Enna, Italy *Correspondence to lombardovalentina89@gmail.com

Disclosure:

The authors declare no conflicts of interest.

Received:

23.05.23

Accepted:

06.11.23

Keywords:

Anti-programmed death 1 (PD-1), chemotherapy, DNA mismatch repair, dostarlimab, endometrial cancer, immunotherapy, microsatellite instability, next-generation sequencing (NGS), radiotherapy (RT).

Citation:

EMJ Oncol. 2023;11[1]:98-105. DOI/10.33590/emjoncol/10300406. https://doi.org/10.33590/emjoncol/10300406.

Abstract Endometrial carcinoma (EC) is the world’s most common gynaecological malignancy and the fourth most common carcinoma in females. Microsatellite instability high/ mismatch repair deficient (MSI-H/dMMR) EC is the most represented EC subtype and is strongly associated with higher expression of anti-programmed death 1 (PD-1) receptor levels, potentially making these tumours responsive to anti-PD-1 treatment.

This case report describes the screening and treatment strategies of a 67-year-old female diagnosed with EC, which was initially treated with adjuvant therapy with chemotherapy and radiotherapy (RT). However, after the emergence of a secondary tumour lesion in the brain and other secondary body lesions, the patient started dostarlimab therapy (an anti-PD-1 monoclonal antibody) combined with RT, to evaluate a possible synergistic immune-mediated anti-tumour effect. After 5 months

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of therapy, the instrumental follow-up showed a complete brain lesion response, and 5 months later, a partial response of the body lesions too.

In conclusion, this case report outcome supports the combination of RT and immunotherapy to control and manage MSI-H/dMMR ECs.

Key Points 1. This article highlights the synergistic effect of the use of immunotherapy treatment and radiotherapy. The use of this combined treatment could improve the outcome of patients affected by endometrial cancer.

2. The authors highlight how the combination of radiotherapy and immunotherapy could lead to a better management of microsatellite instability high/mismatch repair deficient endometrial cancers, and how this combination could lead to a benefit even for areas distant from the irradiated site.

3. The co-operation of different physicians who collaborate in a multidisciplinary way is increasingly important for optimal management of the patient.

INTRODUCTION Endometrial carcinoma (EC) is the world’s most common gynaecological malignancy, with a global incidence of 382,069 new cases and 89,929 deaths in 2018,1,2 expected to increase due to ageing and rising obesity.3 Post-menopausal females over 68 years are most likely to be affected by EC. Generally, most ECs are diagnosed at a localised stage, with a 5-year overall survival of 80%. In contrast, for advanced disease with lymph node invasion or metastasis, the 5-year overall survival is only 50% and 20%, respectively.2 Most patients are diagnosed at an early stage,2 so EC is generally treated with surgery with or without adjuvant therapy (radiotherapy [RT], chemotherapy) with successful results.1,2 The first-line standard treatment option for patients with advanced or recurrent EC is limited to platinum-based chemotherapy, while no secondline standard therapy is available due to patient comorbidity or performance status after first-line therapy failure.2 While conventional pathologic analysis remains crucial to EC stratification, a diagnostic algorithm using three immunohistochemical markers (p53, MSH6, and PMS2) and a molecular test (exonuclease domain mutation analysis of POLE)

have also been applied to identify different prognostic groups.3 Molecularly, EC can now be classified into four prognostically relevant EC classes based on the type of mutations and somatic copy number variations, genomic characterisation, and microsatellite instability (MSI) assay, including: ultramutated cases with POLE mutations; EC cases associated with MSI status (caused by a defective DNA mismatch repair [dMMR], representing 25–30% of EC cases);2 copy number low; and copy number high.4 The POLE ultramutated and the copy number low subgroups have an excellent and good prognosis, respectively. Compared to the POLE subgroup, the prognosis is intermediate in the MSI/dMMR subgroup, while the copy number high subgroup has the worst prognosis, characterised by p53 abnormalities with a high number of somatic alterations.4 This molecular classification offers the possibility to improve the risk stratification and management of EC cases.

