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Diagnostic Evaluation of HER-2 as a Molecular Target: An Assessment of Accuracy and Reproducibility of Laboratory Testing in Large, Prospective, Randomized Clinical Trials

Authors' Affiliations: ¹ Women's Cancers Program and Departments of ² Pathology and ³ Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine; ⁴ Jonsson Comprehensive Cancer Center, University of California at Los Angeles School of Medicine, Los Angeles, California; ⁵ Department of Pathology, University of Basel, Basel, Switzerland; and ⁶ Breast Cancer International Research Group, Paris, France

Requests for reprints: Michael F. Press, University of Southern California/Norris Comprehensive Cancer Center, NOR5409, 1441 Eastlake Avenue, Los Angeles, CA 98195-6043. Phone: 323-865-0563; Fax: 323-865-0122; E-mail: villalob{at}usc.edu.

Purpose: To critically assess the accuracy and reproducibility of human epidermal growth factor receptor type 2 (HER-2) testing in outside/local community-based hospitals versus two centralized reference laboratories and its effect on selection of women for trastuzumab (Herceptin)–based clinical trials.

Experimental Design: Breast cancer specimens from 2,600 women were prospectively evaluated by fluorescence in situ hybridization (FISH) for entry into Breast Cancer International Research Group (BCIRG) clinical trials for HER-2-directed therapies.

Results: HER-2 gene amplification by FISH was observed in 657 of the 2,502 (26%) breast cancers successfully analyzed. Among 2,243 breast cancers with central laboratory immunohistochemistry (10H8-IHC) analysis, 504 (22.54%) showed overexpression (2+ or 3+). Outside/local laboratories assessed HER-2 status by immunohistochemistry in 1,536 of these cases and by FISH in 131 cases. Overall, the HER-2 alteration status determined by outside/local immunohistochemistry showed a 79% agreement rate [ statistic, 0.56; 95% confidence interval (95% CI), 0.52-0.60], with FISH done by the central laboratories. The agreement rate comparing BCIRG central laboratory 10H8-IHC and outside/local laboratory immunohistochemistry was 77.5% ( statistic, 0.51; 95% CI, 0.46-0.55). Finally, HER-2 status, determined by unspecified FISH assay methods at outside/local laboratories, showed a 92% agreement rate ( statistic, 0.83; 95% CI, 0.73-0.93), with FISH done at the BCIRG central laboratories.

Conclusions: Compared with the HER-2 status determined at centralized BCIRG reference laboratories, these results indicate superiority of FISH to accurately and reproducibly assess tumors for the HER-2 alteration at outside/local laboratories for entry to clinical trials.

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