DNA Damage Response And Repair Gene Mutations Are Associated With Outcomes And Prognosis To Platinum Chemotherapy In Non-small Cell Lung Cancer Patients

ObjectiveDNA damage response and repair(DDR)genes are crucial for maintaining the integrity of the genome.The present study has explored the correlation of DDR gene mutations with tumor mutation load(TMB),clinical characteristics,and outcomes to platinum-based chemotherapy and platinum-based chemotherapy/immunotherapy in non-small cell lung cancer(NSCLC)without EGFR and ALK alterations.MethodsThis study retrospectively collected and analyzed the clinicopathological characteristics of 49 patients with non-small cell lung cancer who received platinum chemotherapy and platinum chemotherapy combined immunotherapy in Foshan First People’s Hospital and Foshan Nanhai People’s Hospital from August 2018 to October 2022.Tumor tissue and blood sample from 49 patients with stage Ⅲ or Ⅳ NSCLC who were without EGFR and ALK alterations were analyzed using targeted next-generation sequencing(NGS).Among them,13 patients received first-line platinum-based chemotherapy,32 patients received first-line platinum-based chemotherapy/immunotherapy.ResultsIn these NSCLC who were without EGFR and ALK alterations,the highly mutated genes included TP53,KMT2D and KRAS,the most mutated DDR gene was FANCG,DDR gene mutations were detected in 20 patients.The mutation frequency of homologous recombination repair(homologous recombination repair,HRR)pathway in lung squamous cell carcinoma(lung squamous cell carcinoma,LUSC)was 30.8%,which is significantly higher than that of the HRR pathway in lung adenocarcinoma(lung adenocarcinoma,LUAD)patients(5.7%).The proportion of distant metastasis was 70%in DDR mutation positive patients,93.1%in DDR mutation negative patients.In DDR positive patients,the percentage of patients with metastasis was lower(p=0.0497).TMB in patients with DDR gene mutations,cell-cycle checkpoint(CCK)pathway mutations and base excision repair(BER)pathway mutations was significantly higher than the patients without corresponding mutations.In the patients received platinum-based chemotherapy/immunotherapy,the disease control rate(DCR)in the DDR mutation-positive group was 55.6%,and the DCR of DDR gene mutation negative group was 100%.The disease control rate was significantly lower in the DDR-positive group compared with that in the DDR-negative group(p=0.0046).In lung adenocarcinoma(LUAD)patients received platinum-based chemotherapy/immunotherapy,poor overall survival(OS)was observed in DDR-positive,with a median OS of 240 days(p=0.012),poor progression-free survival(PFS)and OS were observed in BER-positive and FANCG mutated group.ConclusionDDR gene mutations are associated with tumor metastasis,TMB,and outcomes to platinum chemotherapy/immunotherapy in advanced NSCLC patients.