The value of DNA repair gene and TP53 co-mutation in predicting the response of non-small cell lung cancer to immunotherapy.

[BACKGROUND] While mutations in DNA repair gene (DDR) or TP53 alone have been linked to favorable outcomes in immunotherapy, their co-mutations may not have the same effect. The co-occurrence of DDR and TP53 mutations may actually impair DNA repair, cause more genomic instability, and worsen prognosis, indicating that they may have a context-specific effect.

[METHODS] Clinical characteristics and next-generation sequencing (NGS) data of non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) were collected from cBioPortal ( www.cbioportal.org ). The incidence of DDR mutations was calculated. Kaplan-Meier analyses were performed to determine overall survival (OS) for the DDR+/TP53+ group vs. the DDR+/TP53- group using log-rank testing (p = 0.034). Univariate and multivariate Cox analyses were performed to establish prognostic value.

[RESULTS] Of the 350 patients studied, 78.6% had DDR mutations, 62% had TP53 mutations. The presence of DDR mutation status demonstrated a significant association with tumor mutational burden (TMB). Patients with DDR+/TP53+ mutations had shorter OS outcomes than DDR+/TP53-. Multivariable analysis confirmed that the presence of co-mutations was an independent predictor of poor outcome and diminished ICI efficacy.

[CONCLUSION] While previous reports would suggest that the mutation status of DDR or TP53 leads to a benefit, our results demonstrate that upon co-mutations of DDR/TP53, mutant patients have inferior outcomes in NSCLC for immunotherapy treatments. This signifies that co-mutation status is an important consideration in biomarker-driven treatment strategies.