CPD: Recent Advances in Breast Conserving Therapy

Recent Advances in Breast Conserving Therapy

AUTHORS: Emilie McCormack1, Michael Click2, Karl Sweeney1, Aoife Lowery3 1Department of Surgery, Clinical Sciences Institute, University Hospital Galway, Galway, Ireland 2Department of Radiology, University Hospital Galway, Galway, Ireland 3Discipline of Surgery, School of Medicine, University of Galway, Galway Ireland

Emilie McCormack

Karl Sweeney

Aoife Lowery

Introduction

Breast conserving therapy (BCT), which encompasses breast conservation surgery (BCS) with adjuvant radiation therapy, has been the standard of care for the majority of newly diagnosed early breast cancer for the last four decades. Outcomes of BCT have been repeatedly validated as an oncologically safe locoregional treatment option in early breast cancer with similar long term survival,1-4 reduced psychological morbidity5 and less medical and surgical complications when compared to mastectomy.6

Diagnostic and therapeutic advances have dramatically improved breast cancer outcomes, now approaching >98% survival at 5 years for those diagnosed at stage I with favourable clinical and molecular features.7 Additionally the improved understanding of tumour biology and standard use of targeted adjuvant therapies, such as anti-oestrogen and antiHer2 therapy, has contributed to these improved outcomes.

Surgery is the mainstay of curative treatment for breast cancer and the evolution of oncoplastic surgical techniques, combined with a shift towards less conservative margin requirements, has expanded the indications for breast conserving surgery, facilitating this approach in larger tumours8 and reducing the requirement for mastectomy to achieve locoregional control (76.6% vs 22.4%).9 The Early Breast Cancer Trialists Collaborative Group demonstrated adjuvant radiotherapy to be an essential component of successful BCT to reduce both recurrence and mortality.10 While adjuvant radiotherapy has up to recently been routinely recommended for all cases of breast conserving surgery, for early breast cancers emerging evidence supports de-escalation in dose fractionation and omission in low risk patients.11, 12

The profile of breast cancers being managed has also evolved with the introduction of breast cancer screening programmes, and enhancement of diagnostic strategies for breast cancer which have facilitated an increase in the detection of non-palpable breast lesions which necessitate localisation strategies.13, 14

In this review we will summarize the recent advances in early breast cancer diagnosis, localization and BCS and discuss the evidence that has contributed to a de-escalation in locoregional treatment for some breast cancers – and will discuss ongoing clinical trials that have the potential to further evolve the treatment landscape.

Breast Cancer Detection

Breast cancer can either be symptomatic or screen detected at presentation. BreastCheck, the national breast screening programme in Ireland, invites women aged 50-69 years of age to participate with the aim of diagnosis at an early stage where contemporary multimodal therapy will be curative. Patients are screened with digital mammography (sensitivity 85%, specificity 90%15) and if mammographic abnormalities are detected, are recalled for further radiological assessment. Assessment has recently incorporated the use of digital breast tomosynthesis (DBT) to aid in cancer diagnosis along with digital mammography and ultrasound. DBT captures multiple Xray projections across an arc that are reconstructed into a stacked image. This enables a three-dimensional view of the parenchyma with more detailed lesion characterisation. DBT is associated with an increased cancer detection rate from 1.2 to 4.6 per 1000 examinations, compared to digital mammography.16 It is particularly advantageous for assessing dense breast tissue and may reduce false recalls.17

With the enhancement in breast cancer detection due to screening and improved diagnostics there has been a subsequent rise in impalpable tumours.13 The proportion of small (<2cm) tumours has increased with screening, from 36% to 68% of detected breast cancers with a concurrent rise in DCIS diagnosis.14

Tumour localisation techniques

The increasing detection of impalpable breast cancers has mandated the evolution of tumour localisation techniques as a surgical adjunct to aid in accurate identification of the tumour intraoperatively. Accurate preoperative tumour localisation techniques are important to inform optimal surgical approach and technique to achieve clear surgical margins reducing need for reintervention after BCS and decreased locoregional recurrence.18