In MSI-H/dMMR EC, DNA replication anomalies are no longer corrected by MLH1, MSH2, MSH6, and PMS2 proteins, and this is associated with the expression of higher levels of programmed death 1 (PD-1) receptor, which potentially makes these tumours responsive to anti-PD-1 treatment.5 Indeed, among gynaecological cancers, EC highlights the greatest

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overexpression of PD-1 and its programmed death-ligand 1 (PD-L1).2 Dostarlimab is an anti-PD-1 monoclonal antibody that inhibits PD-1 receptor binding to PD-L1 and PD-L2, and has demonstrated durable antitumour activity in several tumours, including MSI-H/dMMR EC, colorectal cancer, and nonsmall cell lung cancer. Given its efficacy and safety profile, dostarlimab is approved as monotherapy in patients with MSI-H/ dMMR previously treated with a platinum-containing regimen.2,5 Moreover, accumulating evidence indicates that chemotherapy, RT, and other immunomodulators could synergise anti-PD-1/PD-L1 treatment by enhancing cancer antigen release, APC function, or effector activity; thus, a combined strategy is deemed as a rational and feasible approach to achieve optimal treatment effects.6 In this case report, dostarlimab therapy was suggested in a 67-year-old female diagnosed with EC to be started in combination with RT, to evaluate a synergistic immune-mediated antitumour effect.

METHOD This manuscript has been prepared according to CAse REport (CARE) guidelines. Written consent was obtained from the patient to publish this case report.

CASE REPORT At the time of presentation, due to the occurrence of metrorrhagia, a 67-year-old female underwent several diagnostic tests that led to an interventional hysteroscopy procedure at the Obstetrics and Gynecology Unit of Cannizzaro Hospital, Catania, Italy. The histological examination of a lesion tissue sample showed the presence of a widely necrotic adenocarcinoma with poor differentiation, mostly consistent with endometrioid histotype. The patient was then hospitalised, and an abdomen CT scan revealed a heterologous lesion in the uterus and nodular lesions in the left adrenal gland and the right lateroconal fascia. Centimetre- and sub-centimetre-sized lymph nodes were also

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observed in the interportal-caval site, lumboaortic site, mesenteric adipose tissue, and iliac and bilateral femoral-inguinal regions.

Two months later, a longitudinal puboumbilical laparotomy, total hysterectomy with bilateral adnexectomy, and systematic pelvic lymphadenectomy were performed because of the emergence of a tumour diagnosed as a poorly differentiated endometrioid adenocarcinoma (G3) of the endometrium, with a solid growth pattern and areas of necrosis (FIGO Stage IIIC G3 V1).

Based on a multidisciplinary discussion and literature guidelines,3,7 the patient was recommended to start adjuvant therapy with chemotherapy and RT, in sequence. After the second cycle of chemotherapy with carboplatin and taxol, the treatment was discontinued due to the emergence of a scalp neoformation. The lesion was surgically removed, and the histology showed a gynaecological origin. A cranial MRI showed bone infiltration and contact of the lesion with the dura mater. A CT scan revealed the presence of a secondary tumour lesion in the brain (Figure 1) and several other places.

Six months after initial presentation, the patient underwent RT on the left temporal-parietal lesion with a dosage of 42Gy (6Gy/Fx), and the evaluation of the MSI was initiated through two parallel methods.

The first method (PCR-MSI evaluation) required: the use of DNA extracted from both the paraffin-embedded tumour and the patient’s normal tissue; the amplification of microsatellite (STR) sequences belonging to the Bethesda panel, consisting of two mononucleotide loci (BAT-25 and BAT-26) and three dinucleotide loci (D5S346, D2S123, and D17S250); and an electrophoretic run on the QIAxcel system (Qiagen, Venlo, the Netherlands). This method showed no evidence of STR length alterations on the STRs analysed. The second method (next-generation sequencing [NGS]MSI evaluation) consisted of testing a somatic oncology multigene panel to evaluate splicing variants, insertions and deletions, and single nucleotide variants by circulating free DNA extraction. In addition, through liquid biopsy, 486 genes and nine loci MSI (BAT40(T)37, MONO-27(T)27, BAT26(A)27,

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Figure 1: Cranial CT scans on brain metastasis before treatment.

