Originally published as JCO Early Release 10.1200/JCO.2007.14.8197 on February 9 2009

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Guidelines for Human Epidermal Growth Factor Receptor 2 Testing: Biologic and Methodologic Considerations

From the Department of Pathology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany; Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom; Health Quality Research, Altarum Institute, Ann Arbor, MI; Division of Hematology and Oncology, Department of Medicine, Geffen School of Medicine, University of California, Los Angeles; Department of Pathology and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Corresponding author: Michael F. Press, MD, PhD, Department of Pathology and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Ave, Ste 5409, Los Angeles, CA 90033; e-mail: press{at}usc.edu.

The goal of this review is to systematically address a number of issues raised in the American Society of Clinical Oncology–College of American Pathologists (ASCO-CAP) guidelines on testing for the human epidermal growth factor receptor 2 (HER-2) alteration. A group of investigators who are experienced in the conduct and interpretation of HER-2 assay methods reviewed the ASCO-CAP guidelines and address several areas of the HER-2 testing guidelines with a particular emphasis on biologic and methodologic considerations. Although HER-2 status determined by immunohistochemistry (IHC) and the status determined by fluorescent in situ hybridization (FISH) are significantly correlated, we feel that standard considerations of laboratory testing, including test accuracy, reproducibility, and precision, as well as the current data favor FISH over IHC assay methods for determining HER-2 status. These considerations are clearly important in clinical practice because HER2 amplification is directly linked to protein expression levels in breast cancer. However, this protein is not consistently analyzed in formalin-fixed tissues as a result of variability in fixation methods and times and the impact of fixation on HER-2 protein antigenicity. Conversely, gene amplification and FISH are significantly less dependent on tissue fixation methods, making this assay more reproducible between central and peripheral laboratories than IHC. Moreover, review of the existing data demonstrate that FISH is more strongly correlated with responsiveness to either trastuzumab or lapatinib treatment. Until other methods achieve similar test accuracy, reproducibility, and predictive value, we suggest FISH as the primary HER-2 testing modality for women with breast cancer who are candidates for HER-2–targeted therapies.

Supported in part by the Breast Cancer International Research Group, grants from the Breast Cancer Research Foundation and Expedition Inspiration, and Grant No. CA48780 from the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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