Next-generation sequencing identifies potential mechanisms of primary resistance to trastuzumab-containing therapies in HER2-positive gastric cancer: Analysis based on real-world data and online databases.

Trastuzumab-containing therapy remains a treatment option for patients with HER2-positive gastric cancer (GC). However, primary resistance to trastuzumab is a challenge. Therefore, it is essential to identify biomarkers for predicting the efficacy of trastuzumab-based treatment. First, we retrospectively collected the clinical data of HER2-positive GC patients receiving trastuzumab-containing therapies at the Affiliated Hospital of Qingdao University from October 2019 to August 2024. The patients were divided into long-term and short-term response groups according to progression-free survival (PFS) time, treatment lines and regimens. The next-generation sequencing (NGS) results of these patients were analyzed to identify biomarkers for predicting the efficacy of trastuzumab-containing therapies. Next, the cBioPortal database and LAVA database were screened to explore molecular profiling data. A total of 38 patients were included at our center and were categorized into a responder group (N = 28) and a nonresponder group (N = 10). ERBB2 L755S alteration, CDKN2A insertion, and RICTOR amplification (0% vs 10.0%, P = .263, for all of the above factors) were only observed in nonresponders. Among the ERBB2-amplified samples from GC patients in the cBioPortal database, TP53 missense mutations (51.1%) and CCNE1 amplifications (25.5%) were the most common co-mutations associated with ERBB2 amplification. Moreover, the incidences of ERBB2 L755S were 16.7% in ERBB2-amplified GC and 52.9% in ERBB2-amplified breast cancer (P = .179) according to the LAVA database. ERBB2 L755S, CDKN2A insertion, and RICTOR amplification might confer resistance to trastuzumab and/or immunotherapy in HER2-positive GC, thus highlighting the clinical significance of NGS in guiding personalized treatment in these patients.