The interaction between microsatellite instability high (MSI-high) gastric cancer and chemotherapy on survival.
Authors: Vos Elvira Lise , Maron Steven Brad , Krell Robert Wallace , Nakauchi Masaya , Fiasconaro Megan , Walch Henry S. , Capanu Marinela , Ku Geoffrey Yuyat , Ilson David H. , Janjigian Yelena Y. , Vanderbilt Chad , Tang Laura H. , Strong Vivian E. 
Published: January 2021

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Background: Subgroup analysis of trials data suggested a favorable prognostic role for microsatellite instability high (MSI-high) status in resectable gastric cancer, but a lack of survival benefit from neoadjuvant/adjuvant chemotherapy; questioning current standard of care for MSI-high locally advanced gastric cancer. To help guide treatment decision making, we retrospectively studied the interaction between MSI status and chemotherapy on survival in a single institution. Methods: All clinically advanced (tumor stage 3-4 or positive lymph nodes) gastric cancer patients that underwent gastrectomy between 2000-2018 with MSI status available from immunohistochemistry (IHC, deficient mismatch repair protein expression (dMMR) vs proficient (pMMR)) or DNA next generation sequencing testing (NGS, MSI-high vs low/stable (MSS)) were included. Clinicopathological characteristics and overall survival (OS) was compared between patients with neoadjuvant/adjuvant chemotherapy and without, stratified for MSI status, by Kaplan-Meier and Cox regression analysis. Results: From a total of 1,844 clinically advanced patients with resection, MSI status was available in 559 as determined by IHC in 420, NGS in 88, and both in 51 with a concordance rate of 50/51 (98%). Tumors were dMMR/MSI-high in 84 (15%) and pMMR/MSS in 475 (85%). Patients with dMMR/MSI-high tumors were more often older, female, and had distal tumors with intestinal subtype. Neoadjuvant and/or adjuvant chemotherapy was administered in 53 (63%) in the dMMR/MSI-high group and 367 (77%) in the pMMR/MSS (p = 0.006). Median (interquartile range) time of follow-up was 32 (19-57) months. In the total cohort, OS after 3 years was 82% in the dMMR/MSI-high and 59% in pMMR/MSS (p < 0.001). In the patients with neoadjuvant/adjuvant chemotherapy only, the dMMR/MSI-high had improved OS (3-years OS: 80% vs 60%, p = 0.001), and after adjustment for age and clinical tumor stage in multivariable analysis, dMMR/MSI-high status was associated with improved OS (HR 0.38 95%CI 0.22-0.68). In the dMMR/MSI-high group only, 3-year OS was 80% with chemotherapy vs 86% without (p = 0.374), and chemotherapy was not associated with a difference in OS after multivariable analysis (HR 1.03 95%CI 0.40-2.66). In case of neoadjuvant chemotherapy, grade 1 pathological response ( > 90%) was observed in 1/41 (2.4%) of the dMMR/MSI-high tumors vs 43/278 (16%) of the pMMR/MSS tumors respectively (p = 0.026). Conclusions: The incidence of MSI-high tumors in our cohort of clinically locally advanced, resectable, gastric cancers was 15%. Patients with MSI-high tumors had worse pathological treatment response to neoadjuvant chemotherapy, but better OS, compared to microsatellite stable tumors. However, in patients with MSI-high tumors, OS was not altered by neoadjuvant/adjuvant chemotherapy. We recommend assessing MSI status in locally advanced gastric cancer.