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To evaluate the concordance between HER2 gene amplification, determined by fluorescence in situ hybridization (FISH), and HER2 protein overexpression assessed by an immunohistochemical (IHC) assay. The IHC protocol used was a research assay, known as the Clinical Trial Assay (CTA), developed to select women with metastatic breast cancer (MBC) for three pivotal clinical trials of trastuzumab therapy.A direct-labeled, dual-probe FISH assay was used to determine HER2 amplification in 623 fixed breast cancer tissue specimens. These specimens had been stored as paraffin-embedded sections for 2-5 years. All specimens had been analyzed for HER2 protein expression by the CTA. To assess the reproducibility of FISH results in archived material, we evaluated a separate group of 617 breast cancer tissue specimens at two different laboratories.Informative FISH results were available for 529 (85%) of the 623 specimens. Overall concordance between FISH and IHC results was 82% (95% CI; 78-85%). Assay agreement between FISH results and specimens with immunostaining scores of 0, 1+, and 3+ were 97, 93 and 89%, respectively. However, only 24% of specimens with 2+ immunostaining scores had HER2 amplification by FISH; there was assay disagreement in 76% of specimens in this IHC subgroup. Interlaboratory FISH concordance was 92% (95% CI; 89-94%), indicating very good assay reproducibility in these archived specimens.HER2 status determined by CTA-IHC and FISH are significantly correlated; however, differences between these two assays can affect patient selection for trastuzumab therapy.