Dr Rimm on Unmet Needs in Distinguishing Between HER2-Low and HER2-Ultralow Breast Cancer

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 primary challenges in distinguishing between HER2-low and HER2-ultralow breast cancer using current immunohistochemistry diagnostic kits.

The biggest challenge is that the current diagnostic kits for measuring HER2 levels operate outside the appropriate dynamic range, Rimm begins. Essentially, the current tests can differentiate between HER2 gene–amplified cases and non-amplified cases, but this involves detecting a high number of molecules, he reports. HER2-low cases involve fewer molecules, and the tests are not designed to detect HER2 at this lower range, Rimm emphasizes, adding that this may be compared with trying to weigh mice on a scale meant for elephants, leading to inaccurate results.

Studies have shown that pathologists struggle to accurately differentiate between HER2 0 and HER2 1+ disease, where HER2 0 is considered HER2-low disease and HER2 0 is considered HER2-negative disease, he continues. Despite extensive training and global comparisons, the accuracy of these tests remains at approximately 80%, which is insufficient for patient care, Rimm adds. In comparison, molecular tests for other diagnostics, such as EGFR mutations in the realm of lung cancer, have a reproducibility of 99%, which is the standard that breast cancer researchers should aim for, he says.

Currently, pathologists are being asked to distinguish even finer gradations, such as HER2 half from HER2 0, which is not feasible given that distinguishing HER2 0 from HER2 1+ is already challenging, Rimm expands. This approach seems poorly thought out and unrealistic, likely driven by the financial motives of drug companies rather than practical diagnostic capabilities, he emphasizes. Consequently, the attempt to differentiate HER2 0 from HER2 1 or HER2 levels that are less than 1 but greater than 0, is impractical and undermines the field of pathology by imposing impossible tasks on diagnostic tests, Rimm concludes.