Moleculaire veranderingen en PD-L1 expressie waarden geven een zogeheten gecombineerde positieve score (CPS). Uit een studie onder 2518 patiënten met gastro-oesofageale adenocarcinoom uitgevoerd door CARIS blijkt dat bij patiënten met actief herstel van mismatch en microsatellietstabiele ziekte de KRAS-, TP53- en RAS-MAPK-pathway-mutaties geassocieerd werden met een hogere gecombineerde positieve score (CPS).
Mutaties in de RAS-MAPK-pathway vertoonden een gunstige voorspelling voor een betere algehele overleving (OS), terwijl TP53-mutaties geassocieerd waren met een kortere algehele overleving (OS) in deze groep met behandeling met immuuntherapie met anti-PD medicijnen.
Uit het studieabstract:
Highlights:
- 1.
GEA tumors with mutations in KRAS, TP53 and RAS-MAPK pathway are associated with high PD-L1 CPS in the pMMR&MSS subgroup.
- 2.
RAS-MAPK pathway alteration may be a positive predictor and TP53 mutation a negative predictor for ICI efficacy in GEA.
- 3.
RAS-MAPK pathway alteration and TP53 mutation are positively and negatively, respectively, associated with tumor immunity.
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
Published:March 30, 2021DOI:https://doi.org/10.1016/j.annonc.2021.03.203
Abstract
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.
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Article Info
Publication History
Accepted: March 28, 2021
Received in revised form: March 21, 2021
Received: December 6, 2020
Publication stage
In Press Journal Pre-ProofFootnotes
Financial support
This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, the V Foundation for Cancer Research, Eddie Mahoney Memorial Research Fund.
Conflict of interests
H.-J.L. reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. J.X, B.Y, M.O, D.S, and W.M.K. are employers of Caris Life Sciences. A.F.S reports funding for research, travel, and the speaker’s bureau from Caris Life Sciences. B.A.W reports receiving honoraria from Bayer, Sirtex, Lilly, Taiho, and HalioDx. All remaining authors have declared no conflicts of interest.
Author contributions
Conception and design: J. Wang, J. Xiu, W.M.Korn, H.-J. Lenz
Development of methodology: J. Wang, J. Xiu, Y. Baca, W. Zhang, H.-J. Lenz
Acquisition of data (carried out experiments, acquired and managed patients, provided facilities, etc.): J. Wang, J. Xiu, Y. Baca, A. F. Shields, A. Grothey, B.A. Weinberg, J.L. Marshall, E. Lou, M. Khushman, D. P.S. Sohal, M. Hall, F. Battaglin, H. Arai, K. Natsuko, S. Soni, W. Zhang, M. Oberley, D. Spetzler, W. M. Korn, H.-J. Lenz.
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J. Wang, J. Xiu, Y. Baca, W. Zhang, M. Oberley, D. Spetzler, W.M. Korn, H.-J. Lenz
Writing, review, and/or revision of the manuscript: J. Wang, J. Xiu, Y. Baca, A. F. Shields, A. Grothey, B.A. Weinberg, J.L. Marshall, E. Lou, M. Khushman, D. P.S. Sohal, M. Hall, F. Battaglin, H. Arai, S. Soni, W. Zhang, M. Oberley, D. Spetzler, L. Shen, W. M. Korn, H.-J. Lenz.
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases, providing experimental materials): J. Wang, J. Xiu, Y. Baca, L. Shen, H.-J. Lenz
Study supervision: H.-J. Lenz
Identification
Copyright
© 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
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