Mutations in DNA damage response pathways as a potential biomarker for immune checkpoint blockade efficacy: evidence from a seven-cancer immunotherapy cohort
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Updated: Oct 14, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Wenjing Zhang1, Liwen Zhang1, Hao Jiang1
1Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Weifang Medical University, Weifang, Shandong 261053, China.
Abstract:
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.
Insights
Mutations in DNA damage response (DDR) pathways significantly improve survival for patients receiving immune checkpoint blockade (ICB) therapy, particularly in bladder and colorectal cancers. Specific DDR gene mutations and patient factors like high mutation burden predict better ICB outcomes.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Emerging evidence links DNA damage response (DDR) pathway mutations to outcomes in immune checkpoint blockade (ICB) therapy.
- Previous studies often suffered from small sample sizes, limited cancer types, and lacked multivariate analyses, potentially yielding unreliable conclusions.
- Understanding the prognostic value of DDR mutations is crucial for optimizing cancer immunotherapy strategies.
Purpose of the Study:
- To evaluate the association between DDR mutations and immunotherapy prognosis in a large cohort of ICB-treated patients.
- To explore the intrinsic prognostic impact of DDR mutations in treatment-naive patients.
- To assess the relationship between DDR mutations and the tumor microenvironment.
Main Methods:
- Retrospective analysis of 1363 ICB-treated patients from the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort.
- Analysis of 4286 ICB-treated-naive patients from The Cancer Genome Atlas (TCGA) cohort.
- Multivariate Cox regression models and stratified analyses were employed to assess prognostic factors and survival benefits.
Main Results:
- DDR mutations were significantly associated with prolonged overall survival in ICB-treated patients (HR: 0.70, P < 0.001).
- Favorable ICB prognosis in DDR-mutated patients was observed in bladder and colorectal cancers (HR: 0.59, P=0.034 and HR: 0.33, P=0.006, respectively).
- Positive predictive factors for ICB survival benefits in DDR-mutated patients included age >60, male gender, high tumor mutation burden, and PD-1/PD-L1 treatment. Mutations in MRE11A, MSH2, ATM, and POLE genes predicted favorable ICB prognoses.
- DDR-mutated patients exhibited an improved immune microenvironment.
Conclusions:
- DDR mutations are a significant predictor of favorable immunotherapy outcomes, especially in specific cancers and patient subpopulations.
- Identifying patients with DDR mutations can inform patient selection for ICB therapy and clinical trial design.
- These findings support the development of tailored immunotherapy strategies based on DDR mutation status.
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