Laboratory Testing for HER2/neu in Breast Carcinoma: An Evolving Strategy to Predict Response to Targeted Therapy

Nils M. Diaz, MD, Interdisciplinary Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, Florida. Submitted July 1, 2001; accepted August 9, 2001

Cancer Control. 2001;8(5) 

In This Article

Abstract and Introduction

Background: Laboratory testing of HER2/neu in breast carcinoma has become vital to patient care following the approval of trastuzumab as the first therapy to target the HER2/neu oncoprotein. Initial clinical trials used immunohistochemistry (IHC) to test for HER2/neu overexpression in order to select patients for therapy. Fluorescence in situ hybridization (FISH), which tests for gene amplification, is more specific and sensitive than IHC when either assay is compared with HER2/neu overexpression as determined by Northern or Western blot analysis. Many weak overexpressors on IHC testing are not gene amplified on FISH analysis. Such weak overexpressors may be considered false-positives and raise the question of how best to test for HER2/neu.
Methods: The literature was surveyed regarding testing for HER2/neu overexpression in breast carcinomas and alternative testing strategies.
Results: False-positive results are a significant problem when IHC is exclusively used to test for HER2/neu overexpression. The false-positives are overwhelmingly confined to the group of 2+ positives and do not respond to targeted therapy. In contrast, concordance between IHC and FISH is high when immunostaining is interpreted as either negative or strongly positive (3+). Whereas some recent studies have suggested that FISH may better predict response to anti-HER2/neu therapy than IHC, others have indicated that IHC is as effective a predictor as FISH. IHC is less technically demanding and costly than FISH.
Conclusions: IHC analysis of HER2/neu in breast carcinoma is a useful predictor of response to therapy with trastuzumab when strongly positive. Negative immunostaining is highly concordant with a lack of gene amplification by FISH. Most weakly positive overexpressors are false-positives on testing with FISH. Thus, screening of breast carcinomas with IHC and confirmation of weakly positive IHC results by FISH is an effective evolving strategy for testing HER2/neu as a predictor of response to targeted therapy.

Since amplification of the HER2/neu (human epidermal growth factor receptor 2, also referred to as c-erbB-2) gene in invasive breast carcinomas was initially associated with a poor prognosis,[1] interest in the biology of the protein was directed to its potential as a target for therapy. Trastuzumab (Herceptin), a humanized monoclonal anti-HER2 antibody[2,3] is the first therapy approved by the Food and Drug Administration (FDA) that is directed against the HER2/neu oncoprotein. Its efficacy in treating patients with metastatic breast carcinoma is predicted by either HER2/neu protein over-expression or gene amplification.[4] This article reviews how the strategic testing for HER2/neu is evolving together with targeted therapeutic options.

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