dMMR Endometrial Cancer: Meaning

MMR is short for mismatch repair. It is a proofreading system your cells use while copying DNA. It catches small errors that slip in when a cell divides. The lowercase d in dMMR means deficient. The proofreader is broken.

When the system fails, errors pile up. They pile up fastest in short repeating stretches of DNA called microsatellites. That is why you will see a second term used almost interchangeably: MSI-H, meaning microsatellite instability high. Both describe the same failure. They just measure it in two different ways.

In endometrial cancer, that failure has become one of the most consequential findings on a pathology report.

The usual method is immunohistochemistry, or IHC. It uses stains to show whether certain proteins are present in tumor tissue. Four proteins get stained: MLH1, PMS2, MSH2, and MSH6.

A normal result shows all four present. Loss of staining for one or more means the mismatch repair system is deficient. The pattern of which proteins went missing points toward which gene is involved. That is why the report lists them one by one, not as a single yes or no.

There is a follow-on step when MLH1 is the one missing. NCI names MLH1 promoter hypermethylation as a cause of microsatellite instability in sporadic cancers. That is a chemical switch. It silences a gene without changing the gene's sequence. So a methylated MLH1 result points to a tumor-only event, not an inherited one.

There is a second approach. Microsatellite instability testing reads the repeat sequences directly, instead of looking at proteins.

The Cancer Genome Atlas found four molecular subtypes. NCI lists them:

1. POLE ultramutated. NCI notes this subtype has clinical meaning. Added therapy after surgery is avoided.
2. Microsatellite instability hypermutated. This is the dMMR group.
3. Copy number low.
4. Copy number high.

NCI states these groups can sort patients into low-risk and high-risk categories. Knowing which one your tumor is tells you more than grade alone.

This is the reason dMMR status is worth the extra staining.

On June 17, 2024, FDA approved a new regimen for adults with primary advanced or recurrent endometrial carcinoma. It is pembrolizumab with carboplatin and paclitaxel, then pembrolizumab alone. The trial was KEYNOTE-868, also called NRG-GY018. It randomized 810 patients and sorted them by mismatch repair status.

Both groups benefited, but not equally.

• In the dMMR group: the hazard ratio for progression-free survival was 0.30. The 95 percent confidence interval ran from 0.19 to 0.48. Median progression-free survival was not reached with pembrolizumab. With chemotherapy alone it was 6.5 months.
• In the pMMR group, meaning the repair system still works: the hazard ratio was 0.60, with a range of 0.46 to 0.78. Median progression-free survival was 11.1 months against 8.5 months.

A hazard ratio of 0.30 means the risk of progression at any moment was about 70 percent lower. Median not reached means something else. At the time of analysis, more than half the dMMR patients on pembrolizumab had still not progressed.

The regimen itself is specific. Paclitaxel and carboplatin by vein for six cycles, at amounts calculated from body size and kidney function. Pembrolizumab goes in either every 3 weeks or, at a larger amount, every 6 weeks. It runs until the cancer grows, until side effects force a stop, or until 24 months.

Dostarlimab is the other checkpoint inhibitor in this space. FDA cleared it for dMMR solid tumors no matter where they started. The basis was a 41.6 percent response rate in 209 patients. That approval covers adults only.

A dMMR tumor raises a question about your family, not just your treatment.

Lynch syndrome is an inherited condition. It comes from germline changes in the same repair genes: MLH1, MSH2, MSH6, and PMS2, plus EPCAM. It is one of the recognized risk factors for endometrial cancer.

The distinction that matters is where the change lives. Tumor testing describes the cancer. Germline testing uses blood or saliva. It looks for a change present in every cell of your body. That kind of change can pass to children and be shared with siblings.

A dMMR tumor result does not by itself mean you have Lynch syndrome. MLH1 methylation makes it less likely. But it is the trigger for the conversation. For women who do carry Lynch syndrome, StatPearls describes surveillance starting at ages 30 to 35. It uses transvaginal ultrasound and endometrial biopsy.

Molecular status does not replace the standard workup.

Vaginal bleeding after menopause is still the main warning symptom. Others are unusual discharge, painful urination, pain with sex, and pelvic pain. Diagnosis runs through four tools: endometrial biopsy, dilation and curettage, transvaginal ultrasound, and hysteroscopy.

Surgery still leads for most patients. That means total hysterectomy, usually with bilateral salpingo-oophorectomy. The second term means removing both ovaries and both fallopian tubes. Radical hysterectomy removes more surrounding tissue. Radiation, chemotherapy, and hormone therapy fill out the options.

NCI lists these risk factors. Obesity and metabolic syndrome. Estrogen-only hormone replacement. Tamoxifen taken for breast cancer. Type 2 diabetes. Polycystic ovary syndrome. Family history, Lynch syndrome, and endometrial hyperplasia.

• Which of the four proteins showed loss on immunohistochemistry?
• If MLH1 was lost, was promoter hypermethylation testing done, and what did it show?
• Was microsatellite instability testing done as well, and did the two agree?
• Which of the four molecular subtypes is my tumor, and was POLE tested?
• Does my stage and subtype make me a candidate for pembrolizumab with carboplatin and paclitaxel?
• Have I been referred to genetic counseling for germline testing?
• If germline testing is positive, who in my family should be tested, and at what age?

A dMMR result on its own is not an emergency. What follows from it can be. Pembrolizumab works by taking a brake off your immune system, so the immune system can turn on your own organs.

• Call your care team the same day if you are on pembrolizumab and your bowels loosen, you see blood or mucus in the stool, or you get severe belly pain. Immune-related colitis is treated with steroids, not with ordinary anti-diarrhoea medicine, so the team needs to know early.
• Call 911 or go to an emergency department if you get chest pain, or breathlessness that is there while you sit still.
• Call your care team the same day if you develop a new or worsening cough, or find yourself short of breath on effort you used to manage. Pembrolizumab can inflame the lungs.
• Call your care team the same day if the whites of your eyes or your skin turn yellow, your urine goes dark, or you bruise and bleed more easily than usual.
• Call your care team within a day or two if vaginal bleeding starts after menopause, or bleeding becomes heavier or different from your usual pattern. This is the main warning symptom for endometrial cancer, and it still matters after a diagnosis is made.
• Call your care team within a day or two if you feel unusually tired, cold, or lightheaded on pembrolizumab. Checkpoint drugs can upset the thyroid and other hormone glands.

• https://medlineplus.gov/druginfo/meds/a614048.html
• https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq
• https://www.cancer.gov/types/uterine/patient/endometrial-treatment-pdq
• https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma
• https://www.cancer.gov/about-cancer/treatment/types/agnostic-cancer-therapies-hp-pdq
• https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq
• https://www.ncbi.nlm.nih.gov/books/NBK525981/
• https://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment