P-184 Prognostic value of mTOR expression and mismatch repair gene profile in advanced gastric and gastro-oesophageal cancer

Abstract

Gastric carcinoma remains the second most common cause of cancer-related deaths. Although the outcomes have recently improved, there are some patients showed rapid progression and resistance to chemotherapy. PI3K/AKT/mTOR pathway is an important promoter of cell growth, metastasis, and resistance to chemotherapy. Recently FDA approved pembrolizumab for the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) gastric cancer in the second-line or subsequent setting. This prospective study enrolled 76 denovo metastatic gastric and gastro-oesophygeal cancer patients with age 31-70 years. Patients received first-line chemotherapy (XELOX). Pretreatment mTOR expression and MMR status assessed by IHC staining to measure expression levels of proteins involved in DNA mismatch repair (ie, MLH1, MSH2, MSH6, PMS2) on formalin-fixed paraffin-embedded tumor tissues from primary or metastatic site. 40 patients (52.6%) gastro-esophageal junction tumors, 24 patients (31.6%) fundus & body tumors while 12 patients (15.8%) antrum &pyloric tumors. mTOR expression was significantly presented in gastro-esophageal junction tumors (68.2%) followed by fundus & body tumors (20.5%) then antrum &pyloric tumors (11.4%) with P 0.006. However, dMMR was significantly presented in fundus & body tumors (43.8%) followed by 37.5% in gastro-esophageal junction tumors and 18.8% in antrum &pyloric tumors, P value (0.003). Patients with high mTOR expression showed significant poor response to chemotherapy (61.4% progressed disease versus 38.6% were responsive, P 0.04). Tumors with dMMR were also poor responder for treatment (66.7% progressed disease versus 33.3% were responders, P 0.06) most of these tumors were in fundus &pylorus (59%). In this study there were only 21 patients with low mTOR expression associated with proficient MMR, out of them nine patients showed complete response to first-line chemotherapy. Upon progression only 15 patients received ramucirumab and paclitaxel (according to financial and insurance support). Out of them; ten patients (66.6%) showed stable disease and were highly expressing mTOR in concordance with dMMR in their pretreatment biopsies which may denoting a crosstalk between mTOR and vascular endothelial growth factor (VEGF). High mTOR expression was associated with significant both short PFS (median, 10 months vs. 19 months; P = 0.01) and short OS (median, 23 months vs. 35 months; P = 0.003). dMMR tumors were associated with short PFS (median, 12 months vs. 20 months; P = 0.08) and significant short OS (median, 20 months vs. 37 months; P = 0.04). This study further validates high mTOR and dMMR expression as poor prognostic biomarkers correlated with poor response, short PFS and OS so, they could be used for tailoring first or second lines treatment in advanced and metastatic gastric or gastro-esophageal cancer in further studies. Tumors with high mTOR expression and dMMR could get more benefit from combination anti VEGF with other targeted as immune check point inhibitors in first line or upon progression as a second line treatment.