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). <i>ERBB2 L755S</i> alteration, <i>CDKN2A</i> insertion, and <i>RICTOR</i> amplification (0% vs 10.0%, <i>P</i> = .263, for all of the above factors) were only observed in nonresponders. Among the <i>ERBB2</i>-amplified samples from GC patients in the cBioPortal database, <i>TP53</i> missense mutations (51.1%) and <i>CCNE1</i> amplifications (25.5%) were the most common co-mutations associated with <i>ERBB2</i> amplification. Moreover, the incidences of <i>ERBB2 L755S</i> were 16.7% in <i>ERBB2</i>-amplified GC and 52.9% in <i>ERBB2</i>-amplified breast cancer (<i>P</i> = .179) according to the LAVA database. <i>ERBB2 L755S</i>, <i>CDKN2A</i> insertion, and <i>RICTOR</i> 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.