Microsatellite instability and sex differences in resectable gastric cancer - A pooled analysis of three European cohorts.

Objective: Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability (MSI)-high and microsatellite stable (MSS) gastric cancer (GC).
Design: We analysed MSI status by polymerase chain reaction (PCR) and/or mismatch repair (MMR) status by immunohistochemistry in a pooled analysis of individual patient data from one retrospective cohort from Cologne, and the randomised phase III clinical trials D1/D2 and CRITICS. All patients had resectable adenocarcinoma of the stomach and/or gastro-oesophageal junction. Patients were treated with either surgery only or perioperative chemo(radio)therapy.
Results: MSI and/or MMR analyses on 1307 tumours resulted in 1192 (91.2%) MSS and/or MMR proficient (MMRP) [median age, 65 years; 759 males (63.7%); 619 treated with surgery only (51.9%)], and 115 (8.8%) MSI-high [median age, 69 years; 67 males (58.3%); 76 treated with surgery only (66.1%)] GC cases. Males had shorter overall survival (OS) than female MSI-high GC (5-year OS 34.7% vs. 69.7%; hazard ratio (HR) 2.68, 95%CI 1.60 to 4.49; p < 0.001). Females with MSI-high had longer OS than those with MSS/MMRP GC (HR 0.61, 95%CI 0.41 to 0.92; p = 0.02). Males with MSI-high did not have longer OS than those with MSS/MMRP GC (HR 1.26, 95%CI 0.94 to 1.69; p = 0.12).
Conclusions: MSI-high GC males had a significantly worse prognosis compared to their female counterparts in three independent cohorts. In addition, the favourable prognostic value of MSI was only seen in females and not in males. These observations emphasise the need to consider sex differences in prognosis and treatment effects in oncology.
Clinical Trial Registration: The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MIvBH has served in a consultant or advisory role for Medtronic, Mylan, Alesi Surgical, Johnson and Johnson, BBraun, and received funding for research from Olympus, Stryker, all fees paid to the institution and unrelated to the present study. AC received grants form Dutch Cancer Society, Dutch Colorectal Cancer Group, Hofmann-La Roche, all fees paid to the institute and unrelated to the present study. HWMvL has served in a consultant or advisory role for BMS, Daiichy, Lilly, MSD, Nordic Pharma, Novartis, Servier, and received funding for research or study medication from Bayer, BMS, Celgene, Janssen, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier, and received research funding from the Dutch Cancer Society, Dutch Research Council, European Research Council, MaagLeverDarm Stichting, all fees paid to the institution and unrelated to the present study. NCTvG has served on the advisory boards of BMS and MSD. Topics were unrelated to the present study. NCTvG received funding for research from Cancer Center Amsterdam and The Netherlands Organization for Health Research and Development (ZonMW) [848101003], all fees paid to the institute, but related to the present study. All remaining others have declared no conflicts of interest.
(Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)