Wire guided tumour localisation is the most broadly used technique for localisation of impalpable tumours. This approach involves the radiologist inserting a soft wire with the tip anchored in the targeted lesion under image guidance, large tumours can be bracketed, with two wires aiming to delineate the extent of the lesion Fig 1a +1b. There are a number of limitations to wire guided localisation which include risk of wire dislodgement, increased patient discomfort and difficulties in resource management. The localising wire is required to be inserted on the morning of surgery, which may lead to operating theatre delays, and is labour intensive requiring a radiologist performed procedure which is additional to the diagnostic biopsy. These limitations have prompted the development of novel methods of tumour localisation, some of which have recently been adopted into clinical practice.13, 18, 19 Radioactive seeds were introduced in the early 2000’s as an alternative to wire localisation with the primary aim of reducing the risk of wire dislodgement and therefore improving intra-operative localisation accuracy. The seeds can be inserted radiologically at the time of diagnostic biopsy for radiologically suspicious lesions or ahead of the day of surgery, which can improve theatre flow and patient experience,13 Fig 2a+2b. There is also an improvement in cosmetic outcomes as this approach decouples wire insertion location and surgical incision.13 Magnetic-marker localization (ML) involves the magnetic tracing of a non-ferromagnetic marker coil using a magnetic localizer intraoperatively, with radiofrequency-guided localisation radar reflectors and anchor guided localisation having been introduced as other novel methods.18

Operator dependence in estimating the extent of the lesion at the time of surgery based on imaging increases the risk of positive resection margins.13 Novel surgeon driven localisation techniques have been developed to address this challenge; including intraoperative ultrasound, Radioactive occult lesion localization (ROLL), the intratumoral injection of Technetium99 under ultrasound-guidance with use of a handheld gamma probe to localize the extent of the tumour. Indocyanine green fluorescence works similarly with the use of photodynamic eye to demonstrate the full extent of the tumour. Cryoassisted localisation, which involves the insertion of a cryoprobe under ultrasound guidance in the operating room to create an ice ball around the lesion, has been described as a technique to make the lesion palpable therefore aiding resection.20, 21 Intraoperative ultrasound can be performed for real time guidance and can be performed by the surgeon or a radiologist, supine magnetic resonance imaging which uses realtime magnetic resonance imaging18 can be used similarly. Table one summaries the different localisation techniques with advantages and disadvantages described.

Davey et al a performed a network meta-analysis of randomised controlled trials comparing localisation techniques in non-palpable breast lesions with 24 RCTS and 4236 breasts.18 The primary outcome measure was margin positivity rate, with secondary outcomes including reoperation rates, duration of operation (minutes), complication rate, cost, specimen characteristics and disease recurrence when clear margins were achieved. Cryo-assisted localisation followed by wire guided localisation had the highest rates of margin positivity of 28.2% and 20.1% respectively with reoperation rates of 18.9% and 17.3%. Intraoperative ultrasound guidance had significantly lower margin positivity and reoperation rates when compared to wire guidance alone, 5.4% and 4.8% respectively.18 The MELODY (Methods for Localization of Different types of breast lesions) (EUBREAST 4) Study is a multicentre prospective cohort trial, currently recruiting, to evaluate different image-guided methods for localization of non-palpable malignant breast lesions that will investigate their safety, clinical effectiveness, with a focus on patient, surgeon, and radiologist preference. NCT 05559411.22

Surgical Excision Margins

Positive resection margins after breast conserving surgery are associated with increased risk of local recurrence,23 as such effective breast cancer surgery requires complete tumor removal and most national and international guidelines recommend reoperation, either in form of re-excision or mastectomy, until clear margins have been reached.24

Re-operation rates vary widely, with population-based studies reporting a range of 15-35%, and the requirement for further surgery can result in increased patient anxiety, delays to adjuvant treatment, poor cosmetic outcome and increased complication rates and costs.25, 26 Therefore, re-operation rate has been included as a quality indicator of breast cancer management in several countries.27

