EBV and MSI Status in Gastric Cancer: Does It Matter?

SIMPLE SUMMARY: Gastric cancer is characterized by high morphologic and molecular heterogeneity. Microsatellite instability (MSI-high) and Epstein–Barr-virus-positive (EBV+) tumors have been associated with better prognosis, but the benefit of perioperative chemotherapy (POPChT) in these tumors is still debatable. Moreover, recent evidence has suggested that response to treatment and prognosis are sex-modulated. We aimed to evaluate the prognostic and predictive value of tumor-specific molecular subtypes on survival and response to POPChT. In our cohort, we did not find differences in overall survival and progression-freesurvival between microsatellite stable (MSS)/EBV-, MSI-high or EBV+ tumors in patients submitted to direct surgery or POPChT. However, females with MSI-high tumors showed a significantly better OS than females with MSS tumors when submitted to POPChT, while in males, the opposite behavior was observed. Thus, our findings may help to pave the way to personalized treatment in GC, considering both patients’ and disease characteristics. ABSTRACT: We investigated the impactof microsatellite instability (MSI) and Epstein–Barr virus (EBV) status in gastric cancer (GC), regarding response to perioperative chemotherapy (POPChT), overall survival (OS), and progression-free survival (PFS). We included 137 cases of operated GC, 51 of which were submitted to POPChT. MSI status was determined by multiplex PCR and EBV status by EBV-encoded RNA in situ hybridization. Thirty-seven (27%) cases presented as MSI-high, and seven (5.1%) were EBV+. Concerning tumor regression after POPChT, no differences were observed between the molecular subtypes, but females were more likely to respond (p = 0.062). No significant differences were found in OS or PFS between different subtypes. In multivariate analysis, age (HR 1.02, IC 95% 1.002–1.056, p = 0.033) and positive lymph nodes (HR 1.82, IC 95% 1.034–3.211, p = 0.038) were the only prognostic factors for OS. However, females with MSI-high tumors treated with POPChT demonstrated a significantly increased OS compared to females with MSS tumors (p = 0.031). In conclusion, we found a high proportion of MSI-high cases. MSI and EBV status did not influence OS or PFS either in patients submitted to POPChT or surgery alone. However, superior survival of females with MSI-high tumors suggests that sex disparities and molecular classification may influence treatment options in GC.