Controversies in HER 2 Oncogene Testing : What Constitutes a True Positive Result in Patients With Breast Cancer ?

HER2 gene amplification is directly related to HER2 protein overexpression in human breast cancers. This somatically acquired genetic alteration is associated with shorter disease-free and overall survival of patients in the absence of HER2-targeted therapy. Because HER2-targeted therapies have significantly improved outcomes for patients whose cancers have this alteration, accurate assessment of the alteration with companion diagnostics has become critically important. US Food and Drug Administration (FDA)-approved companion diagnostics assess either HER2 gene amplification using fluorescence in situ hybridization (FISH) or HER2 protein overexpression using immunohistochemistry (IHC) assays. In an effort to standardize these evaluations of HER2 status, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have convened committees to establish guidelines for evaluation of HER2 status. Although results with HER2 IHC assays have been more problematic, our focus in this perspective is an overview of current issues related to HER2 assessment by FISH. Current ASCO-CAP guidelines for HER2 FISH assay interpretation designate 5 different groups according to HER2 FISH ratio and average HER2 gene copy number per tumor cell. These ASCO-CAP FISH groups are "group 1," designated in situ hybridization [ ISH]-positive, which has a HER2-to-chromosome 17 centromere (CEP17) ratio >= 2.0 and an average HER2 gene copy number per tumor cell >= 4.0; FISH "group 2," also currently designated as "ISH-positive", which has cancer cells with HER2-to-CEP17 ratio >= 2.0 but an average HER2 gene copy number per tumor cell <4.0; FISH "group 3," also currently designated as "ISH-positive", has cancer cells with HER2-to-CEP17 ratio <2.0 and an average HER2 gene copy number per tumor cell >= 6.0; FISH "group 4", currently designated as "ISH-equivocal", which has cancer cells with HER2-to-CEP17 ratio <2.0 and an average HER2 gene copy number per tumor cell >= 4.0 and <6.0; FISH "group 5", designated as ISH-negative, which has cancer cells with HER2-to-CEP17 ratio <2.0 and an average HER2 gene copy number per tumor cell <4.0. At the time when these guidelines were published, there were no studies using this interpretative strategy and, therefore, no available data related to prevalence rates of each FISH group, correlation of each FISH group with HER2 protein expression, or correlation of each group with clinical outcomes, either with or without HER2-targeted therapies. We and others have assessed these prevalence rates and correlations.