Molecular features influencing clinical outcome of advanced HER2-positive gastric cancer receiving trastuzumab plus chemotherapy

Less than half of the human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients respond to trastuzumab plus chemotherapy, and the outcomes are unsatisfactory. Understanding the underlying mechanisms remains crucial for identifying patients who are more likely to benefit from treatment. We performed targeted DNA sequencing on paired pre-treatment and progressive tumour tissues from 22 HER2-positive advanced GC patients undergoing first-line treatment with trastuzumab and chemotherapy. Clinicopathological and genomic characteristics were assessed for the correlation with clinical outcomes. A performance status (PS) of 0–1 was associated with improved progression-free survival (PFS) and overall survival (OS) than a PS of 2. Poorly differentiated tumours exhibited shorter PFS than moderate or moderate-poor ones. Pre-treatment amplification of <i>MYC</i> or <i>TOP2A</i> gene was association with increased PFS, and suggested a potential benefit for OS. Patients with higher tumour mutation burden (TMB) experienced significantly worse PFS, while higher chromosome instability (CIN) appeared to be correlated with longer PFS. Compared to non-responders, responders had a higher CIN but similar TMB and intratumoural heterogeneity (ITH). PS and <i>MYC</i> amplification emerged as independent factors related to PFS according to multivariate survival analysis. Additionally, after treatment, TMB significantly increased in non-responders, while CIN significantly decreased in responders. Pre-treatment <i>MYC</i> amplification and PS were independently associated with clinical outcomes in HER2-positive advanced GC patients treated with first-line trastuzumab plus chemotherapy. Dynamic post-treatment changes in TMB and CIS provide valuable insights into the relationship between therapeutic response and distinct evolutionary trajectories.

仅有不足半数的人表皮生长因子受体2（human epidermal growth factor receptor 2, HER2）阳性胃癌（gastric cancer, GC）患者可从曲妥珠单抗联合化疗中获益，且治疗结局不尽如人意。阐明其潜在机制，对筛选更易从该治疗方案中获益的患者至关重要。本研究对22例接受曲妥珠单抗联合化疗一线治疗的HER2阳性晚期胃癌患者的配对治疗前及进展后肿瘤组织开展靶向DNA测序，评估临床病理及基因组特征与临床结局的相关性。体力状态（performance status, PS）评分为0~1的患者，其无进展生存期（progression-free survival, PFS）及总生存期（overall survival, OS）均优于PS评分为2的患者。低分化肿瘤的无进展生存期短于中分化或中低分化肿瘤。治疗前MYC或TOP2A基因扩增与更长的无进展生存期相关，且提示总生存期可能获得获益。肿瘤突变负荷（tumor mutation burden, TMB）较高的患者无进展生存期显著更差，而较高的染色体不稳定性（chromosome instability, CIN）似乎与更长的无进展生存期相关。与无应答者相比，应答者的染色体不稳定性更高，但肿瘤突变负荷及瘤内异质性（intratumoural heterogeneity, ITH）相似。经多变量生存分析显示，体力状态评分及MYC扩增是与无进展生存期相关的独立影响因素。此外，治疗后无应答者的肿瘤突变负荷显著升高，而应答者的染色体不稳定性显著降低。治疗前MYC基因扩增及体力状态评分，是接受曲妥珠单抗联合化疗一线治疗的HER2阳性晚期胃癌患者临床结局的独立相关因素。治疗后肿瘤突变负荷与染色体不稳定性的动态变化，为揭示治疗应答与不同肿瘤进化轨迹之间的关联提供了重要见解。