HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma

The CAP periodically reevaluates published evidence-based guidelines to determine whether newer evidence or evolving clinical practice warrants revised guidance. Since 2016, HER2 testing in gastroesophageal adenocarcinoma (GEA) has been influenced by changes in treatment options and increased use of alternative specimen types. Expanded molecular/genomic testing approaches have also raised new implementation questions, supporting the need for revised recommendations.

Yes. The 2016 guideline remains valid, and several of its key statements were reaffirmed as Good Practice Statements. This update adds new recommendations and addresses evolving areas of practice, but it does not replace the foundational guidance established in 2016.

Genomic testing using tissue and/or liquid biopsy may be used concurrently or subsequently to support clinical decision-making. However, evidence indicates that IHC with reflex ISH (when indicated) remains the preferred approach for establishing HER2 status because genomic methods show variable concordance and limited sensitivity compared with IHC/ISH.

Yes, usually. Biopsy and resection specimens show high concordance (typically >90%), although tumor heterogeneity can lead to occasional discordance. Metastatic lesions are also generally concordant with the primary tumor (usually >80%), but conversion (HER2 negative↔positive) can occur after treatment progression. Cytology cell blocks (eg, effusions) may be used when other tissue is unavailable, though concordance data are limited and interpretation may be more challenging.

Yes. In advanced GEA, HER2 status can change after treatment (including loss of HER2 positivity), which may affect whether HER2-targeted therapy remains appropriate. This is a change from the 2016 guideline, which recommended repeat testing at progression mainly for patients with unknown or previously negative HER2 status. In this update, repeat HER2 testing may be performed in previously HER2-positive cases before starting second-line therapy. Tissue-based testing is preferred; liquid biopsy may be used when tissue-based resampling is not feasible.

CAP expert panels use the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision Framework, a structured and standardized approach for developing clinical recommendations. While the certainty (level) of evidence is an important factor, it is not the only determinant of recommendation strength. The panel also considers the balance of benefits and harms, along with key implementation factors such as values and preferences, resource use, health equity, accessibility, and feasibility, drawing on expert judgment to reach the final strength of recommendation.