Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer

Abstract

Since the release of the DESTINY-Breast04 (DB-04) trial findings in June 2022, the field of pathology has seen a renaissance of HER2 as a predictive biomarker in breast cancer. The trial focused on patients with metastatic breast cancer who were classified as "HER2-low," i.e., those with immunohistochemistry (IHC) HER2 1 + or 2 + and negative in situ hybridization (ISH) results. The study revealed that treating these patients with trastuzumab deruxtecan (T-DXd) instead of the oncologist's chosen chemotherapy led to outstanding improvements in survival. This has challenged the existing binary HER2 pathological classification system, which categorized tumors as either positive (overexpression/amplification) or negative, as per the ASCO/CAP 2018 guideline reaffirmed by ASCO/CAP 2023 guideline update. Given that DB-04 excluded patients with HER2 IHC score 0 status, the results of the ongoing DB-06 trial may shed further light on the potential benefits of T-DXd therapy for these patients. Roughly half of all breast cancers are estimated to belong to the HER2-low category, which does not represent a distinct or specific subtype of cancer. Instead, it encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations. However, HER2-low offers a distinctive biomarker status that identifies a specific therapeutic regimen (i.e., T-DXd) linked to a favorable prognosis in breast cancer. This unique association emphasizes the importance of accurately identifying these tumors. Differentiating between a HER2 IHC score 0 and score 1 + has not been clinically significant until now. To ensure accurate classification and avoid misdiagnosis, it is necessary to adopt standardized procedures, guidelines, and specialized training for pathologists in interpreting HER2 expression in the lower spectrum. Additionally, the utilization of artificial intelligence holds promise in supporting this endeavor. Here, we address the current state of the art and unresolved issues in assessing HER2-low status, with a particular emphasis on the score 0. We explore the dilemma surrounding the exclusion of HER2-zero patients from potentially beneficial therapy based on traditional HER2 testing. Additionally, we examine the clinical context, considering that DB-04 primarily involved heavily pretreated late-stage metastatic breast cancers. We also delve into emerging evidence suggesting that extrapolating HER2-low status from the original diagnosis may lead to misleading results. Finally, we provide recommendations for conducting high-quality testing and propose a standardized pathology report in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Keywords: Biomarkers; Breast cancer; HER2; HER2-low; Pathology report.

Fig. 1

Spectrum of HER2 positivity according to ASCO/CAP guidelines. Comprehensive visual representation of HER2 expression levels in BC depicting the final HER2 status through pathological interpretation and scoring. IHC, immunohistochemistry; ISH, in situ hybridization. Breast Biomarker Reporting, CAP Cancer Protocol Templates, v v1.5.0.1 (March 2023), available at: https://documents.cap.org/documents/Breast.Bmk_1.5.0.1.REL_CAPCP.pdf

Fig. 2

Standard operating procedures (SOPs) for optimizing HER2-low status assessment. This schematic representation provides a critical examination of the entire process for HER2 testing in pathology laboratories, encompassing pre-analytical, analytical, and post-analytical stages. Essential tips and potential pitfalls are provided for each phase, guaranteeing comprehensive guidance for pathologists and addressing critical areas throughout

Fig. 3

Pathology report optimization for HER2 test in HER2-low breast cancer. This refined report presents an integrated approach to accurately assess the HER2 status in breast cancer cases classified as HER2-Low in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements. By synergistically combining immunohistochemistry and in situ hybridization techniques, it is essential to provide a clear, precise, and comprehensive report of HER2 status to enable improved treatment decisions and personalized patient management. IHC, immunohistochemistry; CEP17, chromosome enumeration probe 17; DCIS, ductal carcinoma in situ; H&E, hematoxylin and eosin; ISH, in situ hybridization