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 Shen; W M Korn; H J Lenz

doi:10.1016/j.annonc.2021.03.203

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. doi: 10.1016/j.annonc.2021.03.203. Epub 2021 Mar 30.

Authors

J Y Wang¹, J Xiu², Y Baca², H Arai³, F Battaglin³, N Kawanishi³, S Soni³, W Zhang³, J Millstein⁴, A F Shields⁵, A Grothey⁶, B A Weinberg⁷, J L Marshall⁷, E Lou⁸, M Khushman⁹, D P S Sohal¹⁰, M J Hall¹¹, M Oberley², D Spetzler², L Shen¹², W M Korn², H J Lenz¹³

Affiliations

¹ Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
² Caris Life Sciences, Phoenix, USA.
³ Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
⁴ Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
⁵ Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, USA.
⁶ GI Cancer Research, West Cancer Center and Research Institute, Germantown, USA.
⁷ Division of Hematology and Oncology, Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, USA.
⁸ Division of Hematology, Oncology and Transplantation, Masonic Cancer Center, University of Minnesota, Minneapolis, USA.
⁹ Department of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, USA.
¹⁰ Division of Hematology/Oncology, University of Cincinnati, Cincinnati, USA.
¹¹ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, USA.
¹² Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
¹³ Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA. Electronic address: [email protected].

PMID: 33798656
DOI: 10.1016/j.annonc.2021.03.203

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.

Keywords: PD-L1 expression; combined positive score; gastroesophageal adenocarcinoma; genomic landscape; immune checkpoint inhibitor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma* / drug therapy
Adenocarcinoma* / genetics
B7-H1 Antigen* / genetics
B7-H1 Antigen* / metabolism
Female
Genomics
Humans
Immunotherapy*
Male
Mitogen-Activated Protein Kinases
Mutation
Tumor Suppressor Protein p53 / genetics

Substances

B7-H1 Antigen
TP53 protein, human
Tumor Suppressor Protein p53
Mitogen-Activated Protein Kinases