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

J.y. Wang, J. Xiu, Y. Baca, H. Arai, F. Battaglin, N. Kawanishi, S. Soni, W. Zhang, J. Millstein, A.f. Shields, A. Grothey, B.a. Weinberg, J.l. Marshall, E. Lou, M. Khushman, D.p.s. Sohal, M.j. Hall, M. Oberley, D. Spetzler, L. ShenW.m. Korn, H.j. Lenz

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The impact of molecular alterations on programmed death-ligand 1 (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 2518 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 the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases. Results: High, intermediate, and low CPSs 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 mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS–mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS–MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 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-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016). Conclusions: 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 for the development of rational combination immunotherapies in GEAs.

Original languageEnglish (US)
Pages (from-to)906-916
JournalAnnals of Oncology
Volume32
Issue number7
DOIs
StatePublished - Jul 1 2021

Bibliographical note

Funding Information:
This work was supported by the National Cancer Institute at the National Institutes of Health [grant number P30CA 014089 to HJL], Gloria Borges WunderGlo Foundation (no grant number), Dhont Family Foundation (no grant number), Victoria and Philip Wilson Research Fund (no grant number), San Pedro Peninsula Cancer Guild (no grant number), the V Foundation for Cancer Research (no grant number), and Eddie Mahoney Memorial Research Fund (no grant number).

Funding Information:
We thank the staff members of the TCGA Research Network and MSKCC and the cBioportal, as well as the authors for making their valuable research data public. This work was supported by the National Cancer Institute at the National Institutes of Health [grant number P30CA 014089 to HJL], Gloria Borges WunderGlo Foundation (no grant number), Dhont Family Foundation (no grant number), Victoria and Philip Wilson Research Fund (no grant number), San Pedro Peninsula Cancer Guild (no grant number), the V Foundation for Cancer Research (no grant number), and Eddie Mahoney Memorial Research Fund (no grant number). HJL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. JX, YB, MO, DS, and WMK are employees of Caris Life Sciences. AFS reports funding for research, travel, and the speaker's bureau from Caris Life Sciences. BAW reports receiving honoraria from Bayer, Sirtex, Lilly, Taiho, and HalioDx. All other authors have declared no conflicts of interest.

Publisher Copyright:
© 2021 European Society for Medical Oncology

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