HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology

Abstract

Context: ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA.

Objectives: To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making.

Design: The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA.

Results: The panel is proposing 11 recommendations with strong agreement from the open-comment participants.

Recommendations: The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance.

Conclusions: This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.

Keywords: Gastroesophageal adenocarcinoma; Guidelines; HER2 testing.

Figure 1

Algorithm for clinicians. GEA, gastroesophageal adenocarcinoma.

Figure 2

Algorithm for pathologists. Tumor cell cluster is defined as a cluster of five or more tumor cells. Additional recommendations: Pathologists should ensure that biopsy or resection specimens used for HER2 testing are rapidly placed in fixative, ideally within 1 hour (cold ischemic time), and are fixed in 10% neutral buffered formalin for 6 to 72 hours. Routine histology processing and HER2 testing should be performed according to analytically validated protocols. Pathologists should identify areas of invasive adenocarcinoma and also mark areas with strongest intensity of HER2 expression by immunohistochemistry (IHC) in the gastroesophageal adenocarcinoma (GEA) specimen for subsequent scoring when in situ hybridization (ISH) is required.

Figure 3

HER2 immunochemistry showing representative cases for scoring. A, Negative 0: no reactivity, specifically no membranous reactivity is seen in any of the tumor cells. Any cytoplasmic staining is disregarded for scoring purposes. B, Negative 1+: tumor cells with faint/barely perceptible membranous staining. C, Equivocal 2+: tumor cells with weak to moderate, complete, basolateral, and lateral membranous staining. Columnar cells that are sectioned tangentially tend to show a complete membranous staining pattern. D, Positive 3+: tumor cells with a strong, complete, basolateral, and lateral membranous reactivity. Also note that cells showing a complete membranous staining pattern are often tangentially sectioned columnar cells (HER2, ×40 [A, C, and D] and ×20 [B]).

Figure 4

HER2 and CEP17 FISH show scores of representative cases. A, Not amplified: ratio 1.0. Mean number of HER2 signals per cell is 1.9; mean number of CEP17 signals per cell is 1.8. B, Not amplified: ratio 1.3. Mean number of HER2 signals per cell is 3.4; mean number of CEP17 signals per cell is 2.7. Segmental duplication (or polysomy) likely accounts for signal numbers greater than two per cell. C, Amplified: ratio 3.0. Mean number of HER2 signals per cell is 5.2; mean number of CEP17 signals per cell is 1.7. CEP, chromosome enumeration probe; FISH, fluorescence in situ hybridization.