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Assessment of Methods for Tissue-Based Detection of the HER-2/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry

From the Department of Medicine, Division of Hematology-Oncology, University of California at Los Angeles, UCLA School of Medicine, Los Angeles, CA; and Flinders Medical Centre, Bedford Park, South Australia, Australia.

Address reprint requests to Dennis J. Slamon, MD, PhD, Division of Hematology and Oncology, UCLA School of Medicine, 11–934 Factor Bldg, Los Angeles, CA 90095-1678; email dslamon{at}mednet.ucla.edu

PURPOSE: To compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in detecting the HER-2/neu alteration in human breast cancer.

PATIENTS AND METHODS: Unselected stage I, II, and III breast cancer patients (N = 900) were tested for HER-2/neu gene amplification by FISH in paraffin-embedded, formalin-fixed archival material. Of these samples, 856 were tested for HER-2/neu overexpression by non–antigen-retrieval IHC with the polyclonal antibody R60, the sensitivity and specificity of which was preliminarily compared with the United States Food and Drug Administration–approved HercepTest (Dako Corp, Carpinteria, CA). Patient survival was analyzed in relation to the presence of the HER-2/neu alteration as determined by these two methodologies.

RESULTS: A total of 189 (21%) of 900 patients were positive by FISH and 147 (17.2%) of 856 were positive by IHC. This discrepancy is consistent with expected loss of IHC sensitivity associated with tissue fixation/embedding. The HercepTest did not improve sensitivity and introduced false positives. Comparison of R60-based IHC with FISH demonstrates that patient survival is associated progressively to gene amplification level as determined by FISH, whereas for IHC an association is found only in the highest (3+) immunostaining group. Among FISH-negative tumors, 45 (6.6%) of 678 were IHC-positive, with a survival probability similar to that of FISH-negative/IHC-negative cases; FISH-positive/IHC-negative patients have a survival probability similar to that of FISH-positive/IHC-positive cases.

CONCLUSION: IHC does not consistently discriminate patients likely to have a poor prognosis, whereas FISH provides superior prognostic information in segregating high-risk from lower-risk beast cancers. HER-2/neu protein overexpression in the absence of gene amplification occurs infrequently in breast cancer, in which case, patient outcome is similar to that of patients without the alteration.

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				P. A. Bunn Jr., B. Helfrich, A. F. Soriano, W. A. Franklin, M. Varella-Garcia, F. R. Hirsch, A. Baron, C. Zeng, and D. C. Chan Expression of Her-2/neu in Human Lung Cancer Cell Lines by Immunohistochemistry and Fluorescence in Situ Hybridization and its Relationship to in Vitro Cytotoxicity by Trastuzumab and Chemotherapeutic Agents Clin. Cancer Res., October 1, 2001; 7(10): 3239 - 3250. [Abstract] [Full Text] [PDF]

				J. Baselga Is Circulating HER-2 More Than Just a Tumor Marker? Clin. Cancer Res., September 1, 2001; 7(9): 2605 - 2607. [Full Text] [PDF]

				F. J. Esteva, V. Valero, L. Pusztai, L. Boehnke-Michaud, A. U. Buzdar, and G. N. Hortobagyi Chemotherapy of Metastatic Breast Cancer: What to Expect in 2001 and Beyond Oncologist, April 1, 2001; 6(2): 133 - 146. [Abstract] [Full Text]

				S. Braun, G. Schlimok, I. Heumos, G. Schaller, L. Riethdorf, G. Riethmüller, and K. Pantel erbB2 Overexpression on Occult Metastatic Cells in Bone Marrow Predicts Poor Clinical Outcome of Stage I-III Breast Cancer Patients Cancer Res., March 1, 2001; 61(5): 1890 - 1895. [Abstract] [Full Text]