NR24(T)23, BAT25(T)25, NR22(T)21, HSP110T17(T)17, NR21(A)21, BAT34C4(A)18) were analysed with the NextSeq 550 platform (Illumina, San Diego, California, USA). An instability emerged at the loci MONO-27(T)27, BAT26(A)27, NR24(T)23, BAT25(T)25, NR22(T)21, and HSP110-T17(T)17, resulting in MSI-H. Other uncertain variants were also detected in some of the analysed genes, and a tumour mutational burden (TMB) with an intermediate mutational load (12.90 muts/Mb).

Subsequently, immunohistochemical analysis was performed to assess the mismatch repair (MMR) protein functional status, detecting diffuse nuclear positivity for MSH2 and MSH6 and negativity for MLH1 and PMS2, respectively, leading to the definition of unstable immunophenotype.

The patient also performed a CT scan 6 months after initial presentation, showing the presence of several body lesions (Figure 2).

Around the same time, the patient (performance status: 2–3) started dostarlimab therapy at a dose of 500 mg every 3 weeks for four cycles, followed by 1,000 mg every 6 weeks for all subsequent cycles until tumour progression or severe adverse events occurrence. The instrumental follow-up scheduled 1 year after initial presentation revealed a good response pattern to treatment, with a complete brain lesion response (Figure 3). The patient was then recommended to continue the same treatment. The second follow-up, which took place 9 months after the start of dostarlimab therapy, showed a complete brain lesion response, and a partial response of the body lesions. The last follow-up performed 2 years after presentation showed an additional response to the body lesions (Figure 4).

The patient is currently on treatment, in excellent general condition, and with a performance status switched from 2–3 to 1.

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DISCUSSION EC represented the fourth most common carcinoma in females in 2020, with a global incidence of 382,069 new cases and 89,929 deaths in 2018.2 Up to 30% of patients with EC are diagnosed with MSI-H/dMMR EC, in which the loss of one or more MMR proteins expression (MLH1, MSH2, MSH6, and PMS2) due to genetic or epigenetic mutations is associated with accumulated DNA replication errors at STR regions.5 As a screening strategy, this case report highlighted that performing a single test (e.g., PCR alone) when assessing MSI status can lead to false negatives. Therefore, using the latest generation and more accurate methods, such as NGS, is recommended. Several MMR/MSI assessment screening strategies are available, including PCR, immunohistochemistry, or NGS.5

Early-stage EC can be successfully treated by surgery alone, or surgery with RT or adjuvant chemotherapy (generally platinum-based chemotherapy). However, the prognosis for patients with advanced or recurrent EC is poor.

To the authors’ knowledge, there are no accepted consensus-based guidelines for the standard of care after ongoing disease progression, or after a platinumcontaining regimen.5 New innovative therapies are needed for advanced or recurrent ECs that do not respond to the ‘gold standard’ platinum-based chemotherapy. Among them, immunotherapy seems to be the most promising. Biomarkers effective in predicting patients who will benefit from immune checkpoint inhibitors (ICI), regardless of the tumour histology, appear to be PD-L1 expression, MSI, and TMB. In particular, it is generally accepted that a higher number of mutations (i.e., a higher TMB) is associated with

Figure 2: CT scans on different body lesions before treatment.

A

B

C

D

A) Left obturator internal iliac region; B) axial peri-anal region; C) coronal peri-anal region; and D) left adrenal region.

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Figure 3: Cranial CT scans on brain metastasis after treatment.

an improved response of the patient’s immune system to tumour neoantigens.8 Monotherapy with ICIs, such as PD-1 inhibiting monoclonal antibodies (e.g., dostarlimab), aims to minimise the interaction of PD-1 expressed by T lymphocytes with PD-L1 and PD-L2, resulting in the constant negative feedback inhibition, enabling the immune response against cancerous cells.2 Anti-PD-1 and anti-PD-L1 antibodies have been studied in multiple haematologic and solid tumour types in primary and recurrent settings, and have been shown to be well tolerated, with a consistent safety profile.5 In addition to chemotherapy, RT has long been used to treat malignant tumours; approximately 50% of all oncologic patients have undergone RT, both for early-diagnosed and persistent or recurrent tumors.9 Typically, solid tumours respond to clinical ionising radiation through radiation-induced DNA damage, which, in turn, leads to direct tumoural cell death through cell apoptosis, senescence, and autophagy.

