ES3-3: Adjuvant Therapy in Patients with a Borderline HER-2 Status.
Authors: Oakman C , Migliaccio I , Santarpia L , Di Leo A 
Published: June 2012

Abstract
Adjuvant trastuzumab is indicated in individuals with early breast cancer which has HER2 gene amplification and/or HER2 protein overexpression. In the pivotal phase III adjuvant trials which tested the addition of trastuzumab to chemotherapy, positive HER2 status was defined as strong and complete cell membrane staining by immunohistochemistry (IHC) of &gt;10% of invasive tumor cells or gene amplification determined by fluorescence in-situ hybridisation (FISH) ratio of HER2 gene copy number to chromosome 17 centromeres (CEP17) of &gt;2.0.
The decision to use trastuzumab is based on a binary categorization of HER2 as positive or negative. As such, the definition of HER2 positivity is critical, as it dictates who will or will not receive potentially efficacious treatment. The challenge in creating guidelines for anti-HER2 treatment is that an HER2 result is described as positive or negative, but HER2 exists as a continuum of gene copy number and protein expression.
A source of uncertainty in the management of patients is the discordance between the diagnostic thresholds for HER2 adopted in the adjuvant trastuzumab trials and those specified in the subsequently published American Society of Clinical Oncology and the College of American Pathologists (ASCO-CAP) guidelines. According to ASCO-CAP, HER2 positivity is defined by uniform intense and complete membrane staining by IHC in ≥30% of cells or HER2/ CEP17 FISH ratio≥2.2. The definition is stricter than thresholds applied in the adjuvant trials, identifying a narrower population as HER2 positive.
A further source of uncertainty is discordance between IHC and FISH. There is generally high concordance between the two methods, as increased HER2 protein is generally attributable to HER2 amplification. Discordant results may occur if one assay is correct and the other is incorrect, due to pre-analytic, analytic, and/or post-analytic error. True discordance may be attributable to intra-tumoral heterogeneity or polysomy chromosome 17. Within a tumor, HER2 amplification and/or overexpression may be detected in discrete focal HER2 amplified clones (FHAC) or in individual cells diffusely scattered on a dominant background of HER2 negative/equivocal expression. FHAC have been reported in association with discordance between IHC and FISH. Cells with polysomy chromosome 17 have extra copies of the HER2 gene. In such cases, tumors may be IHC positive although the HER2:CEP17 FISH ratio is not elevated. Notably, available data are inconsistent and uncertainty remains as to whether polysomy 17 without HER2 amplification is associated with protein overexpression
During this session, clinical situations with borderline HER2−status will be presented and discussed. Biological heterogeneity within the same tumor, polysomy chromosome 17, and moderate HER2 positivity may contribute to determination of an uncertain HER2 status, making unclear the benefit of adjuvant trastuzumab in these cases. Clinical considerations highlighting pros/cons of adjuvant trastuzumab in these cases, as well as updated biological information and clinical perspectives, will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr ES3-3.