Margin status is typically measured by the pathologist as distance from the tumour to the inked margin. This is classed as involved if there are tumour cells at the inked margin – the edge of the resected specimen.28

There has been a relative paucity of high-level evidence and consensus in relation to specific margin width and its relation to locoregional recurrence with some discrepancy in international guidelines.29-31 Acceptable margin width from early trials varied significantly, being variably described as either as ‘’positive’’ or ‘’negative’’ for gross tumour at specimen edge without classification as to the width1 with others recommending at least 10mm for DCIS.32, 33 The first consensus was published in 2014 by the Society of Surgical Oncology and the American Society for Radiation Oncology to define what margin width minimizes the risk of ipsilateral breast tumour recurrence (IBTR). Recommendations defined a positive margin – ink on invasive cancer or DCIS as having at least a twofold risk of IBTR but concluded that wider margins than “no ink on tumour” did not significantly lower risk.34 Recommendations included in the NCCP 2015 guidelines on breast cancer management are; for DCIS treated with BCS and adjuvant radiotherapy (RTX), a minimum radial margin of 2mm is acceptable and for tumour not to be touching ink for invasive cancers.29 The most recent recommendations from the National Comprehensive Cancer Network (NCCN) are the same but it is to be noted this is based on data from patients who received whole breast radiation therapy and in the omission or de-escalation of adjuvant radiotherapy the optimal margin width is unknown.30 2018 NICE guidelines on breast cancer management (NG101) however have advised offering re-excision for margins <2mm for invasive cancer and DCIS. Molecular subtype has not been shown to have an impact on margin status and therefore this does not need additional consideration for surgical decision making in relation to margin width.35 However, it is to be noted that triple negative and Her 2 expressing. tumours have an increased local regional recurrence risk compared to luminal tumours.36

A recent meta-analysis comprising 112,140 patients over 41 years with early invasive breast cancer (stage I- III) demonstrated a tumour on ink, or positive margin, distal recurrence risk of 25.4% and local recurrence of 15.9% compared to negative margin(>2mm) risks of 7.4% and 3.9% respectively as well as overall lower survival rates. Close margins (0.01mm to <2mm) had similar findings in terms of recurrence, the effects of which were not attenuated by the usage of chemotherapy and the authors recommended margins of at least 1mm for both invasive cancer and DCIS and recommended a change to international guidelines based on their findings.28

Margin status and the requirement for clear margins is an important discussion point with patients during their initial consultation for BCS due to the potential 20 -25% reoperation rate caused by compromised margins.37 Recommendations to reduce reoperation rates include specimen orientation on 3 sides, intraoperative specimen radiograph review, the incorporation of oncoplastic techniques to allow a larger specimen size with good cosmesis, cavity shaves and consideration for intra-operative pathologic assessment.38

There are several new proposed techniques and models incorporating technology and machine learning for predicting margin positivity and for pathological assessment. One such study developed a nomogram based on initial diagnosis and surgical factors for predicting positivity in DCIS to aid clinicians in decision making regarding margins re-excision vs mastectomy with positive success.39 Intraoperative 3D specimen imaging and handheld devices for intraoperative margin assessment have shown early promising results.40

Surgical Technique – the evolution of Oncoplastic Breast Conserving Surgery

The aim of successful BCS is adequate tumour resection with clear margins with an oncologically safe and satisfactory cosmetic outcome for both locoregional control and patient satisfaction.5, 28 Patient factors and tumour factors have to be taken into consideration when planning operative technique as well as patient preference with cosmetic outcome largely relating to the tumour resection size as a percentage of whole breast volume.41 There are some absolute and relative contraindications for BCT including inflammatory BC, metastatic disease, previous breast irradiation, strong family history or BRCA mutation carriers.31

