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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02992-x

摘要内容如下：

在DESTINY-GASTRIC01试验中，曲妥珠单抗Deruxtecan（T-DXD）对人类表皮生长因子受体2阳性（HER2+）胃癌患者的临床改善具有统计学意义。Destiny-Gastric01的探索性结果表明，HER2-low胃癌患者可能受益。HER2表达或基因改变的空间和时间异质性是胃癌肿瘤的固有特征，在识别可能对T-DXD有反应的患者方面存在挑战。与治疗反应相关的特异性生物标志物尚未得到广泛研究。进行探索性分析以评估循环肿瘤DNA和组织样本中的基线HER2相关生物标志物，并研究T-DXD耐药的机制。在HER2+胃癌患者的主要队列中，基线HER2相关生物标志物与客观缓解率（ORR）相关。主要队列中HER2阳性和HER2（erbB2）血浆基因扩增之间的一致性为64%。循环肿瘤DNA中的其他关键驱动基因扩增，特别是MET、EGFR和FGFR2，与数值上较低的ORR相关。在12例HER2功能获得性突变患者中，ORR为58.3%（7/12）。无论免疫组织化学样本采集的时间如何，ORR均一致。需要在更大的研究中进行进一步的调查。

英文原文如下：

Abstracts

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2+) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2+ gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

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