Mismatch Repair (MMR) in Endometrial Cancer

by Jason Wasserman MD PhD FRCPC
March 26, 2026

Mismatch repair (MMR) testing is one of the most important tests performed on endometrial cancer, the cancer that starts in the lining of the uterus. Every newly diagnosed endometrial cancer should be tested for this biomarker. The result tells your doctor whether the cancer’s internal DNA repair system is working properly. If it isn’t — a finding called MMR deficiency, or dMMR — two things follow: the cancer is likely to respond well to a type of drug called immunotherapy, and there is a real possibility that the cancer developed because of an inherited condition called Lynch syndrome, which can raise cancer risk for your family members. Understanding your MMR result is one of the most useful things you can do to make sense of your treatment options and what comes next.

What the test looks for

Every time a cell divides, it copies its DNA. Small errors happen regularly during this process. Your body’s mismatch repair (MMR) system — made up of four proteins called MLH1, PMS2, MSH2, and MSH6 — acts like a spell-checker, finding and fixing those errors before they become permanent. These proteins work in pairs: MLH1 with PMS2, and MSH2 with MSH6. If either protein in a pair is lost, the repair system for that pair stops working.

When the MMR system fails inside a cancer cell, errors accumulate across the cell’s DNA. This produces a pattern called microsatellite instability (MSI-H), which laboratory tests can detect. A tumour whose MMR system has broken down is called MMR-deficient (dMMR). A tumour where the system is working normally is called MMR-proficient (pMMR).

Why does this matter for treatment? A dMMR tumour carries many more genetic errors than a pMMR tumour. These errors cause abnormal proteins to appear on the surface of cancer cells — proteins that look foreign to the immune system. The immune system’s fighting cells (T cells) try to attack them, but are blocked by molecular “off switches” on the cancer cells. Immunotherapy drugs called immune checkpoint inhibitors work by releasing those off switches, freeing T cells to attack the cancer. Because dMMR endometrial cancers carry so many of these abnormal proteins, they tend to respond much better to these drugs than pMMR tumours do.

How common is dMMR in endometrial cancer?

Endometrial cancer has the highest rate of dMMR of any common solid cancer. About 25 to 30% of endometrial cancers are dMMR — roughly one in four. This makes it an important finding in this disease, and one of the reasons that MMR testing is now recommended for all newly diagnosed endometrial cancers, regardless of stage or grade.

Of all dMMR endometrial cancers:

About 70% are sporadic — meaning the MMR system failed due to a change called MLH1 methylation, which occurred only within the tumour itself. This is a chemical switch that turns off the MLH1 gene inside the cancer cells. It is not an inherited change and cannot be passed to family members.
About 30% are caused by Lynch syndrome — an inherited condition in which a person is born with a fault in one of the MMR genes. This is hereditary and has implications for the patient’s family. See the Lynch syndrome section below for more details.

MMR status varies by histological type

Endometrial cancer is not a single disease — it is a family of cancers that each start in the lining of the uterus but look and behave differently under the microscope. Pathologists classify endometrial cancers into histological types based on how the cancer cells look and how they are arranged. The type of endometrial cancer you have is stated in your pathology report, and it matters for MMR testing because the frequency of dMMR varies considerably from one type to another.

Endometrial endometrioid carcinoma. This is by far the most common type, making up about 80% of all endometrial cancers. It tends to be lower grade, is strongly linked to estrogen exposure, and is the type most likely to be dMMR — approximately 25 to 35% of endometrioid carcinomas are dMMR. Most dMMR cases in this type are sporadic (caused by MLH1 methylation), though Lynch syndrome accounts for a meaningful proportion. This is the type most patients with endometrial cancer will have, and the MMR data described throughout this article apply most directly to it.
Endometrial serous carcinoma. A less common but more aggressive type that accounts for roughly 10% of endometrial cancers. It behaves quite differently from endometrioid carcinoma and is almost always p53-abnormal. dMMR is uncommon in serous carcinoma — only about 2 to 5% of cases — so a dMMR result in this histological type is less expected and still warrants Lynch syndrome evaluation when it occurs.
Endometrial clear cell carcinoma. A rare type that is considered high-grade by definition. dMMR occurs in approximately 5-10% of clear cell carcinomas. The molecular profile of clear cell carcinoma is heterogeneous — tumours can fall into any of the four molecular groups — making MMR testing an important part of fully characterising this type.
Carcinosarcoma (malignant mixed Müllerian tumour). A rare and aggressive cancer of the uterus that contains two different types of tumour cells. dMMR occurs in a small proportion of carcinosarcomas. These tumours tend to behave aggressively regardless of MMR status, but dMMR testing is still performed because a positive result may open the door to immunotherapy.

The takeaway is straightforward: whatever histological type appears on your report, MMR testing is appropriate and informative. However, the likelihood of finding dMMR — and what it means for your specific situation — is best understood in the context of your cancer type. Your oncologist will interpret your MMR result in light of your histological type, grade, stage, and other molecular findings.

