本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-03091-7

摘要内容如下：

循环肿瘤DNA（ctDNA）是早期尿路上皮癌的潜在生物标志物，但其在转移性疾病中的应用尚不清楚。在3期KEYNOTE-361研究中，在转移性尿路上皮癌患者中，pembrolizumab联合化疗和不联合化疗与单独化疗进行了比较。该研究未达到预先指定的统计学意义的疗效阈值。为了确定反应的潜在生物标志物，我们在KEYNOTE-361中回顾性评估了接受pembrolizumab（n=130）或化疗（n=130）的患者亚组中治疗前后ctDNA与临床结果的相关性。基线ctDNA与pembrolizumab的最佳总体缓解（BOR；P=0.009）、无进展生存期（PFS；P<0.001）和总生存期（OS；P<0.001）相关，但与化疗无关（ALL，P>0.05）。与pembrolizumab相比，化疗诱导的ctDNA从基线到治疗周期2的下降幅度更大；然而，pembrolizumab（n=87）与BOR（P=4.39×10-5）和OS（P=7.07×10-5）的相关性高于化疗（n=102；BOR：P=1.01×10-4；OS：P=0.018）。肿瘤组织知情版本的ctDNA变化指标与临床结果最相关，但当联合建模时，除了RECIST v1.1的放射学变化外，没有显示出统计学上显著的解释OS的独立价值（pembrolizumab p=0.364；化疗（P=0.823）。这些结果表明，免疫治疗和化疗早期ctDNA变化的不同模式及其与长期结果的相关性差异，为液体活检在转移性尿路上皮癌治疗监测中的应用提供了初步见解。临床试验注册：NCT02853305。

英文原文如下：

Abstracts

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated association of pre- and post-treatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA were associated with best overall response (BOR;P = 0.009), progression-free survival (PFS;P < 0.001), and overall survival (OS;P < 0.001) for pembrolizumab, but not chemotherapy (all, P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) were more associated with BOR (P = 4.39 × 10-5) and OS (P = 7.07 × 10-5) versus chemotherapy (n = 102; BOR: P = 1.01 × 10-4; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show statistically significant independent value for explaining OS beyond radiographic change by RECIST v1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights on the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305.

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