Abstract 1691: The impact of genomic mutational status on PD-L1 expression and tumor mutation burden in non-small cell lung cancer
Authors: Qing Zhou, Weiguang Gu, WenFan Fu, Shijie Mai, Daren Lin, Shiyue Zhang, Wenjing Wang, Peng Zhang
Journal: Cancer Research (2019)

Abstract Background: Immune checkpoint inhibitors have provided remarkable antitumor effects in non-small cell lung cancer (NSCLC), while their efficacy in patients harboring driver mutations is still controversial and the correlation between driver gene mutations and PD-L1 expression remains unclear. In this study, we explored the association of PD-L1 expression, tumor mutation burden (TMB) and genomic mutation in NSCLC patients. Methods: FFPE tumor and matched blood samples of 244 NSCLC patients were collected for NGS-based targeted panel sequencing from July 2017 to July 2018. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. PD-L1 expression, TMB and microsatellite instability status (MSI) were assessed in 244 (100%), 188 (77%) and 198 (81%) patients, respectively. Results: There were 145 males (59.4%) and 99 females (40.6%) with a median age of 62 (31-84) years were involved, including 183 adenocarcinomas and 61 squamous carcinomas. PD-L1 expression of negative, 1-49% and ≥50% were 63.5%, 20.9% and 15.6%, respectively. The median value of TMB was 9.2 (0.8-68.9) muts/Mb and TMB≥10 muts/Mb was seen in 30.9% tumors. All the tumors but one were MSS status. The demographic features were comparable among different PD-L1 expression and TMB level (cutoff is 10 muts/Mb) group. We found recurrent mutations (&amp;gt;10%) in 6 genes, including TP53 (67.6%), EGFR (60.7%), CDKN2A (15.2%), KRAS (13.9%), PI3KCA (11.1%) and LRP1B (10.7%). AKT2 (2.5%) amplification was associated with higher TMB (p=0.011). For the relationship between driver genes and immunotherapeutic biomarkers, TP53 were positively associated with higher PD-L1 expression (p&amp;lt;0.001), while BRAF associated with lower PD-L1 (p&amp;lt;0.001); TP53 and BRAF mutations were correlated with higher TMB (p&amp;lt;0.001, p&amp;lt;0.001; respectively), while EGFR, KRAS, ERBB2 and ALK correlated with lower TMB (p&amp;lt;0.001, p&amp;lt;0.001, p&amp;lt;0.001,p=0.046; respectively). Interestingly, in terms of double mutants, NSCLC patients with EGFR and NOTCH1 co-mutations had lower level of TMB than either single mutant alone. EGFR and RBM10 double mutant was associated with lower PD-L1 expression than either single mutant. Conclusion: This study revealed the impact of genomic mutational status on immunotherapeutic biomarkers in NSCLC. TP53 mutation was associated with higher PD-L while TP53, BRAF mutations and AKT2 amplification correlated with higher TMB. EGFR with NOTCH1 or RBM10 co-mutation is associated with lower TMB or PD-L1, which needs further investigation in their impact on immunotherapy. Our study indicated that NGS panel sequencing and co-mutation analysis could provide potentially insights to precise immunotherapy. Citation Format: Qing Zhou, Weiguang Gu, WenFan Fu, Shijie Mai, Daren Lin, Shiyue Zhang, Wenjing Wang, Peng Zhang. The impact of genomic mutational status on PD-L1 expression and tumor mutation burden in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1691.