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

Abstract

Background Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. Methods In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. Results DNA 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, percentage 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. Conclusions We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

Progress and perspectives of perioperative immunotherapy in non-small cell lung cancer

“…Moreover, HR pathway mutations were associated with better responding immunotherapy patients regardless of the treatment regimen and clinicopathological characteristics. It has also been observed that patients on immunotherapy with HR mutations have higher a TMB and longer survival in addition to a substantial number HR pathway alternations in multiracial treatment-free samples ( 51 , 52 ).…”

Progress on neoadjuvant immunotherapy in resectable non-small cell lung cancer and potential biomarkers

“…Tumor bulk RNA sequencing in NADIM trial recently revealed that certain tumor environmental gene expression could predict pCR with the AUC >0.9 ( 73 ). With innovational technique implying in this area, novel markers including mutational signature ( 74 , 75 ), intestinal microbiota ( 76 ), radiomics ( 77 , 78 ) are now under analysis in neoadjuvant setting of NSCLC, with the hope to provide us with a deeper understanding of the tumor environment and evolution. These new markers might perform well when combined with existing markers (TMB, PD-L1, Tumor neoantigen burden, etc.)…”

Genomic landscape and efficacy of HER2-targeted therapy in patients with HER2-mutant non-small cell lung cancer

“…Three patients carried oncogenic mutations involved in the DDR pathway at PD. Since mutations in the DDR pathway were associated with improved survival for immune checkpoint inhibitors in NSCLC (33)(34)(35), a combination of pyrotinib and immune checkpoint inhibitors may vanquish the resistance. SMARCA4 oncogenic mutation was identified in one patient who received pyrotinib.…”