In the era of precision medicine, human epidermal growth factor receptor 2 (HER2) is the most important predictive and prognostic biomarker in breast cancer.The HER2 status of a patient’s tumor can be analyzed at the protein level by immunohistochemistry (IHC) and at the chromosome level by in situ hybridization (ISH) techniques to determine the average HER2 gene copy number.Yet, despite these 2 complementary methods for HER2 testing, there remains a subset of high-risk breast cancer patients (>20%) whose HER2 status is reported as “equivocal,” an assessment that provides no useful information about how to treat the patient. Given there are 2 FDA approved HER2 assays readily available in the clinical laboratory, the currently confused state of HER2 testing in breast cancer is perplexing and raises the following questions: are IHC and dual-probe ISH giving the wrong answer 20% of the time, or alternatively, could these tests be giving the correct answers and we are misinterpreting the data? For the past decade, genomic pathologists have used chromosomal microarrays (CMAs) as a DNA-based approach for obtaining high-resolution images of HER2 gene status on chromosome 17. These studies provide confirmation that ISH is a reliable method for determining average HER2 gene copy number, and it is the HER2 ratio denominators (cep17 or alternative probes) that can introduce instability into the final results. However, even though CMA provides more detailed information about chromosome 17 status in breast cancer than conventional cytogenetics or FISH, the complexity of the method and interpretation make it impractical for routine use by the clinical laboratory as a HER2 testing method.Thus, IHC and fluorescence in situ hybridization will remain for the foreseeable future, the mainstay of HER2 testing in breast cancer.The current challenge is thus not to introduce a new HER2 assay into the clinical laboratory but rather to develop a strategy for reporting unequivocal, biologically accurate results using existing FDA-approved testing methods.
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