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Germline DNA damage response gene mutations as predictive biomarkers of immune checkpoint inhibitor efficacy
Michael J Dennis1,2, Sophia Bylsma3, Lisa Madlensky4,5
1Division of Medical Oncology, Moores Cancer Center, University of California, San Diego, San Diego, CA, United States.
Background:
Impaired DNA damage response (DDR) can affect immune checkpoint inhibitors (ICI) efficacy and lead to heightened immune activation. We assessed the impact of pathogenic or likely pathogenic (P/LP) germline DDR mutations on ICI response and toxicity.
Materials And Methods:
A retrospective analysis of 131 cancer patients with germline DNA testing and ICI treatment was performed.
Results:
Ninety-two patients were DDR-negative (DDR-), and 39 had ≥1 DDR mutation (DDR+). DDR+ patients showed higher objective response rates (ORRs) compared to DDR- in univariate and multivariable analyses, adjusting for age and metastatic disease (62% vs. 23%, unadjusted OR = 5.41; 95% CI, 2.41-12.14; adjusted OR 5.94; 95% CI, 2.35-15.06). Similar results were seen in mismatch repair (MMR), DDR pathways with intact MMR (DDR+MMRi), and homologous recombination (HR) subgroups versus DDR- (adjusted OR MMR = 24.52; 95% CI 2.72-221.38, DDR+MMRi = 4.26; 95% CI, 1.57-11.59, HR = 4.74; 95% CI, 1.49-15.11). DDR+ patients also had higher ORRs with concurrent chemotherapy (82% vs. 39% DDR-, p=0.03) or concurrent tyrosine kinase inhibitors (50% vs. 5% DDR-, p=0.03). No significant differences in immune-related adverse events were observed between DDR+ and DDR- cohorts.
Conclusion:
P/LP germline DDR mutations may enhance ICI response without significant additional toxicity.
Insights
Germline DNA damage response (DDR) mutations significantly improve immune checkpoint inhibitor (ICI) efficacy in cancer patients. These mutations enhance treatment response without increasing toxicity, offering a promising biomarker for therapy selection.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Impaired DNA damage response (DDR) is linked to immune checkpoint inhibitor (ICI) efficacy and immune activation.
- Assessing germline DDR mutations' impact on ICI response and toxicity is crucial for optimizing cancer treatment.
Purpose of the Study:
- To evaluate the association between pathogenic or likely pathogenic (P/LP) germline DDR mutations and response to ICI therapy.
- To determine if germline DDR mutations influence the toxicity profile of ICI treatment.
Main Methods:
- Retrospective analysis of 131 cancer patients who underwent germline DNA testing and ICI treatment.
- Comparison of objective response rates (ORRs) and immune-related adverse events between patients with and without DDR mutations.
Main Results:
- Patients with DDR mutations (DDR+) exhibited significantly higher ORRs (62%) compared to DDR-negative patients (23%).
- Subgroup analyses revealed enhanced ORRs in DDR+ patients across mismatch repair (MMR), DDR pathways with intact MMR (DDR+MMRi), and homologous recombination (HR) subgroups.
- DDR+ patients showed improved ORRs with concurrent chemotherapy or tyrosine kinase inhibitors, with no significant increase in adverse events.
Conclusions:
- P/LP germline DDR mutations are associated with enhanced response to ICI therapy.
- Germline DDR mutations may serve as a predictive biomarker for ICI efficacy without substantially increasing toxicity.
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