However, these cytotoxic effects can also affect leukocytes (lymphopenia following RT), leading to RT being considered an immunosuppressive method. On the other hand, radiation-induced immune system activation has been increasingly observed in recent years, indicating that the antitumour response could also be elicited by RT. In addition, this immune-mediated anti-tumour effect of RT could also benefit the regression of metastasis distant from the irradiated region, and this effect is called the abscopal effect.9 This case report’s outcomes seem to be in agreement with this, as a complete response of the brain metastasis (Figure 3) and partial response of the body lesions (Figure 4) were observed 5 months after RT, performed together with the initiation of dostarlimab therapy. To date, the patient still highlights a good response to the treatment and an excellent general condition, with a performance status of 1.

Since immunotherapy can reduce patient immune tolerance toward the tumour, it is

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Figure 4: CT scans on different body lesions after treatment.

A

B

C

D

A) Left obturator internal iliac region; B) axial peri-anal region; C) coronal peri-anal region; and D) left adrenal region.

possible that combining RT and immunotherapy may amplify the anti-tumour immune response through the occurrence of the abscopal effect.

As has already been previously validated, some combination therapies, including antiPD-1/PD-L1 treatment in combination with chemotherapy, RT, and other ICIs, have greater antitumour efficacies and higher response rates compared to monotherapy.6 These combined approaches simultaneously boost multiple pathways in the cancer-immunity cycle, removing immunosuppressive inputs, and promoting an immune-supportive tumour microenvironment.

This synergistic anti-tumour effect has already been documented in pre-clinical and clinical studies,6,9-11 supporting the combination of RT and immunotherapy for TMB control and management of MSI-H/dMMR EC.

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CONCLUSION EC is the world’s most common gynaecological malignancy, with most patients with EC diagnosed with the MSI-H/dMMR EC subtype, which is strongly associated with the expression of higher PD-1 receptor levels, potentially making these tumours responsive to anti-PD-1 treatment.

In this scenario, the anti-tumour activity of dostarlimab (an anti-PD-1 monoclonal antibody) has been investigated, in combination with RT, in a 67-year-old female diagnosed with MSI-H/ dMMR EC, who presented with a secondary brain tumour lesion, and several other body lesions.

After 5 months of therapy, the instrumental follow-up showed a complete brain lesion response, and 5 months later, it has been possible to also evaluate a partial response of the body lesions.

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The authors suggest that this anti-tumour response could also be enhanced by the immune-mediated anti-tumour effect of RT, which was performed together with the initiation of dostarlimab therapy, and also allowed the

References 1.

Kristeleit R et al. Patient-reported outcomes in the GARNET trial in patients with advanced or recurrent mismatch repairdeficient/microsatellite instabilityhigh endometrial cancer treated with dostarlimab. Int J Gynecol Cancer. 2022;32(10):1250-7.

2.

Rousset-Rouviere S et al.

Endometrial carcinoma: immune microenvironment and emerging treatments in immuno-oncology.

Biomedicines. 2021;9(6):632.

3.

Concin N et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer.

2021;31(1):12-39.

4.

Cuccu I et al. Role of genomic and molecular biology in the modulation of the treatment of

regression of metastasis distant from the irradiated region through the abscopal effect.

In conclusion, this case report supports the combination of RT and immunotherapy for TMB control and management of MSI-H/dMMR EC.

endometrial cancer: narrative review and perspectives.

Healthcare (Basel). 2023;11(4):571.

5.

Oaknin A et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instabilityhigh (dMMR/MSI-H) or proficient/ stable (MMRp/MSS) endometrial cancer: interim results from GARNET – a phase I, single-arm study. J Immunother Cancer.

