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Wang JY , Xiu J , Baca Y , Arai H , Battaglin F , Kawanishi N , Soni S , Zhang W , Millstein J , Shields AF , Grothey A , Weinberg BA , Marshall JL , Lou E , Khushman M , Sohal DPS , Hall MJ , Oberley M , Spetzler D , Shen L , Korn WM , Lenz HJ
Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy
Ann Oncol. 2021 Jul;32(7) :906-916
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PURPOSE: The impact of molecular alterations on PD-L1 combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs. PATIENTS AND METHODS: Genomic alterations of 2,518 GEAs were compared in three groups (PD-L1 CPS≥10, high; CPS=1-9, intermediate; CPS<1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on MSKCC and TCGA databases. RESULTS: CPS-high, intermediate, and low were seen in 18%, 54% and 28% of GEAs respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with dMMR/MSI-H, but independent of TMB distribution. Tumors with mutations in KRAS, TP53 and RAS-MAPK pathway were associated with higher PD-L1 CPSs in the pMMR&MSS subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype patients [27 vs. 13 months, hazard ratio (HR)=0.36, 95% confidence interval (CI): 0.19-0.7, p=0.016] and a similar trend was observed in the MSS subgroup (p=0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-wildtype patients in the MSS subgroup (5 vs. 21 months, HR=2.39, 95%CI: 1.24-4.61, p=0.016). CONCLUSION: This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and the development of rational combination immunotherapies in GEAs.
1569-8041 Wang, J Xiu, J Baca, Y Arai, H Battaglin, F Kawanishi, N Soni, S Zhang, W Millstein, J Shields, A F Grothey, A Weinberg, B A Marshall, J L Lou, E Khushman, M Sohal, D P S Hall, M J Oberley, M Spetzler, D Shen, L Korn, W M Lenz, H J Journal Article England Ann Oncol. 2021 Mar 30:S0923-7534(21)01100-5. doi: 10.1016/j.annonc.2021.03.203.