Research Paper Volume 13, Issue 21 pp 24136—24154
Mutations in DNA damage response pathways as a potential biomarker for immune checkpoint blockade efficacy: evidence from a seven-cancer immunotherapy cohort
- 1 Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical University, Weifang, Shandong 261053, China
- 2 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
Received: July 3, 2021 Accepted: October 26, 2021 Published: November 8, 2021https://doi.org/10.18632/aging.203670
How to Cite
Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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, P < 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 [P = 0.034] and 0.33 [P = 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 P < 0.01). Mutations of 4 DDR genes, including MRE11A, MSH2, ATM, and POLE could predict favorable ICB prognoses (all P < 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.