2022;10(1):e003777.

ovarian cancer (review). Int J Oncol. 2021;59(1):53.

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Palmeri M et al. Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers.

ESMO Open. 2022;7(1):100336.

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Liu Y et al. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors.

J Hematol Oncol. 2018;11(1):104.

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Mol Cancer. 2022;21(1):28.

10. Nabrinsky E et al. A review of the abscopal effect in the era of immunotherapy. Cureus.

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11. Deng L et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest.

2014;124(2):687-95.

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Acquired PTEN Loss May Mediate Dabrafenib and Trametinib Resistance in BRAF V600E-Mutated Epithelioid Glioblastoma: A Case Report and Literature Review Authors:

Abrar Ahmed,1 Liana Nobre,2 Warren Mason,3 Julie Bennett,2,3 Uri Tabori,2 Cynthia Hawkins,2 *Seth Climans4 1. Schulich School of Medicine and Dentistry, Western University, London, Canada 2. The Hospital for Sick Children, Toronto, Canada 3. Princess Margaret Cancer Centre, Toronto, Canada 4. London Regional Cancer Program, London, Canada *Correspondence to seth.climans@lhsc.on.ca

Disclosure:

The authors have declared no conflicts of interest. The patient’s parents consented to molecular analysis of the tumour and to this research publication.

Received:

25.04.23

Accepted:

14.06.23

Keywords:

BRAF V600E, case report, chemotherapy resistance, dabrafenib, epithelioid glioblastoma (E-GBM), PTEN loss, trametinib.

Citation:

EMJ Oncol. 2023; DOI/10.33590/emjoncol/10305035. https://doi.org/10.33590/emjoncol/10305035.

Abstract Epithelioid glioblastoma is a rare and aggressive variant of glioblastoma that is common in children and young adults. This variant frequently has a BRAF V600E mutation, and in recent years, this is often treated with BRAF and mitogen-activated protein kinase kinase inhibitors. An 18-year-old female initially presented with headaches and vomiting. They were diagnosed with an epithelioid glioblastoma and treated with temozolomide chemoradiotherapy. Upon progression, they had to redo surgery and then received dabrafenib and trametinib. They had one last surgery shortly before fatal tumour progression. Retrospective molecular analysis of three tumour specimens showed a PTEN mutation that arose upon first progression, but was not there initially. There were no new tumour mutations after initiation of dabrafenib and trametinib. The acquired PTEN mutation may have conferred resistance to dabrafenib and trametinib. This case highlights the potential importance of early treatment with BRAF and mitogen-activated protein kinase kinase inhibitors in high-grade BRAF V600E-mutated gliomas, ideally before the tumour develops resistance to targeted therapy.

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Key Points 1. The combination of BRAF and mitogen-activated protein kinase kinase inhibitors has

recently shown to help treat some patients with BRAF-mutated high-grade glioma, but it is not entirely clear why some patients respond, while others do not.

2. The authors report a case of a young female with a BRAF V600E-mutated epithelioid

glioblastoma treated with temozolomide chemoradiotherapy. Upon tumour recurrence a PTEN loss of function mutation became apparent and they did not respond to dabrafenib and trametinib.

3. Loss of function PTEN mutations may confer resistance to dabrafenib and trametinib

in glioma, so earlier targeted therapy treatment (before PTEN mutation occurs) might improve outcomes.

INTRODUCTION Proto-oncogene B-Raf or BRAF is a gene found on chromosome 7q34 in humans that encodes the protein B-RAF, a member of the RAF group of serine/threonine protein kinases.1 Once activated, BRAF goes on to phosphorylate the downstream mitogen-activated protein kinase kinase (MEK) protein as part of the mitogenactivated protein kinase signalling pathway.² This pathway helps to regulate growth, proliferation, differentiation, and apoptosis of cells.2 Activating mutations of the BRAF gene lead to uncontrolled cell growth. This can be found in non-malignant lesions such as low-grade gliomas and nevi.3,4 Usually second hits are required to circumvent oncogene-induced senescence and induce the formation of malignant tumours.

