Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Department of Clinical Education Center, Kyushu University Hospital, Fukuoka, Japan.
JCO Precis Oncol. 2024 May;8:e2300681. doi: 10.1200/PO.23.00681.
The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer.
We conducted a retrospective study using real-world clinical data and next-generation sequencing-based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment.
In 114 patients with human epidermal growth factor receptor-2 (HER2)-positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were (82%), (80%), and (36%). Multivariate Cox regression analysis revealed amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; = .044). Analyses of 1,450 G/GEJ cancers revealed significant / coamplification (41% relative to 11% amplification in -nonamplified tumors; < .0001). -activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with -mutated tumors showed shorter PFS than those without mutations after T-DXd treatment (mPFS, 105 180 days; = .046).
amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in coamplified tumors. -activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.
尚未阐明基因组改变对曲妥珠单抗-deruxtecan（T-DXd）的反应和耐药性的影响。因此，我们试图确定预测胃癌或胃食管交界处（G/GEJ）癌对 T-DXd 敏感性的因素。
我们使用来自日本全国性数据库的真实世界临床数据和基于下一代测序的全面基因组分析（CGP）数据进行了一项回顾性研究，该数据来自晚期 G/GEJ 癌症患者。我们分析了基因组改变与 T-DXd 治疗后患者生存之间的关系。
在 114 名接受 T-DXd 治疗的人表皮生长因子受体 2（HER2）阳性 G/GEJ 癌症患者中，最常改变的基因是 （82%）、 （80%）和 （36%）。多变量 Cox 回归分析显示，在 91 名在接受 T-DXd 治疗前获得 CGP 样本的患者中， 扩增是 T-DXd 治疗后无进展生存期（PFS）较短的显著预测因子（中位 PFS，131 天 189 天；风险比 [HR]，1.90 [95%CI，1.02 至 3.53]； =.044）。对 1450 例 G/GEJ 癌症的分析显示， / 共扩增（41%相对 非扩增肿瘤中的扩增； <.0001）。还在 3.7%的 G/GEJ 癌症和 8.8%接受 T-DXd 治疗的 HER2 阳性 G/GEJ 癌症中检测到 -激活突变。与 T-DXd 治疗后没有 突变的患者相比，携带 -突变肿瘤的患者的 PFS 更短（mPFS，105 180 天； =.046）。
在 HER2 阳性 G/GEJ 癌症中， 扩增可能导致对 T-DXd 的原发性耐药，提示细胞周期可能是 共扩增肿瘤的潜在治疗靶点。-激活突变也可能减弱 HER2 阳性 G/GEJ 癌症中 T-DXd 的疗效。
