Unlocking the Potential of HER2-Targeted Treatments
We spoke to Chief Oncologist Dr. Morten Mau Sorensen and Dr. Kristian Egebjerg from Copenhagen University Hospital – Rigshospitalet in Denmark, whose research focuses on expanding HER2-targeted therapies to esophageal squamous cell carcinoma and improving diagnostic methods to identify HER2-positive patients across various cancer types.
Nearly three decades ago, a groundbreaking study published in Science marked a turning point in oncology. This paper revealed that the HER2 oncoprotein is found in greater abundance on the surface of breast cancer cells. This discovery stands as one of the most significant milestones in the pursuit of effective breast cancer treatments. HER2, short for human epidermal growth factor receptor 2, is a tyrosine kinase protein within the epidermal growth factor receptor (EGFR) family, which plays a key role in the regulation of cell growth. Its over-expression is associated with the proliferation and survival of tumour cells. Early research revealed that the HER2-positive breast cancer subtype often exhibited aggressive disease progression, higher recurrence rates, and poorer overall survival compared to HER2-negative tumours. Consequently, HER2 overexpression was initially used as a marker of poor prognosis. At the same time, researchers at UCLA were studying trastuzumab or Herceptin, a monoclonal antibody specifically designed to target the HER2 protein. Following its FDA approval in 1998, trastuzumab transformed the prognosis for patients with HER2-positive breast cancer, leading to increased survival rates, reduced recurrence, and improved outcomes in advanced metastatic cancer. It marked one of the first major successes in targeted cancer therapy.
Beyond Breast Cancer Treatment: Widening the Her2 Indication
Over the next ten years, scientists attempted to replicate this success in other HER2expressing cancers, such as ovary, salivary gland, lung, bladder, and gastric cancer. Another breakthrough came in 2010 when researchers discovered that trastuzumab improves survival in HER2-positive gastric or esophageal adenocarcinoma (GE-ADC). Around the same time, T-DM1, a conjugate of trastuzumab, and the chemotherapeutic agent DM1 (emtansine) was developed. T-DM1 improved outcomes in HER2-positive lung and colorectal cancers. Widening the indication of trastuzumab and newer HER2-targeted therapies brought new challenges. Prevalence of HER2 positivity is relatively high in breast cancer and GE-ADC, occurring in 20-25% of cases, but it is far less common in other cancers, with prevalence rates ranging from 2-5%. While trastuzumab is a cornerstone in the treatment or HER2positive GE-ADC, its efficacy in esophageal squamous cell carcinoma remains yet unexplored. These two challenges have inspired the work of Dr. Morten Mau Sorensen and Dr. Kristian Egebjerg at Copenhagen University Hospital – Rigshospitalet in Denmark. Their project, “Expanding the indication of HER2 targeted treatment in solid tumours” funded by the Independent Research Fund Denmark,
aims to address two questions: How effective is trastuzumab in treating HER2-positive esophageal squamous cell carcinoma? How can we identify patients across solid cancer types that will benefit from targeted HER2 therapy?
Exploring HER2-Targeted Treatment in Esophageal Squamous Cell Carcinoma
Esophageal cancer ranks as the eighth most common cancer worldwide, with esophageal squamous cell carcinoma accounting for the majority of cases. Despite advances, the prognosis for ESCC remains poor, with a fiveyear survival rate of 15–25%. Patients with advanced metastatic disease rely on palliative chemotherapy, which minimally improves survival. The ToGA trial showed that HER2targeted therapies improve survival in GEADC, and appropriate screening guidelines have been developed to evaluate HER2 status. Small studies have identified HER2 positivity in some ESCC cases, but currently, there are no approved HER2-targeted treatments for ESCC. Dr. Egebjerg, Dr. MauSorensen and their team highlight the need to identify potentially effective HER2-targeted therapies in this aggressive cancer type. For this reason, they conducted a meta-analysis involving 18 studies and 1,505 patients to determine HER2 prevalence in ESCC. They found that the estimated prevalence
of HER2 positivity was 8.6%. Although preclinical studies support the efficacy of trastuzumab in HER-positive ESCC, clinical trials are still lacking. “There is an obvious need to identify drug targets to improve therapies in ESCC. With around 500.000 newly diagnosed cases of ESCC worldwide each year, HER2 targeted treatment could potentially open a new treatment paradigm in a substantial sub-population of ESCC patients” says Dr. Mau-Sorensen. To bridge this gap, the team initiated the HERES trial, a non-randomised trial that evaluates the addition of trastuzumab to standard systemic therapy in HER2-positive ESCC, focusing on six-month progression-free survival as the primary objective. Additionally, they aim to assess response rates, overall survival, and treatment safety. In a sub-project, the team aims to establish a reliable and specific HER2 scoring system adapted to the squamous cell pathology, that will ensure an accurate identification of patients who will benefit from targeted therapy. The HERES trial, funded by the Danish Cancer Society and the Danish Comprehensive Cancer Centre, offers hope to a patient population with a poor prognosis and limited treatment options.
high HER2 prevalence, however, in cancers with lower HER2 prevalence, IHC becomes impractical due to high costs, labour intensity, and requirement for the use of limited tumour tissue. IHC only tests for one target at a time, which limits its utility when looking for other biomarkers. IHC is subject to marked interobserver variability, especially in pantumor settings lacking standardised scoring guidelines. As highlighted in their Journal of Clinical Oncology article, inconsistent validation of IHC assays across tumor types leads to discrepancies between local and central test results, increasing false positives and negatives. This underscores the urgent need for standardised, validated diagnostic methods to accurately identify patients eligible for treatments like trastuzumab deruxtecan.