Mutations are thus common oncogenic triggers as it has been estimated that BRAF gene mutations are involved in 8% of all malignancies, the most frequent of which are melanoma and thyroid cancers.5 Activating mutations of the BRAF gene include fusions and point mutations.

The former drives oncogenic changes through genomic rearrangement. Specifically, the 3’ part of the BRAF gene that encodes for the kinase domain is placed at the 5’ position after another gene.6 The auto-inhibitory area of the BRAF gene is consequently lost, triggering constitutive activation of the oncoprotein.6 The most common point mutation is a substitution of thymine for adenine at nucleotide position 1799 within the BRAF gene, which results in the

substitution of valine for glutamic acid.7 This also causes constitutive activation through the failure of inhibition of BRAF activity. These BRAF alterations are found in glioblastoma (GBM), pleomorphic xanthoastrocytoma, and low-grade gliomas in children.8 Moreover, it was also found that clinically distinct subsets of secondary high-grade glioma are defined by the presence of BRAF V600E mutation.9 Lastly, the BRAF V600E point mutation is common in epithelioid GBM (E-GBM).10 BRAF V600E commonly occurs concurrently with the silencing of the PTEN tumour suppressor gene.11 For example, more than 30% of all melanomas also have a PTEN loss of function mutation.12 The PTEN gene encodes for a protein that has scaffolding functions in a cell and dephosphorylates lipids such as phosphatidylinositol-3,4,5-trisphosphate.13 By acting as the phosphatase for this lipid, the protein antagonises the phosphoinositide 3-kinase (PI3K)/Akt pathway, resulting in inhibition of cell proliferation, therefore regulating the cell cycle.13 The loss of PTEN results in aberrant activation of the PI3K/Akt pathway. This is an oncogenic trigger, as the PI3K/Akt signal transduction pathway when functioning normally is responsible for controlled cell proliferation, growth, and survival.14 PTEN loss of function mutation is also commonly found in GBM, as hemizygous or homozygous deletion have been found to occur in more than 90% of patients with GBM.15 The impact of PTEN loss of function mutations in survival of patients

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GBM is not definitively known as some studies state that the mutation is closely associated with the prognosis,16 while others state that there is no significant association.17 The combination of both loss of PTEN and BRAF V600E point mutation has been reported in cases of GBM, giant cell GBM, rhabdoid GBM, and supposed Grade 3 oligodendroglioma.15 Of interest are the range of alterations that can occur in combination with BRAF V600E as cancers transform. Alterations that can occur in combination with BRAF V600E may point to why the acquisition of this alteration may be a mechanism of resistance.

Below is a novel case of a patient with BRAF V600E-mutated E-GBM who later developed PTEN loss of function mutation only after initial temozolomide chemoradiotherapy. This is the first case that suggests PTEN loss may mediate resistance to dabrafenib and trametinib in a BRAF V600E-mutated high-grade glioma.

CASE PRESENTATION A previously healthy 18-year-old female developed headaches, sometimes followed by vomiting. Family history was non-contributory and the patient was not on medications. These symptoms worsened over 6 months. The patient then developed daily vomiting for 1 week and was admitted to hospital. They underwent CT imaging, which demonstrated an expansile heterogeneously enhancing right temporal lesion. Their MRI imaging revealed areas of susceptibility artifact and possible calcification.

There was a mass effect that compressed the surrounding sulci, the right lateral ventral, and third ventricle. There was 10 mm of midline shift.

The patient was taken to the operating room for an initial craniotomy for tumour resection.

There was a gross total resection of the tumour (Figure 1). On a pathologic examination the patient was diagnosed with an ‘anaplastic ganglioglioma’. They were treated with focal radiotherapy (60 Gy in 30 fractions) with concomitant temozolomide. The patient experienced persistent neutropenia after concomitant temozolomide and consequently did not receive adjuvant temozolomide.

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Follow-up MRI 10 months later revealed tumour progression (Figure 1). The patient underwent a second resection approximately 1 month following initial resection. Pathologic examination at this time revealed E-GBM and a BRAF V600E mutation was identified.

