TABLE 3 College of American Pathologists’ Recommendations for HER2 Testing (18)

General recommendations

 The prognostic and predictive value of erbB-2 (Her2/neu) in invasive breast cancer is compelling and may warrant erbB-2 testing as a routine part of the diagnostic work-up. ErbB-2 testing of primary invasive cancers should be recommended before utilization of Herceptin, an anti-erbB-2 novel therapeutic agent, and may assist in predicting response to systemic agents.

 The predictive value of erbB-2 in some patient groups will require further validation through randomized clinical trials.

 Since many significant issues relating to the translational application of erbB-2 testing are unresolved (e.g., testing methods, reagents, interpretation, controls), a conservative approach is warranted.

 It is unclear whether fluorescence in-situ hybridization (FISH) assays are superior to immunohistochemistry, or whether FISH should be considered an adjunct or replacement.

 Given the current lack of standardization and comparability data, specific reagents and/or methods for erbB-2 testing cannot yet be recommended. It should be recognized that erbB-2 testing is a work in progress and data to resolve these important issues are not available.

Specific recommendations

 The method and primary reagent should be reported with the assay result. The name of the reagent kit used and the commercial supplier should be recorded in a diagnostic comment.

 Controls should be included in each assay. A tissue control (with strongly positive cancer and adjacent benign epithelium) is recommended. Fixed embedded cell lines with normal, slightly amplified, and significantly amplified erbB-2 are strongly recommended as companion assay controls and for assay development.

 Only the invasive component of a tumor (not in situ disease) should be scored.

 For immunohistochemistry, membranous reactivity only should be considered positive.

 ErbB-2 staining should not be observed in adjacent stroma or inflammatory cells, nor should benign epithelium show membranous reactivity. If staining is observed in benign components, the assay may be considered indeterminate.

 Reporting should include an estimate of the percentage of immunopositive invasive cancer cells. If a separate scoring system or cut point is also used to define positivity, it must be defined in a diagnostic comment.

 Variance in methodology (including any changes to FDA approved or supplier recommended protocols) should be recorded in a diagnostic comment.

 Indeterminate cases may warrant confirmatory testing using another method.

 Laboratory erbB-2 data and their correlation with histologic grade should be reviewed on a regular, ongoing basis.