A recent Cochrane review encompassing data from 178,813 patients demonstrated the safety of ‘oncoplastic’ BCS when compared to traditional BCS in terms of both local recurrence and disease free survival.8 Oncoplastic surgery aims to provide optimum effectiveness of surgical resection with plastic surgery reconstruction techniques based on two different principles of volume displacement and volume replacement with the aim of conserving breast shape and size. Oncoplastic techniques allow for excision of large tumours with wide margins with satisfactory cosmetic appearances and oncological outcomes.8 The choice of incision will depend on the tumour size, location, and reconstruction technique, as well avoiding scar visibility in clothing. Cosmetic incisions should be circum-areolar, along langers lines or along maximal lines of tension. Reducing excess skin, to account for the loss of volume, may also be considered.8

Volume displacement techniques include Mastopexy or mammoplasty: Local parenchymal flaps are of importance in both reconstructing the shape of the breast but also in covering the pectoralis to avoid skin tethering caused by radiotherapy. Commonly radial or purse string mastopexy is performed with other variations existing such as racquet handle or batwing mastopexy with improved long term cosmetic outcomes.8, 42 Contralateral breast reduction mastopexy aids surgeons operating on patients with large tumours (>5cm) in large breasts where there may be a struggle to maintain symmetry with simple mastopexy. In this situation the patient undergoes bilateral reduction type surgery through Wise-pattern incisions with the tumour bracketed preoperatively under radiological guidance.43 An important operative step when planning oncoplastic BCT is to clip the cavity at the time of surgery to allow proper targeting for radiotherapy as the volume displacement and incision can make this more challenging.30

Volume replacement techniques include rotational and free flaps with several described in the literature most commonly chest wall perforator flaps.8 The use of implants may be considered, particularly in patients with a smaller cup size and proportionally larger tumours. The best results are obtained with bilateral breast implants, with a smaller implant on the contralateral side.44 Other delayed techniques include autologous fat grafts into defects that can become more apparent with healing and scar formation.45

Radiotherapy

The Early Breast Cancer Trialists Collaborative Group provided evidence demonstrating that patients who had undergone BCS and were treated with adjuvant radiation therapy (RTX) had a 10-year absolute risk reduction of 15.7% for any recurrence, locoregional or distant, and an absolute decrease in breast cancer mortality by 3.8% at 15 years in all comers.10 They did identify that the reduction in recurrence or benefit of radiotherapy varied with age, tumour size, tumour grade, ER status and tamoxifen use10 with recent evidence supporting a shift towards de-escalation for certain subsets of patients in practice in relation to low-risk patients. Recent changes in practice include that patients over the age of 70 with T1 tumours who are ER positive should be considered for partial breast radiation or omission of RTX if treated with endocrine therapy.30 RTX in older women however, where risk of locoregional recurrence may impact quality-oflife, is still a preferred treatment and whole breast radiation therapy plus a boost to the tumour bed is recommended in high grade tumours including tumours >/= T3 or T2 tumours with high risk factors including high grade tumours, extensive lymphovascular invasion or absence of oestrogen or progesterone receptor expression.29, 46 Omission of RTX in T1 AND T2 ER positive tumours in women over 65, is associated with increased local recurrence compared to whole breast RTX (9.5% vs 0.9%) but had no impact in overall survival or distal recurrence.11

Hypofractionation has improved patient convenience and compliance and reduced associated toxicities. Radiation dermatitis is the most common early complication of RTX, with regional therapy a risk factor for late onset lymphoedema as well as cardiac and pulmonary complications.46 Hypofractionation, a higher dose of radiation (>2Gy) delivered in fewer fractions has mature data supporting improved locoregional control, overall survival and cosmetic outcomes with reduced tissue toxicity compared to traditional and has now been recommended as first line therapy.12