In retrospect, the patient was found to have a PTEN loss of function mutation that was not present at initial surgery, but was present at their second surgery, before receiving dabrafenib and trametinib. This loss of function was the result of a frameshift deletion. The patient’s CDKN2A status was unknown. The first tumour sample was also shown to have a single nucleotide variant in TP53 p.P152L, which was not detected in later samples. This variant when present in the germline does not tend to result in the development of brain tumours. It has been seen on rare occasions in gliomas.18 In this patient, the variant may have been incidental and not pathogenic.

The patient developed a drop metastasis to the cervical spine and consequently received focal radiotherapy (20 Gy in five fractions) to the cervical spine 20 days following the second resection. They were approved for compassionate access to dabrafenib and trametinib, and began taking these 1 month following the second surgery. There was no response to the treatment and the primary tumour developed clinical progression 4 months after receiving compassionate dabrafenib and trametinib. The treatments were stopped approximately 6 months after the second resection due to further disease progression.

The patient developed uncal herniation as a result of recurrent GBM, which required a third resection approximately 5 months after their second resection (Figure 1). The patient died 1 month after the third resection, 17 months after initial diagnosis.

DISCUSSION E-GBM is a variant of GBM that is more common in adolescents and young adults.19 The cancer is differentiated from other GBM variants by frequent dissemination to the leptomeninges.20,21 Genetic analysis studies reveal that close to 50% of E-GBM have a BRAF V600E mutation.22 As such, BRAF inhibitors such as dabrafenib and

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Figure 1: Timeline of clinical, radiological, and pathological information for an 18-year-old patient with epithelioid glioblastoma treated with temozolomide chemoradiotherapy, followed by dabrafenib and trametinib.

MRI

First Symptoms

Died

Cervical metastasis

Cranial radiation

radiation

Dabrafenib + Trametinib

TMZ

First craniotomy “Anaplastic ganglioglioma” -28

0

28

56

Second craniotomy Epithelioid GBM

Third craniotomy Residual/recurrent GBM

84 112 140 168 196 224 252 280 308 336 364 392 420 448 476

Days

TP53

SNV p.P152L VAF 12%

No mutation detected

No mutation detected

BRAF

SNV p.V600E VAF 41%

SNV p.V600E VAF 71%

SNV p.V600E VAF 58%

PTEN

Frameshift deletion p.K6Rfs*4 VAF 1%

Frameshift deletion p.K6Rfs*4 VAF 41%

Frameshift deletion p.K6Rfs*4 VAF 49%

GBM: glioblastoma; SNV: single nucleotide variant; TMZ: temozolomide; TP53: tumour protein 53; VAF: variant allele frequency.

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MEK inhibitors such as trametinib have induced clinical responses.23 For example, in one case of E-GBM treated with this combination therapy, the patient achieved clinical and radiological stability for 53 months after starting treatment.24,25 This case represents the first description of PTEN mutation in a patient with BRAF V600Ealtered E-GBM. There are however two cases documented in The Cancer Genomic Atlas (TCGA) with similar tumour molecular alterations (i.e., GBM with BRAF V600E and PTEN silencing mutations).24,25 The first patient had a left parietal GBM and a PTEN frameshift deletion. They were treated with the Stupp protocol.24,25 Upon first progression, they received irinotecan and bevacizumab. After the second progression, they received temozolomide and re-irradiation.

The patient died 12 months after diagnosis.24,25 The second TCGA patient also had a left parietal GBM, a PTEN frameshift deletion, and underwent Stupp protocol. The patient developed tumour progression but details about latter line therapies and survival time are unavailable.24,25 Notably, the TCGA listed four patients with GBM who had the BRAF V600E mutation, and they had survival times between 3–46 months. The average survival time for patients with BRAF V600E mutations without a concurrent PTEN loss of function mutation was 17.25 months, and the median was 10.00 months.24,25 Comparatively, the patient described in this case report had a survival time of 12 months from the time of first diagnosis. Interestingly, a search of the TCGA database for low-grade gliomas with concomitant BRAF and PTEN mutations revealed no hits. These double hits seem to mark highgrade behaviour and histology.

