Association of DNA damage response and repair gene (DDR) mutations and microsatellite instability (MSI), PD-L1 expression, tumor mutational burden (TMB) in gastroesophageal cancers
Michael Cerniglia BS, Joanne Xiu PhD, Axel Grothey MD, Michael Pishvaian MD PhD, Jimmy Hwang MD, John Marshall MD, Ari M. VanderWalde MD MPH, Anthony F. Shields MD PhD, Heinz-Joseph Lenz MD , W. Michael Korn MD, Mohamed Salem MD, Philip A. Philip MD PhD, Richard M. Goldberg MD , Sunnie S. Kim MD
DNA damage response and repair genes (DDR) encode proteins that assist in homology-directed repair. These proteins interact with other DNA repair proteins and form a system for DNA damage repair.
The prevalence of genetic deficiencies in the mechanism of homologous recombination across all tumor lineages has been well characterized.1 Certain gastric cancers have been shown to harbor deficiencies in the homologous recombination pathway.2
Studies also show DDR mutations upregulate PD-L1, increase tumor mutational burden, and are associated with higher tumor infiltrating lymphocytes.3,4
Therefore deficient homologous recombination and biomarkers for immune checkpoint inhibition are a possible opportunity for immunotherapy in upper GI
We investigated the association of DDR mutations in gastric (GC), esophageal (EC), and gastroesophageal junction (GEJ) cancers with known predictors for
immune checkpoint inhibitors.
To compare the association of known predictive biomarkers (MSI, PD-L1, TMB) to checkpoint inhibitors in DDR-mutated upper GI malignancies vs. non-DDRmutated upper GI malignancies
To correlate specific DDR alterations (e.g. ARID1A, ATRX, BRCA2, PTEN, RAD50, WRN) in gastric, esophageal, and gastroesophageal junction cancers with MSI, PD-L1, and TMB
Molecular profiles of tumors obtained from patients with gastric, esophageal, and gastroesophageal cancers were reviewed to identify DDR mutations and their association with MSI, PD-L1, and TMB. The molecular profiles were generated from tumors submitted to CARIS Life Sciences.
20 DDR mutations were tested by Next-Generation Sequencing (NGS) with a 592-gene panel on a total of 1935 (709 Esophageal; 831 Gastric; 355 Gastroesophageal junction) cancers.
MSI was assessed by NGS or fragment analysis, PD-L1 by IHC (22c3 for CPS or SP142), and TMB by NGS (TMB-high ≥10 mutations/megabase [mt/MB]).
Based on the molecular profiles examined within this study, DDR mutations are prevalent across all gastroesophageal cancers. Out of esophageal, gastric, and gastroesophageal junction cancers, DDR-mutations are most pronounced in gastric cancers.
Biomarker expression of MSI-H, TMB-high, and high PD-L1 are significantly more prevalent in the DDR-mutated cohort compared to the non-DDRmutated cohort.
Out of the 20 DDR mutations examined, alterations in ARID1A, ATRX, BRCA2, and PTEN are correlated with MSI-H and TMB-high. In contrast ARID1A, BRCA2, RAD50, and WRN are correlated with increased PD-L1 expression. These highly prevalent DDR mutations should be investigated as possible biomarkers for treatment.
These findings may help identify patients for tailored immunotherapy approaches in future clinical trials. By further identifying associations of DDR
alterations and immuno-oncology predictive biomarkers, rational drug combinations may be implemented in the treatment of upper gastrointestinal cancers.