DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).

Abstract

9100 Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as ≥10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high (≥50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( < 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with ≥3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of ≥3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.