Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical University, Weifang, Shandong 261053, China.
Tianjin Cancer Institute, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Aging (Albany NY). 2021 Nov 8;13(21):24136-24154. doi: 10.18632/aging.203670.
Recently several studies have demonstrated the implications of mutations in DNA damage response (DDR) pathways for immune checkpoint blockade (ICB) treatment. However, smaller sample sizes, lesser cancer types, and the lack of multivariate-adjusted analyses may produce unreliable results. From the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort, we curated 1363 ICB-treated patients to evaluate the association of DDR mutations with immunotherapy prognosis. Besides, 4286 ICB-treated-naive patients from the Cancer Genome Atlas (TCGA) cohort were used to explore the intrinsic prognosis of DDR mutations. Factors in the microenvironment regarding DDR mutations were also assessed. We found that patients with DDR mutations exhibited a significantly prolonged immunotherapy overall survival via multivariate Cox model in the MSKCC cohort (HR: 0.70, < 0.001). Specific cancer analyses revealed that patients with DDR mutations could obtain the better ICB prognosis in bladder cancer and colorectal cancer (HR: 0.59 [ = 0.034] and 0.33 [ = 0.006]). Stratified analyses showed that age >60, male gender, high mutation burden, and PD-1/PD-L1 treatment were the positive conditions for ICB survival benefits of DDR mutations (all < 0.01). Mutations of 4 DDR genes, including , , , and could predict favorable ICB prognoses (all < 0.01). A better immune microenvironment was observed in DDR mutated patients. Mutations in DDR pathways or single DDR genes were associated with preferable ICB efficacy in specific cancers or subpopulations. Findings from our study would provide clues for tailing clinical trials and immunotherapy strategies.
最近有几项研究表明，DNA 损伤反应 (DDR) 途径的突变对免疫检查点阻断 (ICB) 治疗有影响。然而，较小的样本量、较少的癌症类型以及缺乏多变量调整分析可能会产生不可靠的结果。我们从纪念斯隆-凯特琳癌症中心 (MSKCC) 队列中筛选了 1363 名接受 ICB 治疗的患者，以评估 DDR 突变与免疫治疗预后的关系。此外，我们还从癌症基因组图谱 (TCGA) 队列中筛选了 4286 名接受 ICB 治疗的初治患者，以探讨 DDR 突变的内在预后。还评估了 DDR 突变与微环境相关的因素。我们发现，通过 MSKCC 队列中的多变量 Cox 模型，DDR 突变患者的免疫治疗总生存期显著延长 (HR: 0.70, < 0.001)。具体癌症分析显示，DDR 突变患者在膀胱癌和结直肠癌中可以获得更好的 ICB 预后 (HR: 0.59 [ = 0.034] 和 0.33 [ = 0.006])。分层分析显示，年龄 >60 岁、男性、高突变负荷和 PD-1/PD-L1 治疗是 DDR 突变对 ICB 生存获益的阳性条件 (均 < 0.01)。4 个 DDR 基因 (、、和 ) 的突变可以预测 ICB 的良好预后 (均 < 0.01)。DDR 突变患者的免疫微环境更好。DDR 通路或单个 DDR 基因的突变与特定癌症或亚群中更好的 ICB 疗效相关。我们的研究结果为临床试验和免疫治疗策略的制定提供了线索。
