Microsatellite instability (MSI), mainly caused by dysfunction of mutL homolog 1 (MLH1), was classified as one of distinctive molecular subtype of gastric cancer. MSI was also reported to be associated with high PD-L1 expression and high Immunoscore (IS), a density analysis of tumor-infiltrating lymphocytes. This study aimed to investigate the association between MLH1, PD-L1 expression, and IS and chemosensitivity and prognosis in gastric cancer.
A total of 271 patients who underwent gastrectomy (R0/1) for gastric cancer between 2008 and 2016 in our institution were retrospectively analyzed. Immunohistochemistry was performed to evaluate MLH1 and PD-L1 expression. IS was evaluated by the density of CD3+ and CD8+ lymphocytes in the center and invasive margin of tumor and classified into two groups; IS-High or IS-Low. The relationship between these markers and the pathological effect of neoadjuvant chemotherapy (NAC) was examined in patients with NAC, and recurrence-free survival (RFS) was compared separately with and without NAC.
Low MLH1, high PD-L1 expression, and IS-High was observed in 29 (11%), 70 (26%), and 114 (42%) patients, respectively. Low MLH1 expression was significantly associated with high PD-L1 expression (P = 0.006) and IS-high (P = 0.04). In patients with NAC (n = 114), low MLH1 expression was significantly associated with low chemosensitivity (lower proportion of pathological effect Grade≥1b, P = 0.006), although PD-L1 expression and IS were not associated with chemosensitivity (P = 0.99, P = 0.08). In patients without NAC (n = 157), low MLH1 expression and IS-High were significantly associated with better RFS (P = 0.02, P < 0.001), however not associated in patients with NAC (P = 0.70, P = 0.07). While, PD-L1 expression was not associated with RFS in both patients with and without NAC (P = 0.20, P = 0.51). Multivariate analysis revealed that high MLH1 expression and IS-low were one of the independent risk factors for RFS (HR: 2.9 [1.3-6.9] P = 0.014, HR:1.9 [1.2-3.0] P < 0.001).
Although low MLH1 expression and IS-high may be associated with better prognosis, low MLH1 expression may be also associated with low chemosensitivity.
Clinical trial identification
Legal entity responsible for the study
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University.
Has not received any funding.
All authors have declared no conflicts of interest.