Publications

BACKGROUND

• 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
  cancers. ^5,6
• We investigated the association of DDR mutations in gastric (GC), esophageal (EC), and gastroesophageal junction (GEJ) cancers with known predictors for
  immune checkpoint inhibitors.

OBJECTIVES

• 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

METHODS

• 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]).

CONCLUSIONS

• 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.