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.

Keywords: Biomarker; Homologous recombination deficiency; NSCLC; Neoadjuvant immunotherapy; Whole-exome sequencing.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Mutational analysis results between MPR and non-MPR groups. a Landscape of frequent SNV and InDel on cancer driver genes. b Pathway enrichment analysis on mutated tumor suppressor genes. c Three HRD metrics including TAI, LST and HRD-LOH calculated on non-aneuploid samples. d HRDscore calculated on non-aneuploid samples. e Correlation between HRDscore and percentage of viable tumor cells in all non-aneuploid samples

Fig. 2

Clonal HR pathway gene deactivation impacts neoadjuvant immunotherapy consequences in NSCLC patients. a TMB value distribution between MPR/non-MPR groups. b Correlation between TMB and percentage of viable tumor cells. c Clonal TMB value in two groups. d Correlation between clonal TMB and percentage of viable tumor cells. e Existence of HR pathway genes’ clonal SNV in two groups. The size of the circle was proportional to the mutation number. P values were calculated by Fisher’s exact test on all and SCC samples. f Subclonal SCNA fragment number in two groups. g Correlation between subclonal SCNA fragment number and percentage of viable tumor cells. h Deletion status of 13 HR core pathway genes in MPR/non-MPR groups. P values were calculated by Fisher’s exact test or one-side Wilcoxon rank-sum test. Adenocarcinoma samples were marked with pink triangles. i Correlation between focal deletion number of the 13 genes and percentage of viable tumor cells. j All and clonal neoantigen number generated by two groups. Adenocarcinoma samples were marked with pink triangles. k Clonal TNB value distribution in two groups. l Correlation between clonal TNB and percentage of viable tumor cells