Dr Rimm on the Effect of Inaccurate HER2 IHC Testing for Patients With Breast Cancer

“Inaccurate IHC testing doesn’t affect cancer diagnosis; it affects subclassification of the cancer. We all know that the diagnosis is breast cancer, and so this test is not a diagnostic test; it’s what's called a companion diagnostic test.”

David Rimm, MD, PhD, Anthony N. Brady Professor of Pathology, professor, medicine, Medical Oncology, Yale School of Medicine; director, Physician Scientist Training Program, Pathology Research, director, Tissue Microarray Facility, director, Yale Pathology Tissue Services, Pathology, Yale Cancer Center, discusses the effect of inaccurate HER2 immunohistochemistry (IHC) testing on the subclassification of patients with breast cancer.

Inaccurate IHC testing does not directly affect the diagnosis of cancer but rather its subclassification, which plays a critical role in guiding treatment decisions, Rimm begins. Although breast cancer is diagnosed independently, the IHC test for HER2 is a companion diagnostic test, according to Rimm. This means it is specifically tied to determining eligibility for HER2-targeted therapies, such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), which has significantly improved patient outcomes, he explains.

However, the accuracy of the HER2 IHC test remains a concern, Rimm continues, saying that patients classified as HER2 1+ whoare actually HER2 0 may receive T-DXd unnecessarily and achieve no benefit from the drug. Conversely, some patients classified as HER2 0 might have low levels of HER2 expression that could make them eligible for treatment with HER2-directed therapies but are excluded because the test did not detect sufficient expression, he reports. This misclassification limits the effectiveness of personalized treatment and prevents some patients from accessing potentially beneficial therapies, Rimm emphasizes.

The regulation of HER2 IHC tests further complicates the issue, Rimm expands. Unlike other IHC stains used as binary diagnostic tools to confirm cancer diagnoses, since the HER2 IHC test functions as a companion diagnostic, it is regulated by the FDA as a device rather than a stain, he says. Other IHC stains fall under lower regulatory classifications due to their confirmatory nature, he notes. This distinction highlights the unique role and challenges of HER2 IHC testing, as it directly affects therapeutic decision-making rather than serving as a simple diagnostic aid, Rimm concludes.