Mismatch repair deficiency or microsatellite instability in locally advanced rectal cancer patients treated with total neoadjuvant therapy.

Data on the prognostic value of dMMR/MSI-H in locally advancer rectal cancer (LARC) are inconsistent and mostly from patients treated with conventional neoadjuvant therapy. We sought to evaluate oncological outcomes by mismatch repair/microsatellite (MMR/MS) status in LARC patients treated with total neoadjuvant therapy (TNT). Patients from the International Real-World Study of TNT in Rectal Cancer tested for dMMR/MSI-H by immunohistochemistry and/or molecular testing were included. Pathological complete response (pCR), complete response (CR, pCR + clinical complete response), event-free survival (EFS) and overall survival (OS) were assessed by MMR/MS status in the overall and matched populations.

For the latter, variable-ratio matching according to nine variables (age, year of diagnosis, tumour location, staging modality, cT stage, cN stage, presence of lateropelvic lymphadenopathy, distance from the mesorectal fascia, TNT regimen) was applied. Of 1911 patients, 1320 (69.1%) (09/2012-09/2025) had information on the MMR/MS status, 46 (3.5%) having dMMR/MSI-H tumours. No outcome differences were found by MMR/MS status in the overall population. In the matched population (n = 372), pCR was 14.2% among patients with pMMR/MSS tumours versus 12.5% among those with dMMR/MSI-H tumours (adjusted OR 1.07, 95%CI 0.39-2.91, p = 0.899), while CR was 18.9% and 16.7%, respectively (adjusted OR 0.95, 95%CI 0.35-2.58, p = 0.917). 3-year EFS and 5-year OS were 65.8% and 79.2%, and 67.6% and 93.5% in patients with pMMR/MSS and in those with dMMR/MSI-H tumours, respectively (adjusted HR EFS 1.30, 95%CI 0.57-2.89, p = 0.527; adjusted HR OS 2.52, 95%CI 0.67-9.42, p = 0.171).

In this study, the dMMR/MSI-H phenotype did not hold prognostic value in LARC patients treated with TNT.