This issue of the American Journal of Hematology/Oncology® contains an important editorial and call to action for a change in how we interpret HER2 at the genomic level. As one of the early discovered gene amplifications that soon became a “druggable” target, HER2 analysis had a shaky start. One of the initial antibodies used to qualify patients for the trastuzumab trials was a rabbit polyclonal antibody that was rather sensitive, but not very specific. As monoclonal antibodies were validated to perform this task, there was still concern about tissue processing and accuracy—either false positives due to “antigen retrieval” using microwave heating or false negatives due to formalin fixation over a long weekend and loss of the epitope. The advent of fluorescence in situ hybridization (FISH) promised to solve this problem, in particular for HER2, where overexpression was felt to be uniformly driven by excess gene copy number and appeared to better predict clinical response to single-agent trastuzumab therapy.¹

Fast forward to the last 5 years and several iterations of American Society of Clinical Oncology/College of American Pathologists guide- lines that have tried to accommodate both single- and dual-probe (normalized) FISH to define positivity and equivocal results—which have become the bane of clinical decision making and heated discussions at tumor boards. This is in distinction to next-generation sequencing assays that make amplifications calls on the basis of copy number alone since whole chromosome polysomy is less common than loss or gain at loci at or around the centromere to which dual-probe FISH results are normalized and there is evidence that cases with low HER2 expression and borderline HER2 copy number may not benefit from trastuzumab.² As Dr Gunn points out, we may be better off simply casting off centromeric normalization and use absolute HER2 copy number. Of course, this may lower the number of equivocal results, but it will be very difficult to prove that this allows for more accurate decision making and treatment assignment and, ultimately, improved out- comes. Data from NSABB B-47 testing adjuvant trastuzumab in HER2-low cases and correlations with newer genomic assays may eventually provide more definitive data to change the standard.³

References

1. Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005;6(3):240-246.
2. Press MF, Sauter G, Buyse M, et al. HER2 gene amplification testing by fluorescent in situ hybridization (FISH): comparison of the ASCO-College of American Pathologists guidelines with FISH scores used for enrollment in Breast Cancer International Research Group clinical trials. J Clin Oncol. 2016;34(29):3518- 3528. doi: 10.1200/JCO.2016.66.669.
3. Chemotherapy with or without trastuzumab after surgery in treating women with invasive breast cancer. https://clinicaltrials.gov/ct2/show/NCT01275677. Updated January 31, 2017. Accessed April 27, 2017.