Proposal of Modification for the Definition of Genetic Heterogeneity in HER2 Testing in Breast Cancer

To the Editor.—In the recently published guidelines for HER2 testing in breast cancer, it defines HER2 genetic heterogeneity (GH) and provides practice guidelines for examination of the tissue and reporting criteria for that analysis.1 HER2 GH is defined as “more than 5% but less than 50% of infiltrating tumor cells with a [HER2/CEP17] ratio higher than 2.2.” It also states that “[i]f more than 50% of the infiltrating tumor cells have a ratio higher than 2.2, then the tumor is considered HER2 amplified,” and “[i]nterpretation of HER2 gene amplification should be rendered based on the overall ratio defined according to the American Society of Clinical Oncology/CAP [College of American Pathologists] HER2 guidelines.”2,3 It seems that interpretation of the findings of certain cases based on the above 3 guidelines may not be uniform. For example, in one of our recently encountered cases, we examined 60 infiltrating tumor cells. The HER2/CEP17 signal ratio of 34 cells (56.7%) was 2.3, and the ratio of 26 cells (43.3%) was 1.0, whereas the overall ratio was 1.76. Because more than 50% (56.7%) of the tumor cells have a ratio higher than 2.2 (2.3), it is not considered HER2 GH but, rather, HER2 amplified. This interpretation is obviously incorrect in 2 ways: The tumor consists of 2 populations of tumor cells having different HER2 signal ratios that fit HER2 GH, and the tumor is not HER2 amplified based on the American Society of Clinical Oncology/CAP HER2 guidelines that the HER2/CEP17 ratio be less than 1.8 (1.76).2,3 The key problem behind this misinterpretation is caused by using 50% as the upper limit to define GH. Because the guidelines use 5% as the lower limit to define HER2 GH, they should use 95% (100% − 5%) as the upper limit. The rationale is that if we consider a tumor having more than 5% of HER2-amplified tumor cells as HER2 GH, the same should hold true for those that have more than 5% of nonamplified cells. Therefore, we propose the HER2 GH guidelines be revised to “more than 5% but less than 95% of infiltrating tumor cells with a HER2/CEP17 ratio higher than 2.2.” If this modified definition is used, our case and cases like it would be considered HER2 GH and would not be considered HER2 amplified.The authors have no relevant financial interest in the products or companies described in this article.