Challenges & recommendations for identification of human epidermal growth factor receptor-2 (HER2)-low metastatic breast cancer in India: Expert opinion statement

Sep 24, 2026

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Expert opinion statement addressing challenges in accurately identifying HER2-low status in metastatic breast cancer patients in India. It summarizes evidence that the DESTINY-Breast04 and DESTINY-Breast06 phase 3 trials established trastuzumab deruxtecan (T-DXd) efficacy in HER2-low disease, making correct classification clinically crucial. The statement highlights variability between HER2 IHC 0 and 1+ due to pre-analytical/analytical variables, interpretation difficulties, and intratumoural heterogeneity, and proposes standardized operating procedures, quality control, and specialized training to improve reproducibility and patient selection for novel therapies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Review Article

Background: HER2-low definition and clinical need

Evidence from DESTINY-Breast trials

Sources of variability in HER2 testing

Challenges in interpretation

Recommended standardized approach

Indian J Med Res 162, September 2025, pp 279-292 DOI: 10.25259/IJMR_2009_2024 Review Article Challenges & recommendations for identification of human epidermal growth factor receptor-2 (HER2)-low metastatic breast cancer in India: Expert opinion statement Neeraj Arora 1, Jyoti Bajpai2, Amanjit Bal5, Atul Batra6, Anurag Gupta7, Deepak Kumar Mishra9, Geetashree Mukherjee10, Trupti Pai3, Mayur Parihar11, Geeta V. Patil Okaly12, Shilpa Prabhudesai4, Milap Shah8 & Somashekhar S.P.13 1Department of Molecular Biology, & Molecular Genetics, Unipath Specialty Laboratory, Ahmedabad, Gujarat, Departments of 2Medical Oncology, & 3Pathology, Tata Memorial Centre, 4Center of Oncopathology, Tata Trust Mahalaxmi Engineering Estate, Mumbai, Maharashtra, 5Department of Histopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, 6Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, 7Department of Genomics, Ampath, 8Department of Histopathology, Yashoda Hospital, Hyderabad, Telangana, Departments of 9Hematology and Molecular Pathology, 10Histopathology, & 11Hematology and Cytogenetics, Tata Medical Center, Kolkata, West Bengal, 12Department of Histopathology, Kidwai Memorial Institute of Oncology, & 13Department of Oncology, Aster CMI Hospital, Bengaluru, Karnataka, India Received December 5, 2024; Accepted June 11, 2025; Published November 12, 2025 Results from a recent Phase 3 clinical trial (DESTINY-Breast04) established the efficacy of the antibodydrug conjugate, trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer with immunohistochemistry (IHC) score 1+ or 2+ and without in situ hybridization amplification, defining anew category of metastatic breast cancer known as human epidermal growth factor receptor 2 (HER2)-low. Across studies of patients with primary or metastatic breast cancer, approximately 50 per cent have HER2-low tumours, thereby emphasizing the importance of accurately identifying these tumours. Results from the DESTINY-Breast06 trial further corroborated the DESTINY-Breast04 results showing T-DXd as a new standard of care for patients with HER2-low and HER2-ultralow (defined as IHC score 0 with membrane staining) metastatic breast cancer following one or more lines of hormone therapy. Differentiating between HER2 IHC scores 0 and 1+ shows significant interobserver variability, possibly because the low scores did not have any clinical relevance until now. To establish a standardized approach in scoring of HER2-low tumours in India, a panel of experts comprising histopathologists, molecular pathologists, and clinicians met to discuss guidelines on HER2 testing. The identification of HER2-low expression depends on multiple methodological pre-analytical and analytical variables, including sample handling, fixation, processing, antigen clones, staining methodology, and substrates. The panel also focused on the challenges in the interpretation of HER2-low status. Challenges in the pre-analytical and analytical phases could be addressed by rigorous quality control procedures and training the pathologists. In the post-analytical phase, the subjective mode of HER2 assessment and Overexpression/amplification of human epidermal growth factor receptor 2 (HER2) is reported in almost © 2025 Indian Journal of Medical Research, published by Scientific Scholar for Director-General, Indian Council of Medical Research This open access publication is protected under CC-BY-NC-SA 4.0 280 INDIAN J MED RES, SEPTEMBER 2025 HER2 intratumoural heterogeneity in HER2-low breast cancer are factors that influence HER2-low assessment. The panel recommended robust standard operating procedures to overcome these challenges. The central point of discussion was to implement clear guidelines, careful supervision of pre-analytical and analytical issues, and specialized training for accurate HER2 testing that would help select patients eligible for novel therapies.

FAQs

What defines HER2-low metastatic breast cancer in this expert statement?

HER2-low is characterized by immunohistochemistry (IHC) score 1+ or 2+ without HER2 gene amplification by in situ hybridization, and HER2-ultralow is described as IHC 0 with membrane staining.

Why is accurate identification of HER2-low tumors important?

About half of patients have HER2-low tumors, and correct classification enables selection of patients eligible for HER2-directed novel therapies such as trastuzumab deruxtecan.

What are the key challenges affecting HER2-low assessment?

The statement emphasizes pre-analytical and analytical factors (sample handling, fixation, processing, antigen clones, staining methods, substrates), subjective assessment after testing, and HER2 intratumoural heterogeneity.

Sep 24, 2026

Uploaded by dhado