Systematic Review of HER2 Breast Cancer Testing

Abstract

HER2 status is of great clinical value in breast tumors for the identification of those patients who are eligible for trastuzumab therapy. There is a debate about the advantages and disadvantages of immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and where, when, how, and who would perform HER2 testing. The purpose of this study was to analyze clinical and analytic validity and clinical utility for HER2 testing (IHC and FISH) for the appropriate selection of breast cancer patients who were suitable for trastuzumab therapy. A systematic review of the literature was carried out using online databases (MedLine, Embase, Centre for Reviews and Dissemination and the Cochrane Library). It brings up to date the cost-effectiveness analysis published by Technology Assessment Unit of the McGill University Health Centre (MUHC). The articles that were selected according to the following inclusion criteria: (1) included breast cancer patients, (2) used IHC and FISH assays, (3) reported the sensibility, specificity, reliability of IHC and FISH, or concordance between both techniques, and (4) were published in any language. A critical appraisal was performed using an ad hoc scale based on CASPe (Critical Appraisal Skills Programme Spanish) criteria. Literature search generated 17 studies that satisfied the inclusion criteria. Most articles evaluated the HercepTest and PathVysion assays. FISH was considered the gold standard test. We calculated the FISH positivity rate in each IHC score category. The percentage of FISH positive results (median) was estimated as 3.5 for IHC0, 5.8 for IHC1+, 17 for IHC2+, and 83.5 for IHC3+. Our findings have shown high concordance rates between IHC and FISH in tumors IHC0 and IHC1+, and discordance rates among cases with IHC2+ and IHC3+. In these cases, FISH is considered gold standard for confirming or excluding HER2 amplification.

Effects of the Change in Cutoff Values for Human Epidermal Growth Factor Receptor 2 Status by Immunohistochemistry and Fluorescence In Situ Hybridization: A Study Comparing Conventional Brightfield Microscopy, Image Analysis-Assisted Microscopy, and Interobserver Variation

“…These cases had negative HercepTest results (IHC 0 or 1+) but were amplified by FISH. Such HER2 FISH-amplified and IHC-negative cases are well described in the literature 12 and have recently been found to represent 3.5% of IHC 0 and 5.8% of IHC 1+ cases. 20 Considering the frequency of IHC 0 and 1+ cases in this study, between 4 and 5 IHC-negative-and-FISH-positive samples would be expected.…”

“…Overall, the percentage of agreement (concordance) was calculated, and k statistics were also used to assess agreement between the 2 methods and to describe agreement among the different pathologists. 12 All statistical analyses were done using SPSS 17 or 18 for Windows (SPSS Inc, Chicago, Illinois).…”

“…There is still no consensus on which of these methods is the most predictive. [12][13][14] Since 1998, HER2 testing has been based on the HercepTest guidelines approved by the US Food and Drug Administration (FDA). Other IHC tests have been approved by concordance to the HercepTest.…”

Quantification of HER2 by Targeted Mass Spectrometry in Formalin-Fixed Paraffin-Embedded (FFPE) Breast Cancer Tissues

“…Overall, this may indicate that the current recommendation that the HER2 amplification status be assessed by IHC or FISH, with the latter considered as the gold standard, might show exceptions. Indeed, the nonconcordance between protein expression and gene amplification is about 17% for IHC scores of 2ϩ (46).…”

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

“…Using cell lines, it was possible to establish a standardized IHC procedure and scoring system in which cells containing Ͻ20,000 receptors would show no staining (0), cells containing approximately 100,000 receptors would show partial membrane staining with Ͻ10% of the cells showing complete membrane staining (1ϩ), cells containing approximately 500,000 receptors would show light to moderate complete membrane staining in Ͼ10% of the cells (2ϩ), and cells containing approximately 2,300,000 receptors would show strong, complete membrane staining in Ͼ10% of the cells (3ϩ). Studies have shown that when a standardized IHC assay is performed on specimens that are carefully fixed, processed, and embedded, there is good to excellent correlation between gene copy status and protein expression levels [162][163][164][165]. However, the ability to accurately determine HER-2 protein expression status by IHC can be significantly impacted by technical issues accentuated by the tissue fixation in formaldehyde, tissue processing, and embedding procedure in heated paraffin wax.…”