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

False-Positive Results Using IHC

Jacobs et al[8] drew attention to the presence of false-positive HercepTest results by retesting breast carcinomas, which were interpreted as negative by FISH and by other IHC methods using the same antibody. This finding highlights and suggests several important concepts relating to IHC testing for HER2/neu expression. First, such testing is intended as a quantitative test. Second, the test result will vary according to the method utilized, including the primary antibody used, antigen detection and retrieval techniques, the scoring system, the expertise of the pathologist analyzing the test, and the use of other technologies (eg, image analysis). For example, Jacobs and associates[8] reduced the number of false-positive results using the HercepTest kit by modifying the scoring system to take into account the level of staining of nonneoplastic epithelium.

Concordance Between Different IHC Antibody Reagents and FISH Testing for HER2/neu Status in Breast Carcinoma.

Several reports have now verified that false-positive results are an issue in testing for HER2/status by IHC.[4,9,10,11,12,13,14] The "gold standard" used to identify these false-positive results has been testing for HER2/neu gene amplification by FISH. This is due to the greater specificity and sensitivity of FISH when either test is compared with HER2/neu overexpression as determined by Northern and Western blot analyses.[15,16] However, errors may also occur with FISH analysis (approximately 5%). The percentage of IHC false-positive results varies by different IHC antibodies and methods. Representative studies that compare overexpression by IHC testing and gene amplification by FISH in the assessment of HER2/neu status in breast carcinomas are presented in the above Table.

Studies have shown that the problem of false-positive results involves IHC techniques most significantly when the result is 2+.[4,9,10,11,12,13,14] As few as 17% of 2+ HercepTest carcinomas demonstrate gene amplification by FISH.[13] The overwhelming majority of 3+ positives are amplified. However, in a study by Mass et al,[4] 11% of 3+ positive tumors did not demonstrate gene amplication by FISH, indicating that false-positive results are a potential problem in this group as well. False-negative results, ie, IHC-negative/FISH-positive carcinomas, are rare in the 0-1+ group.

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