HER2-positive gastric cancer (GC) makes up 15–20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

HER2 阳性胃癌 (GC) 占所有 GC 发病率的 15-20%，曲妥珠单抗靶向治疗是标准治疗方法。然而，曲妥珠单抗的耐药机制仍未完全了解，并在临床实践中提出了重大挑战。在这项研究中，对 23 名 GC 患者在曲妥珠单抗治疗前（基线）和进行性疾病（PD）时的成对肿瘤组织进行了全外显子组测序（WES）。确定了可能与曲妥珠单抗的原发性和/或获得性耐药相关的临床病理学和分子特征。Lauren 肠型分类与无进展生存期 (PFS) 相比弥漫型更长（HR = 0.29，P = 0.019）。具有低肿瘤突变负荷 (TMB) 的患者 PFS 明显更差，而高染色体不稳定性 (CIN) 与延长的 OS 相关（HR = 0.27；P  = 0.044）。对治疗有反应的患者的 CIN 高于无反应者，并且随着反应的改善观察到 CIN 增加的积极趋势 ( P  = 0.019)。在我们的队列中，最常见的获得突变的基因是AURKA、MYC、STK11和LRP6 ，各有 4 名患者。我们还发现了克隆分支模式与生存之间的关联，与其他分支模式相比，广泛的克隆分支模式与较短的 PFS 更密切相关（HR = 4.71；P = 0.008）。我们确定了潜在的分子和临床因素，这些因素提供了关于晚期 HER2 阳性 GC 患者与曲妥珠单抗耐药性潜在关联的见解。