e20580 Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. Recently, Immune checkpoint inhibitors (ICIs) have been shown to have the potential to improve the prognosis of SCLC, but little is known about immunotherapeutic biomarkers. Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in small cell lung cancer. Herein, we analyze the mutational pattern of HRR related genes in a Chinese SCLC cohort and further analyze the relationship between HRR-gene mutations and tumor mutational burden. Methods: Target gene sequencing (543 genes) was performed in 133 Genecast cohort with small cell lung cancer. PD-L1 expression were evaluated for 90 among 133 patients using the SP142 PD-L1 immunohistochemistry assay. Results: Among 133 patients, 47 (35.3%) had HRR-gene mutations. ATM (8.3%), NBN (4.5%) and BRCA2 (4.5%) were the top 3 mutated HRR-gene in the cohort，followed by ATR (3.8%), BARD1 (3.8%), BRCA1 (3.8%), PALB2 (3.8%), RAD50 (3.8%), CHEK2 (3.0%), BLM (3.0%), BRIP1(2.3%), CHEK1(1.5%), RAD52(1.5%), and MRE11A (0.8%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (11/47, 23.4%) and 3 (3/47, 6.4%) patients, respectively. 1 (1/47, 2.1%) patient carried both germline and somatic variants. Genomic landscape revealed that TP53 and RB1 were commonly mutated genes in SCLC cohort. Mutations in KMT2D, AR and RTK-RAS pathway occurred more frequently in the HRR-Mut group, compared with the wildtype ones. Furthermore, we found that mutations in HRR-gene were associated with high TMB (Wilcoxon, p = 0.048), and patients with high TMB (≥median) showed a higher proportion of positive PD-L1 expression in 90 SCLC patients. Conclusions: Our data indicated that genomic alterations associated with HRR-genes have a positive correlation with high TMB, and detection of HRR-gene mutation status probably could help identify patients who might benefit from immune checkpoint blockade therapy. Keywords: Small cell lung cancer, Homologous recombination deficiency, Immunotherapy.
Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer
