Antonio C. Wolff*, M. Elizabeth H. Hammond*, Jared N. Schwartz*, Karen Hagerty, D. Craig Allred, Richard Cote, Mitchell Dowsett, Patrick L. Fitzgibbons, Steven Gutman, Wedad Hanna, Patricia Keegan, Amy Langer, Lisa M. McShane, Soonmyung Paik, Mark D. Pegram, Edith A. Perez, Michael F. Press, Anthony Rhodes, Catharine Sturgeon, Sheila Taube, Raymond Tubbs, Gail H. Vance, Marc van de Vijver, Thomas Wheeler, Judy Yost, and Daniel F. Hayes*

*ASCO/CAP Expert Panel Co-Chairs

Purpose: To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker.

Methods: The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations.

Results: Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy.

Recommendations: The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.




ASCO’s practice guidelines and technology assessments reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research.  Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a guideline or assessment was submitted for publication.  Guidelines and assessments are not continually updated and may not reflect the most recent evidence.  Guidelines and assessments cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments.  It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient.  Accordingly, adherence to any guideline or assessment is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances.  ASCO guidelines and assessments describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials.  ASCO and CAP assume no responsibility for any injury or damage to persons or property arising out of or related to any use of this guideline, or to any errors or omissions