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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Mismatch-repair-deficient endometrial cancer has lost the machinery that corrects copying errors in DNA, so it accumulates thousands of mutations that make it visible to the immune system. Adding dostarlimab or pembrolizumab to chemotherapy in advanced disease cut the risk of progression by about seventy percent, and many patients remain in remission years later.
Loss of MLH1, PMS2, MSH2 or MSH6 on immunohistochemistry, or microsatellite instability on a molecular test, defines this class. In most tumours the cause is methylation of the MLH1 promoter; in a minority it is a germline mutation in a mismatch-repair gene, which is Lynch syndrome, so every deficient tumour without MLH1 methylation should prompt germline testing and family cascade testing. Mismatch-repair-deficient tumours are usually endometrioid, often high grade, with abundant tumour-infiltrating lymphocytes, and they carry an intermediate prognosis at early stage. The class has the same recurrence risk as no specific molecular profile after adjuvant radiotherapy, and PORTEC-3 found no benefit from adding chemotherapy in this group.
The mutational load makes these tumours the most immunotherapy-responsive solid cancers outside melanoma. Pembrolizumab's tumour-agnostic approval for mismatch-repair-deficient tumours in 2017 and dostarlimab's approval after the GARNET trial in 2021 established single-agent checkpoint inhibition after chemotherapy. RUBY then moved immunotherapy to the first line: dostarlimab with carboplatin-paclitaxel raised progression-free survival at two years from 15.7 to 61.4 percent in the deficient population, with a hazard ratio of 0.28. NRG-GY018 found the same with pembrolizumab, a hazard ratio of 0.30 for progression in deficient tumours, and DUO-E with durvalumab a hazard ratio of 0.42. Both dostarlimab and pembrolizumab gained approvals with chemotherapy in 2023 and 2024.
| Setting | Approach | Guideline |
|---|---|---|
| Diagnosis and hereditary risk | Universal MMR immunohistochemistry on every endometrial cancer; MLH1 methylation testing on MLH1-deficient tumours; germline testing and cascade testing of relatives when methylation is absent. | not mapped |
| Early stage after surgery | Adjuvant therapy by stage and risk factors as for no specific molecular profile: vaginal brachytherapy for intermediate risk, pelvic radiotherapy for high-intermediate risk; chemotherapy adds little (PORTEC-3). | not mapped |
| Advanced or recurrent, first line | Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative. | not mapped |
| Recurrent after chemotherapy without prior immunotherapy | Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority. | not mapped |
| Lynch carriers | Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing. | not mapped |