The FAST FORWARD trial has demonstrated the non-inferiority of an ultra-hypofractionation regimen (26 Gy in 5 fractions of 5.2 Gy over 1 week versus standard hypofractionation of 40 Gy in 15 fractions over 3 weeks) for local control of the conserved breast or chest wall.47 The TARGIOT-IORT trial, demonstrated noninferiority of intraoperative radiotherapy to traditional external beam RTX with local recurrence rates at five years of 2.11%and 0.95% respectively for patients with IDC <3.5cm size. cN0-N1.48 Despite the proposed benefit of accelerated partial breast radiotherapy over whole breast radiation in limiting the risk of acute toxicities, at metaanalysis of over 16000 patients generally >60 years of age with T1N0 G1 or G2 or DCIS, overall partial breast radiation yielded inferior effectiveness and higher risk of ipsilateral recurrence but this risk was attenuated when the partial breast radiotherapy was given by external beam radiotherapy with CT planning.49 There are several trials currently evaluating stratification of low risk patients to examine the potential omission of radiotherapy. The PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission) trial is a non-randomized phase II trial (Dana Farber Cancer InstituteNCT02653755), evaluating the omission of whole breast RTX after BCS in breast cancer patients (aged 50–75) deemed at favourable-risk and receiving adjuvant endocrine therapy. The LUMINA study, a multicentric single-arm prospective cohort trial (Ontario Clinical Oncology Group-OCOG), aims to evaluate recurrence risk in postmenopausal women with Luminal A breast cancer as determined by IHC treated with BCS, hormonal therapy and the omission of RTX. Personalisation of adjuvant therapy to incorporate tumour and patient factors will be a critical component of decision-making relating adjuvant radiotherapy following breast conserving surgery going forward.

Future directions in BCT

The future of BCT lies in personalisation and precision, ensuring that each patient has the optimal treatment paradigm based on both tumour and patient factors, incorporating de-escalation of treatment where appropriate.

Technology such liquid biopsy, tumour genomics and molecular profiling may assess targets to improve diagnosis, selection for targeted therapies and disease recurrence.40, 50 Gene expression profiling, such as the Oncotype DXTM score, has established over the last decade that the molecular profile of breast cancer can provide information on recurrence rates with oestrogen receptive, node negative disease.51 The TAILORx trial changed practice that routine adjuvant chemotherapy should be prescribed for all these patients, demonstrating non inferiority of endocrine therapy to chemoendocrine therapy for patients with low to midrange scores (0-25) potentially sparing up to 85% of women with early breast cancer from adjuvant chemotherapy.52

Surgery has been targeted as another area for potential de-escalation. DCIS, the nonobligative precursor for invasive carcinoma (20-30% progression), is under current guidelines treated similarly to invasive cancer with surgery, radiotherapy and endocrine therapy at considerable cost and morbidity risk considering that for patients with low-risk DCIS they may never develop invasive cancer, thereby possibly representing overtreatment. Active surveillance is routine in other low risk cancers such as prostate cancer but only about 3% of patients with DCIS undergo active surveillance.53 COMET is a phase III randomised trial to determine the risks and benefits of guideline comparative care compared to those of active surveillance for low-risk DCIS (over 40 years of age, Grade I/II DCIS without an invasive component on biopsy, hormone receptive positive, HER 2 negative without a physical mass) LORIS, a phase III trial ran out of the UK has been similarly designed to allow for comparison has finished recruitment and is expected to finish analysis in 2029.53, 54 Even for early stage breast cancers there has been a move to de-escalate surgical intervention with vacuum-assisted excision directed by radiologists, a method currently used to excise certain B3 lesions.55 The SMALL trial has recently finished phase 3 recruitment and this study aims to assess the effectiveness of vacuum-assisted excision in the treatment of screen detected grade one luminal A breast cancers that are radiologically node negative.56

As de-escalation in breast cancer care and personalized cancer care is likely to shape future trends, it is anticipated that the burden of cancer treatment will be reduced, at least for those with early stage breast cancer. It is imperative that this evolution takes place with multidisciplinary collaboration and de-escalation in each oncology discipline is undertaken with consideration of how it may interact with evolving practice in the other disciplines, ensuring that optimal oncologic outcomes are maintained.14, 53

References available on request