The role of DNA mismatch repair status in oesophagogastric cancer treated with perioperative chemotherapy: evidence from the MRC ST03 and OE05 trials

BACKGROUND: Mismatch repair deficiency (MMRd) is a key determinant of tumour biology, however, its prognostic significance in patients with resectable oesophagogastric adenocarcinoma treated with perioperative cytotoxic chemotherapy remains uncertain. METHODS: MMR status was assessed in 1424 patients with oesophagogastric adenocarcinoma enroled in the MRC OE05 and ST03 trials, which investigated perioperative chemotherapy regimens. Associations between MMR status, clinicopathological variables, overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) were investigated. RESULTS: In total, 78 (5.5%) tumours were MMRd, 80.8% due to MLH1 loss. Patients with MMRd tumours had improved OS compared with patients with MMR proficient (MMRp) tumours (median unreached vs 28.0 months; p = 0.0009; 5-year rates 50.1% vs. 34.3%), and PFS (median 56.7 vs 21.4 months; p = 0.0032). On multivariable analysis, MMRd remained associated with improved OS (HR 0.60, 95% CI 0.42-0.87; p = 0.007) and PFS (HR 0.64, 95% CI 0.45-0.90; p = 0.011). PPS did not differ by MMR status. DISCUSSION: This is the first study to suggest that perioperative cytotoxic chemotherapy does not abrogate the favourable prognostic impact of MMRd prior to disease progression. However, MMR status did not influence survival after progression. Our results challenge clinical concerns that cytotoxic chemotherapy may be detrimental in patients with resectable MMRd oesophagogastric adenocarcinoma.