The first 60 days: Mismatch-repair-deficient endometrial cancer
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. Below, week by week, is what OnCo's record of Mismatch-repair-deficient endometrial cancer says about the first two months: the order is typical, the timing is yours to ask about. Sections appear only where the record has something to say. Orientation, not medical advice.
What happens now
Staging tests establish exactly what and where the cancer is. Everything else follows from the answers.
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.
Ask which of these were tested and what the results were; see the report reader for what each value means.
These specialties appear in the standard of care for this cancer. In most centres they meet weekly as a tumour board to agree each plan; you can ask when yours was discussed and what was decided.
- PathologistNamed in the standard of care for: Diagnosis and hereditary risk, Early stage after surgery, Lynch carriers.
- SurgeonNamed in the standard of care for: Lynch carriers.
- Medical oncologistNamed in the standard of care for: Early stage after surgery, Advanced or recurrent, first line, Recurrent after chemotherapy without prior immunotherapy.
- Clinical oncologist (radiotherapy)Named in the standard of care for: Early stage after surgery.
A second opinion from a centre that treats many similar cases is normal, not rude; the standard of care tells you what to compare it against.
Each row is a setting from the standard of care, in the order it usually arises. Not all will apply to you; your stage and biomarkers decide which do. The guideline grade, where recorded, says how strong the evidence is.
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).
Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative.
Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority.
Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing.
Generated from this cancer's standard of care, biomarkers and open problems. Take the group that matches where you are. To tick, add your own and print, open the one-page appointment sheet.
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example MMR immunohistochemistry, Microsatellite instability by PCR or sequencing, MLH1 promoter methylation, Germline mismatch-repair gene testing, Tumour mutational burden), and what were the results?These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Recognised subtypes for this cancer include Sporadic MLH1 promoter hypermethylation, Lynch syndrome germline MLH1, MSH2, MSH6 or PMS2 mutation, MSH6-deficient tumours.
- Is germline (inherited) genetic testing recommended for me or my family?Inherited variants can change treatment and matter for relatives.
Diagnosis and hereditary risk
- For my situation (diagnosis and hereditary risk), which of the standard options do you recommend and why?Guideline options include: 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.
Early stage after surgery
- For my situation (early stage after surgery), which of the standard options do you recommend and why?Guideline options include: 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).
- How do the results of PORTEC-3 apply to someone like me?Trial populations differ from individual patients; ask how closely you match.
Advanced or recurrent, first line
- For my situation (advanced or recurrent, first line), which of the standard options do you recommend and why?Guideline options include: Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative.
- Am I a candidate for Dostarlimab, Pembrolizumab, Durvalumab or related drugs, and what side effects should I expect?Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of RUBY / ENGOT-EN6 / GOG-3031 and NRG-GY018 / KEYNOTE-868 apply to someone like me?Trial populations differ from individual patients; ask how closely you match.
Recurrent after chemotherapy without prior immunotherapy
- For my situation (recurrent after chemotherapy without prior immunotherapy), which of the standard options do you recommend and why?Guideline options include: Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority.
- Am I a candidate for Dostarlimab, Pembrolizumab, and what side effects should I expect?Knowing the expected toxicities helps you plan work, family, and supportive care.
Lynch carriers
- For my situation (lynch carriers), which of the standard options do you recommend and why?Guideline options include: Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing.
Any stage
- Are there clinical trials I could join, for example of Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15), Study of Pembrolizumab (MK-3475) in Combination With Adjuvant Chemotherapy With or Without Radiotherapy in Participants With Newly Diagnosed Endometrial Cancer After Surgery With Curative Intent (MK-3475-B21 / KEYNOTE-B21 / ENGOT-en11 / GOG-3053), A frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval, WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers?Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Supportive care improves quality of life and helps patients complete treatment.
- I read that “Whether chemotherapy can be dropped in favour of immunotherapy alone”. How does that affect my plan?Open problems are where trials and second opinions matter most.
- I read that “Why a third of deficient tumours do not respond to checkpoint blockade”. How does that affect my plan?Open problems are where trials and second opinions matter most.
Trials open now for this cancer in OnCo, largest phase first. Joining a trial is a decision like any other: ask what the comparison arm is, whether a placebo is used, and what happens if you leave. The cancer page searches ClinicalTrials.gov live for more.
- Study of Pembrolizumab (MK-3475) in Combination With Adjuvant Chemotherapy With or Without Radiotherapy in Participants With Newly Diagnosed Endometrial Cancer After Surgery With Curative Intent (MK-3475-B21 / KEYNOTE-B21 / ENGOT-en11 / GOG-3053)Phase 3 · active · NCT04634877A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Versus Placebo in Combination With Adjuvant Chemotherapy With or Without Radiotherapy for the Treatment of Newly Diagnosed High-Risk Endometrial Cancer After Surgery With Curative Intent (KEYNOTE-B21 / ENGOT-en11 / GOG-3053)
- Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15)Phase 3 · active · NCT05173987A Phase 3 Randomized, Open-label, Active-comparator Controlled Clinical Study of Pembrolizumab Versus Platinum Doublet Chemotherapy in Participants With Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma in the First-line Setting (KEYNOTE-C93/GOG-3064/ENGOT-en15)
Much of what helps in the first weeks is free if you know to ask: testing, helplines, rides and lodging, second opinions, trial travel.
- Mismatch-repair-deficient endometrial cancer: the full pageMismatch-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.
- One-page appointment sheetYour questions, the words you may hear, what to bring, and space for the answers. Print it.
- Treatment sequencingWhich treatment tends to follow which, line by line.
- NavigatorStandard of care for your stage, what you have tried, and trials near you.
- Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP): Four groups defined by a few tests that predict outcome better than the microscope: POLE-mutated (excellent), mismatch-repair deficient, p53-abnormal (worst), and 'no specific profile'.
- Lynch syndrome: Lynch syndrome is the most common inherited cancer syndrome: a faulty mismatch-repair gene raises lifetime bowel cancer risk to 40-80% and also endometrial and other cancers.
- Hysterectomy: Removing the uterus (womb), often with the cervix, tubes and ovaries.
- Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR): Microsatellite instability is the mark of a broken DNA spell-checker (loss of MLH1, MSH2, MSH6 or PMS2) that leaves thousands of mutations, so the tumour displays abnormal proteins that T cells can recognise.
Every term links to the glossary.