Mismatch-repair deficient (MSI-high) colorectal cancer

Mismatch-repair deficiency arises when MLH1, MSH2, MSH6 or PMS2 is lost, either by sporadic MLH1 promoter methylation (typically right-sided, in older women, often with BRAF V600E) or by a germline mutation in Lynch syndrome, which is why every colorectal cancer is now tested by immunohistochemistry or microsatellite analysis at diagnosis. The tumours accumulate tens of thousands of frameshift mutations, produce abundant neoantigens and are infiltrated by T cells held in check by PD-1; they have a better prognosis when localised and do not benefit from fluorouracil alone as adjuvant therapy.

In metastatic disease KEYNOTE-177 (2020) showed that pembrolizumab alone doubled progression-free survival against chemotherapy (16.5 versus 8.2 months), with 54.8 percent of patients alive at five years and a median survival of 77.5 months; CheckMate 8HW (2024) showed that nivolumab plus ipilimumab cut progression by 79 percent against chemotherapy (median progression-free survival 54.1 versus 5.9 months) and beat nivolumab alone, and the combination was approved first line in April 2025. About a third of patients still progress early, often because of pMMR misclassification, JAK1 or B2M loss or immune-excluded biology.

In localised disease four weeks of neoadjuvant nivolumab and ipilimumab produced pathological complete response in 68 percent of colon cancers in NICHE-2 with no recurrence at three years; the ATOMIC phase 3 trial (2025) showed that adding atezolizumab to adjuvant FOLFOX improves disease-free survival in stage III disease; and in rectal cancer six months of dostarlimab produced a clinical complete response in every patient treated, allowing surgery and radiotherapy to be omitted. For Lynch carriers, colonoscopy every one to two years and daily aspirin (CAPP2) prevent cancers, and frameshift-neoantigen vaccines are in trials.