Jaffer Op Ed about Her2 Guidelines; Comment on Wolff et al. 2023 APLM

 

https://pubmed.ncbi.nlm.nih.gov/37303234/

Human Epidermal Growth Factor Receptor 2 "Low" in Breast Cancer in 2023

In the realm of breast cancer diagnosis and treatment, the Human epidermal growth factor receptor 2 (HER2) has been a pivotal biomarker. Originally, guidelines by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) classified tumors as HER2-positive (overexpression/amplification) or HER2-negative, aiding treatment decisions. However, the landscape transformed with the groundbreaking DESTINY-Breast044 (DB-04) trial results in June 2022. This trial introduced a new category—HER2-low—encompassing tumors with IHC HER2 1+ or 2+ and negative in situ hybridization (ISH). Trastuzumab deruxtecan (T-DXd) proved remarkably effective in this subset, altering the standard HER2 paradigm.

The DB-04 trial's impact was profound, gaining swift endorsements from the National Comprehensive Cancer Network and the US FDA for metastatic breast cancer treatment. Oncologists began seeking HER2-low patients eligible for T-DXd, a therapeutic regimen that, while not indicative of a distinct cancer subtype, offered a favorable prognosis. The updated CAP HER2 biomarker template facilitated patient identification, prompting discussions on formal HER2-low terminology.

However, some experts, including Wolff et al, cautioned against adopting HER2-low as a defined subtype, deeming it a creation for T-DXd eligibility rather than a consistently defined entity. They proposed a footnote differentiating between HER2-overexpressing/amplified tumors and those with low expression. While this approach offers nuanced information, it falls short of establishing a concrete HER2-low label that aids clinicians in identifying eligible patients.

Despite the debate, HER2-low terminology gained informal acceptance in literature, updated biomarker templates, and interdisciplinary discussions. Incorporating HER2-low into practice might pose challenges as it necessitates revising reporting schemas for equivocal IHC 2+ results, which currently involve reflex ISH testing. The authors proposed stricter labeling of IHC negative cases as 0, excluding 1+, while avoiding HER2-low terminology. This recommendation could align reporting practices with the evolving understanding of HER2 status.

The introduction of the term "ultralow" for HER2 1+ ≤ 10% adds complexity. In the DAISY trial, even HER2-negative tumors showed positive T-DXd responses. This prompts questions about true/false negatives in IHC results, possibly linked to detection limitations in the ultralow HER2 range. As IHC remains the primary mode of HER2 detection, best practices include using various control samples, addressing preanalytic conditions, and acknowledging temporal heterogeneity. Pathologists must confirm lower IHC scores at high magnification, striving for consensus in borderline cases.

HER2 evaluation's interobserver variability underscores the need for education and new quantitative assays. Automated image analysis, fluorescent tagging, polymerase chain reaction, and mass spectrometry hold promise for more precise HER2 assessment.

As clinical trial results continue to emerge, the HER2 definition may evolve further. Early DAISY trial results raise questions about T-DXd's efficacy in HER2-null (0) tumors, potentially necessitating a binary HER2 classification in the future.

In conclusion, the introduction of HER2-low as a category in breast cancer marked a significant shift in diagnosis and treatment paradigms. While debate persists over its formal adoption, the therapeutic implications of HER2-low cannot be ignored. This underscores the ongoing need for refining HER2 assessment techniques, education, and adapting to the changing landscape of breast cancer treatment.