Mismatch repair status and outcomes in locally advanced rectal cancer treated with total neoadjuvant therapy

In this video, Dr Nada Benhima presents a real-world analysis evaluating the prognostic value of mismatch repair/microsatellite (MMR/MS) status in patients with locally advanced rectal cancer (LARC) treated with total neoadjuvant therapy (TNT).¹ While dMMR/MSI-H is an established biomarker in colon cancer and is predictive of response to immune checkpoint inhibition, its prognostic relevance in rectal cancer treated with TNT remains less clear.

The study used data from the International Real-World Study of TNT in Rectal Cancer, a large academic collaboration collecting routine-practice data from 71 centres. Of 1,911 patients registered, MMR/MS status was available for 1,320 (69.1%), including 46 (3.5%) with dMMR/MSI-H tumours. To allow a balanced comparison, these patients were matched with patients with pMMR/MSS tumours using nine clinical and tumour-related baseline characteristics, yielding a matched population of 372 patients.

No statistically significant differences were observed between dMMR/MSI-H and pMMR/MSS tumours in pathological complete response, complete response, or event-free survival. Patients with dMMR/MSI-H tumours showed numerically lower short-term response rates and higher local and distant recurrence rates after TNT. Despite this weaker short-term response, overall survival was numerically higher in the dMMR/MSI-H group, which Dr Benhima suggests may reflect subsequent access to immunotherapy upon progression.

These findings suggest that MMR/MS status alone is not a prognostic biomarker in LARC treated with TNT. Systematic MMR/MS testing nonetheless remains essential to identify patients who may benefit from immunotherapy-based strategies, where available.