Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update

Abstract

Purpose: To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.

Methods: ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.

Results: The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations.

Recommendations: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.

Figure 1

Algorithm for evaluation of human epidermal growth factor receptor 2 (HER2) protein expression by immunohistochemistry (IHC) assay of the invasive component of a breast cancer specimen. Although categories of HER2 status by IHC can be created that are not covered by these definitions, in practice they are rare and if encountered should be considered IHC 2+ equivocal. ISH, in situ hybridization. NOTE: the final reported results assume that there is no apparent histopathologic discordance observed by the pathologist. (*) Readily appreciated using a low-power objective and observed within a homogeneous and contiguous invasive cell population.

Figure 2

Algorithm for evaluation of human epidermal growth factor receptor 2 (HER2) gene amplification by in situ hybridization (ISH) assay of the invasive component of a breast cancer specimen using a single-signal (HER2 gene) assay (single-probe ISH). Amplification in a single-probe ISH assay is defined by examining the average HER2 copy number. If there is a second contiguous population of cells with increased HER2 signals per cell, and this cell population consists of more than 10% of tumor cells on the slide (defined by image analysis or visual estimation of the ISH or immunohistochemistry [IHC] slide), a separate counting of at least 20 nonoverlapping cells must also be performed within this cell population and also reported. Although categories of HER2 status by ISH can be created that are not covered by these definitions, in practice they are rare and if encountered should be considered ISH equivocal (see Data Supplement 2E). NOTE: the final reported results assume that there is no apparent histopathologic discordance observed by the pathologist. (*) Observed in a homogeneous and contiguous population.

Figure 3

Algorithm for evaluation of human epidermal growth factor receptor 2 (HER2) gene amplification by in situ hybridization (ISH) assay of the invasive component of a breast cancer specimen using a dual-signal (HER2 gene) assay (dual-probe ISH). Amplification in a dual-probe ISH assay is defined by examining first the HER2/CEP17 ratio followed by the average HER2 copy number (see Data Supplement 2E for more details). If there is a second contiguous population of cells with increased HER2 signals per cell, and this cell population consists of more than 10% of tumor cells on the slide (defined by image analysis or visual estimation of the ISH or immunohistochemistry [IHC] slide), a separate counting of at least 20 nonoverlapping cells must also be performed within this cell population and also reported. Although categories of HER2 status by ISH can be created that are not covered by these definitions, in practice they are rare and if encountered should be considered ISH equivocal (see Data Supplement 2E). NOTE. The final reported results assume that there is no apparent histopathologic discordance observed by the pathologist. (*) Observed in a homogeneous and contiguous population. (†) See Data Supplement 2E for more information on these rare scenarios.

Figure 4

Number of laboratories participating in predictive marker proficiency testing for human epidermal growth factor receptor 2 (HER2) by immunohistochemistry (IHC), HER2 by fluorescent in situ hybridization (FISH), and estrogen receptor (ER) by IHC through the College of American Pathologists (CAP) Laboratory Improvement Program. Arrows indicate the years during which the HER2 and hormone receptor testing guidelines were published by the American Society of Clinical Oncology (ASCO)/CAP. The numbers of participating laboratories are shown both graphically and in tabular form. After the publication of the 2007 ASCO/CAP HER2 and the 2010 ASCO/CAP ER/progesterone receptor testing guidelines, there was a significant increase in the number of laboratories in the United States and elsewhere participating in CAP proficiency testing surveys in breast cancer (http://www.cap.org/apps/cap.portal?_nfpb=true&_pageLabel=accreditation; last checked June 14, 2013). CAP has a core goal to improve the quality of pathology and laboratory services through education and standard setting in order to enhance patient safety, and help laboratories meet or exceed regulatory requirements set by the Centers for Medicare and Medicaid Services, the Joint Commission, and many states in the United States.