Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

Abstract

AbstractBackgroundNeoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer but the study to prioritize effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between patients with distinct response to neoadjuvant immunotherapy in non-small-cell lung cancer (NSCLC) for the derive of biomarkers with indicative capability in predicting outcomes.MethodsIn this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimen followed by surgical resection. Pre-therapy FFPE or fresh tissues and blood samples were analyzed by whole-exome sequencing (WES). Genetic alternation comparisons were conducted between differently-responded patients. Multiple public cohorts were selected for validation.ResultsDNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e. major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percent of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings.ConclusionsWe innovatively associated the HRD event with enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multi-facet public cohorts. We propose the inspection of HR pathway gene status could serve as novel and additional indicators directing immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.