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Relation between mismatch repair status, chemoresponse, survival and anatomic location in gastroesophageal
Gertruda Evaristo1, Amit Katz1, José L Ramírez-GarcíaLuna1
1From the Department of Pathology, McGill University Health Centre, Montréal, Que. (Evaristo, Thai, Guiot, Camilleri-Broët, Marcus, Fiset); the Cancer Research Program and the LD MacLean Surgical Research Laboratories, Department of Surgery, Research Institute of the McGill University Health Centre, Montréal, Que. (Katz, Ramírez-GarcíaLuna, Sangwan, Mueller, Cools-Lartigue, Ferri); the Research Institute of the McGill University Health Centre, Montréal, Que. (Issac, Bertos); and the Division of Thoracic and Upper Gastrointestinal Surgery, Department of Surgery, McGill University Health Centre, Montreal General Hospital, Montréal, Que. (Sangwan, Mueller, Cools-Lartigue, Ferri).
Background:
It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location.
Methods:
We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis.
Results:
In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94).
Conclusion:
Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status.
