Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer

Abstract

Background Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers. Methods We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS). Results Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%, P < 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%, P = 0.005), whereas there was no significant difference between high-and low-PD-L1 expression patients (55.9% vs. 56.6%, P = 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09-0.95; P = 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30-1.63; P = 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy. Conclusions Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.

Clinicopathological evidence of hepatitis B virus infection in the development of gastric adenocarcinoma

“…Thus, the management of GC patients with HBV infection is still a clinical challenge. Hashimoto et al previously reported that the expression of PD‐L1 and MLH1 were negatively correlated in another GC study. Here, we found PD‐L1 seemed lost and MLH1 were often retained in HBV carriers GC patients.…”

MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma

“…In a recent systematic review MSI-H was found to be associated with female sex, older age, intestinal Laurén histological type, mid/lower gastric location, lack of lymph node metastases and TNM stage I-II, but not with ethnicity [33]. Between 6 and 24% of resected gastroesophageal adenocarcinomas are reported to be MSI-H [20,[34][35][36][37][38][39], and this may even mount up to 48% in patients of 85 years and older [40]. However, the percentage sharply drops to less than 10% in patients with synchronous metastatic disease [41], and less than 5% in a beyond-second line treatment setting [19].…”

Review: Gastric cancer: Basic aspects

“…In a study aiming at determining the predictive value of MLH1 and PD‐L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer, Hashimoto et al 26 demonstrated that patients with resectable MSI GC, due to loss of mutL homolog 1 (MHL1), exhibit a good prognosis and negative response to fluorouracil‐based chemotherapy. In a similar study, Di Bartolomeo et al 27 showed that MSI status was independently associated with increased disease‐free survival and overall survival in GC patients randomised for an intensive sequential chemotherapy regimen vs fluorouracil/leucovorin monotherapy as adjuvant treatment.…”