Trastuzumab response

Select individuals based on HER2 protein overexpression or HER2 gene amplification in tumor specimens. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.

Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.

Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Please review the complete therapeutic recommendations that are located here: (1)

FDA-approved medical devices for HER2 can be searched forhere.

First released in 2007 and updated in 2013 and 2018, the recommendations by the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing Expert Panel are aimed at improving the analytic validity of HER2 testing and the clinical utility of HER2 as a predictive biomarker for potential responsiveness to therapies targeting the HER2 protein.

2013: ASCO/CAP Key Recommendations for Oncologists

• Must request HER2 testing on every primary invasive breast cancer (and on metastatic site, if stage IV and if specimen available) from an individual with breast cancer to guide decision to pursue HER2-targeted therapy. This should be especially considered for an individual who previously tested HER2 negative in a primary tumor and presents with disease recurrence with clinical behavior suggestive of HER2-positive or triple-negative disease.
• Should recommend HER2-targeted therapy if HER2 test result is positive, if there is no apparent histopathologic discordance with HER2 testing and if clinically appropriate.
• Must delay decision to recommend HER2-targeted therapy if initial HER2 test result is equivocal. Reflex testing should be performed on the same specimen using the alternative test if initial HER2 test result is equivocal or on an alternative specimen.
• Must not recommend HER2-targeted therapy if HER2 test result is negative and if there is no apparent histopathologic discordance with HER2 testing.
• Should delay decision to recommend HER2-targeted therapy if HER2 status cannot be confirmed as positive or negative after separate HER2 tests (HER2 test result or results equivocal). The oncologist should confer with the pathologist regarding the need for additional HER2 testing on the same or another tumor specimen.
• If the HER2 test result is ultimately deemed to be equivocal, even after reflex testing with an alternative assay (i.e., if neither test is unequivocally positive), the oncologist may consider HER2-targeted therapy. The oncologist should also consider the feasibility of testing another tumor specimen to attempt to definitely establish the tumor HER2 status and guide therapeutic decisions. A clinical decision to ultimately consider HER2-targeted therapy in such cases should be individualized on the basis of individual status (comorbidities, prognosis, and so on) and individual preferences after discussing available clinical evidence.

2018: ASCO/CAP Updated Key Recommendations for HER2 testing

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Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria.

Please review the complete ASCO/CAP recommendations in the 2013 update (22) and 2018 update (4).

Key Points and Recommendations for Clinicians

• Recommendation 1.1: In individuals with advanced GEA who are potential candidates for HER2-targeted therapy, the treating clinician should request HER2 testing on tumor tissue (Type: evidence based; Quality of evidence: high; Strength of recommendation: strong).
• Recommendation 1.2: Treating clinicians or pathologists should request HER2 testing on tumor tissue in the biopsy or resection specimens (primary or metastasis) preferably prior to the initiation of trastuzumab therapy if such specimens are available and adequate. HER2 testing on FNA specimens (cell blocks) is an acceptable alternative (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: recommendation/moderate).
• Recommendation 1.3: Treating clinicians should offer combination chemotherapy and HER2-targeted therapy as the initial treatment for appropriate individuals with HER2 positive tumors who have advanced GEA (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: strong).

Key Points and Recommendations for Pathologists

• Recommendation 2.1: Laboratories/pathologists must specify the antibodies and probes used for the test and ensure that assays are appropriately validated for HER2 IHC and ISH on GEA specimens (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: strong).
• Recommendation 2.2: When GEA HER2 status is being evaluated, laboratories/pathologists should perform/order IHC testing first, followed by ISH when IHC result is 2+ (equivocal). Positive (3+) or negative (0 or 1+) HER2 IHC results do not require further ISH testing (Type: evidence based; Quality of evidence: high; Strength of recommendation: strong).
• Recommendation 2.3: Pathologists should use the Ruschoff/Hofmann method in scoring HER2 IHC and ISH results for GEA (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: strong).
• Recommendation 2.4: Pathologists should select the tissue block with the areas of lowest grade tumor morphology in biopsy and resection specimens. More than one tissue block may be selected if different morphologic patterns are present (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: recommendation/moderate).
• Recommendation 2.5: Laboratories should report HER2 test results in GEA specimens in accordance with the CAP “Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens From Individuals With Adenocarcinoma of the Stomach or Esophagogastric Junction” (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: strong).
• Recommendation 2.6: Pathologists should identify areas of invasive adenocarcinoma and also mark areas with strongest intensity of HER2 expression by IHC in GEA specimen for subsequent ISH scoring when required (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: strong).
• Recommendation 2.7: Laboratories must incorporate GEA HER2 testing methods into their overall laboratory quality improvement program, establishing appropriate quality improvement monitors as needed to ensure consistent performance in all steps of the testing and reporting process. In particular, laboratories performing GEA HER2 testing should participate in a formal proficiency testing program, if available, or an alternative proficiency assurance activity (Type: evidence based; Quality of evidence: moderate/intermediate; Strength of recommendation: strong).
• Recommendation 2.8: There is insufficient evidence to recommend for or against genomic testing in GEA individuals at this time.

Please review the complete ASCO/CAP recommendations here (52).