As the combination of these mutations has not been widely studied in E-GBM, much of what is known stems from investigations of the effects of PTEN and BRAF V600E in cancers outside of the central nervous system. The prolonged activation of the mitogen-activated protein kinase pathway secondary to the BRAF V600E mutation and the activation of the PI3K pathway secondary to the PTEN mutation results in melanoma progression and metastasis development.26 This combination has been previously demonstrated to result in 100% penetrance of melanomas that metastasise to the lungs and lymph nodes.26 Moreover, PTEN loss of function is associated with intrinsic resistance to BRAF and MEK inhibitor drugs,

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therefore limiting the use of these medications in patients with melanomas with both BRAF V600E and PTEN mutations.11 The authors hypothesise that this is what happened to the patient in the present case with PTEN loss leading to intrinsic resistance to dabrafenib and trametinib. Cancers in other parts of the human body have also been shown to involve the combinatory effect of PTEN and BRAF mutations. For example, these mutations were found to drive the expression of c-Myc, confer resistance to castration, and drive metastasis to lymph nodes as well as the lungs in mice models of advanced prostate cancer.27 Additionally, these mutations were reported to confer acquired resistance to BRAF inhibitors dabrafenib/trametinib in a patient with squamous cell lung cancer.28 What makes this reported case notable is the implications for management of patients with E-GBM. First, the patient may have achieved clinical and radiological stability had they been placed on dabrafenib and trametinib after initial surgery. Additionally, the patient may have benefited from being placed on a PI3K inhibitor, as the PI3K/Akt pathway is aberrantly activated by a PTEN loss of function mutation.

Similar to this, further investigations are required to determine if combination therapy co-targeting the BRAF and PI3K/Akt pathway is of benefit for patients with E-GBM with cooccurring BRAF and PTEN mutations. This form of therapy has already shown to be effective in treating melanomas that metastasise to the brain in both in vivo and in vitro experiments.29 In one study, the researchers targeted melanoma brain metastasis cell lines derived from patients with PI3K inhibitor buparlisib, as well as MEK inhibitor trametinib, and compared the effect of combination treatment with monotherapy. The investigators found that relative to monotherapy of trametinib, combination therapy increased apoptosis and diminished tumour growth in vivo.29 However, a potential obstacle in using this strategy in patients with E-GBM is that there are very few PI3K inhibitor drugs that cross the blood–brain barrier and are not neurotoxic.30 If this obstacle can be overcome, co-targeting both pathways may hold promise for new treatment for future patients with E-GBM. Further studies are required on the temporal evolution of molecular alterations in BRAF

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V600E-altered high-grade gliomas. This tumour evolution provides a basis for a trial to include targeted agents, such as BRAF and/or MEK inhibitors, in the initial management of BRAF V600E-mutated high-grade gliomas at diagnosis, rather than solely at progression (as with this patient).

Lastly, it will be interesting to discover whether the findings of the present case apply to other BRAF V600E-mutated high-grade glioma, or even low-grade glioma.

As noted above, BRAF and PTEN mutations occur in combination in many different types of tumours and seem to be more aggressive than BRAF V600E alone. Future investigations will be required to explore tumour evolution in this context and understand mechanisms of drug resistance. This may have broader implications for other BRAF-mutant brain tumours and is significant to understand for high-grade glioma to design rationale clinical trials moving forwards. It is also crucial to understand lowgrade glioma as there is risk of transformation to high-grade glioma, and understanding relevant biomarkers may allow earlier and more aggressive intervention.

In conclusion, this case report highlights the novel finding of an acquired PTEN loss of function mutation in a patient with a BRAF V600E-mutated E-GBM. The combinatorial effect of these mutations likely resulted in the development of intrinsic resistance to BRAF and MEK inhibitor medications, dabrafenib and trametinib, respectively. Current understanding of these mutations in combination stems from the presence in other malignancies such as melanoma, papillary thyroid cancer, and squamous cell lung cancer. Further investigations are required to fully delineate the implications of these mutations on the management of patients’ BRAF V600E glioma.

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