Is It Time for HER2-Low Breast Cancer?
Evaluating the evidence for, and against, distinguishing between HER2-low and HER2-zero breast cancers
Michael Schubert, PhD, is a veteran science and medicine communicator. He holds graduate degrees in biochemistry and molecular biology with a research focus on chromatin structure and function and has written on subjects from subspeciality pathology to fictional science. In addition to writing and editing, he is co-director of the Digital Communications Fellowship in Pathology and Course Trainer at the Lightyear Foundation, an initiative aimed at making science accessible to all.
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Inevitably, when a patient is diagnosed with breast cancer, their HER2 status is evaluated. The current definition, most recently updated in 2023, considers patients HER2-positive when their HER2 status is 3+ by immunohistochemistry (IHC) or fluorescence in situ hybridization (ISH) analysis and HER2-negative when the status is 0 or 1+. (A status of 2+ is considered “equivocal” and requires further evaluation.) HER2-positive tumors are uncommon, making up less than one-fifth of all new breast cancer diagnoses.
Many HER2-positive tumors are treated with trastuzumab, a monoclonal antibody that works by blocking the HER2 receptor to inhibit cell replication, suppressing angiogenesis, and driving cytotoxic action against the cancer cells. Until recently, HER2-negative tumors were not treated with trastuzumab due to their lack of HER2 receptor overexpression. However, the 2023 update to the HER2 testing guidelines approved the use of the antibody-drug conjugate trastuzumab deruxtecan in patients with metastatic cancer and HER2 IHC status 1+ or 2+. The extended approval was based on a clinical trial that showed significant survival gains when treating these patients with trastuzumab deruxtecan.
A recent editorial published in the journal Oncotarget evaluates the currently available data and poses the question: should a new prognostic distinction be drawn between HER2-low (IHC 1+/2+, ISH negative) and HER2-zero (IHC 0, ISH negative) tumors? To reach a conclusion, the authors retrospectively examined a cohort of 410 HER2-negative patients who received no adjuvant systemic treatment. Those classified as HER2-low experienced significantly higher rates of disease-free and overall survival than their HER2-zero counterparts. Results from other studies varied, however; although some confirmed the prognostic value of the HER2-low status, others found no significant differences after controlling for confounding factors.
Although the authors ultimately concluded that it would currently be premature to establish HER2-low status as a separate diagnostic entity, they emphasized the need for more investigation into the designation’s prognostic relevance and diagnostic reproducibility in the lab.