Next-Generation Methods for Pan-Diagnostic
Testing
“RNA-Seq and Mass Spectrometry have the advantage that they can also screen for thousands of other biomarkers simultaneously. They are also more sensitive than NGS and can detect a higher percentage of HER2- positive cases.” In their project,
“The full potential of targeted-treatments can only be achieved when we can reliably and accurately identify the patients who will benefit the most”
Identifying HER2-Positive Patients across Various Cancer Types
“To determine eligibility for HER2-targeted treatment, the critical factor is the amount of HER2 protein present on their cells. Prevalence of high HER2 protein expression (20%) in breast, esophageal, and gastric cancers makes screening efficient, as one in five patients is likely to benefit from these treatments. However, when utilising a tumour-agnostic approach, or looking at HER2 expression across all cancer types, the prevalence is much lower - around 2-5%. While this percentage is small, the total number of cases across all cancers is still high. The challenge lies in identifying these patients which can be done via various methods such as next-generation sequencing (NGS), RNA sequencing (RNAseq), immunohistochemistry (IHC), or mass spectrometry.” explains Dr. Egebjerg. In our conversation, he calls attention to the difficulties scientists face when using current methods for HER2 detection. NGS is commonly used in pan-tumour trials, however, it lacks sensitivity, missing around 50% of HER2-positive cases. IHC is a highly effective screening method in cancers with
“Next Generation detection of HER2 positive patients”, the researchers are using RNA-seq and Mass Spectrometry to develop a method for identifying HER2-positive patients across more than 29 types of cancer. This work is part of the Copenhagen Prospective Personalised Oncology (CoPPO) programme, which has analysed over 3,000 tumour samples since 2013. The goal of this project is to create a reliable HER2-RNA or -protein threshold that can detect HER2-positive tumours without relying on traditional methods. The challenge we are facing with the identification of HER2positive tumors across solid tumor types is one we will encounter over and over again in the near future. This issue is becoming more prominent as pan-tumor indications gain focus, especially with the development of antibody-drug conjugates (ADCs) targeting markers like HER3, MET, B7-H3/CD276, NECTIN4, and PTK7. However, a significant obstacle lies in developing pan-tumor companion diagnostics.
“The full potential of targeted treatments can only be achieved when we can reliably and accurately identify the patients who will benefit the most” he concludes.
EXPANDING THE INDICATION OF HER2 TARGETED TREATMENT IN SOLID TUMORS
Project Objectives
HER2-positive cancers respond to HER2targeted therapy which is widely used in breast and gastric/esophageal adenocarcinomas. This project explores new HER2 screening methods such as RNA-sequencing and mass spectrometry as well as HER2-targeted therapy for HER2 positive esophageal squamous cell carcinomas and other cancers.
Project Funding
The study is funded by the Danish Cancer Institute & Danish Comprehensive Cancer Center, Harboefonden, Independent Research Fund, the Danish Cancer society, and the Capital Region of Denmark. / HER2 IHC and IHC and FISH was conducted by Agilent Technologies. / Screening of HER2 in the HERES trial is supported by Roche Diagnostics.
Project Partners
(1) Departments of Oncology & Pathology: Rigshospitalet Copenhagen, Odense, Aalborg, Aarhus Denmark / (2) Department of Pathology, Zealand University Hospital, Roskilde and Naestved, Denmark / (3) Center for Genomic Medicine, Rigshospitalet Copenhagen, Denmark / (4) The Novo Nordisk Foundation Center for Protein Research - University of Copenhagen, Copenhagen, Denmark / (5) Research Department Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
Contact Details
Kristian Egebjerg, MD, PhD student Dept. of Oncology, Rigshospitalet Blegdamsvej 9
DK-2100 København Ø T: +45 3545 8765
E: kristian.egebjerg.02@regionh.dk W: https://www.rigshospitalet.dk/
Morten Mau-Sørensen is a GI cancer oncologist. His main areas of research are cancer drug development including personalised therapies based on tumor genomics and tumor circulating DNA. He is past president of the Danish Association for Cancer.
Kristian Egebjerg.- Dedicated MD and researcher specialising in oncology, with prior research experience in cardiovascular-, rheumatologic- and infectious diseases. Co-Creator and co-manager of the upper gastro-intestinal oncology research group at Rigshospitalet Copenhagen. Passionate about advancing patient care through innovative research, diagnostics, and therapies in the cross-field between pathology, oncology, and bioinformatics.