MMR status and the molecular classification of endometrial cancer

Over the past decade, researchers have discovered that endometrial cancers can be divided into four molecular groups based on specific DNA features. These groups help predict how the cancer will behave and guide treatment decisions — particularly about how much treatment is needed after surgery. Your MMR result is one of the key pieces of information used to assign your cancer to one of these groups.

The four groups, in order from best to most serious prognosis, are:

POLE-mutated. A small group (about 10% of cases) has a very favourable outlook. These cancers have a specific mutation in a gene called POLE that actually causes them to produce an extremely high number of mutations — yet paradoxically, they rarely come back after surgery. See the POLE in the Endometrial Cancer article for more details.
MMR-deficient (dMMR). About 25 to 30% of cases. These cancers carry an intermediate prognosis — neither as favourable as POLE-mutated nor as concerning as p53-abnormal. They are particularly responsive to immunotherapy, which has transformed treatment options for this group in recent years.
No specific molecular profile (NSMP). The largest group (about 50% of cases) has an intermediate prognosis. These cancers do not carry POLE mutations, do not show MMR deficiency, and have normal p53 staining.
p53-abnormal. About 10 to 15% of cases. Associated with the most serious prognosis. These cancers tend to be high-grade and are treated more aggressively. See the article on p53 in Endometrial Cancer for more details.

Knowing which group your cancer falls into gives your oncology team more information than traditional grade and stage alone — and may affect recommendations about whether you need additional treatment after surgery, and what type.

Why is the test done

To guide treatment decisions

A dMMR result is now one of the central factors in planning treatment for endometrial cancer, particularly for advanced or recurrent disease. Multiple immunotherapy drugs are approved based on this result, and the treatment landscape has changed substantially in recent years. The result also helps inform decisions about how much treatment is needed after surgery for early-stage disease — patients in the dMMR group may be managed differently from those in the pMMR group at the same stage and grade.

To screen for Lynch syndrome

Finding dMMR in an endometrial cancer is the standard first step in evaluating for Lynch syndrome. Because about 30% of dMMR endometrial cancers are Lynch syndrome-related, a dMMR result always prompts further investigation. Lynch syndrome is one of the most common inherited cancer conditions, affecting approximately 1 in 280 people — but most cases are never diagnosed. Identifying it protects not just the patient but potentially their whole family.

To help with prognosis

Knowing your cancer’s molecular group — including whether it is dMMR — gives your team more precise prognostic information. For early-stage endometrial cancer, this helps determine how closely you need to be monitored and whether additional treatment after surgery is recommended.

How the test is performed

MMR testing in endometrial cancer is done on tumour tissue from a biopsy or from the uterus removed during surgery. No additional procedure is usually needed — the tissue already collected for diagnosis is sufficient.

The most common method is immunohistochemistry (IHC). A pathologist uses special stains to check whether the four MMR proteins (MLH1, PMS2, MSH2, and MSH6) are present in the cancer cells. Normal cells in the same tissue sample always stain positively — they act as a built-in check that the test worked correctly. If any protein is absent from the cancer cells, this indicates MMR deficiency.

DNA-based testing — either PCR-based MSI testing or next-generation sequencing (NGS) — can also detect MSI-H directly from the tumour DNA. As comprehensive molecular panel testing becomes more routine in endometrial cancer, MMR status is often reported automatically alongside other results such as POLE mutation status and p53 expression.

How results are reported

Your pathology report will describe the MMR result in one of these ways:

MMR-proficient (pMMR). All four proteins are present. The repair system is intact. This may also be reported as MSS (microsatellite stable) on DNA-based testing.
MMR-deficient (dMMR). One or more proteins are absent. The report will specify which proteins are missing — for example, “loss of MLH1 and PMS2” or “loss of MSH2 and MSH6.” This may also be reported as MSI-H (microsatellite instability-high) on DNA-based testing.

The pattern of which proteins are missing is clinically important — it provides the first clue about whether a dMMR result is likely to be caused by Lynch syndrome or by the more common sporadic process. This is covered in detail in the Lynch syndrome section below.

What the result means

MMR-proficient (pMMR)

A pMMR result means the cancer’s repair system is working normally. This is found in about 70-75% of cases of endometrial cancer. It means immunotherapy based on MMR status alone is generally not the first treatment approach — checkpoint inhibitors work best in dMMR tumours. Lynch syndrome is also unlikely to be the cause, though it cannot be completely ruled out in rare cases.

Treatment for pMMR endometrial cancer is based on stage, grade, and other molecular findings (including p53 and POLE status). It is worth knowing that even in pMMR disease, pembrolizumab in combination with chemotherapy has been approved for advanced or recurrent endometrial cancer regardless of MMR status — meaning not all immunotherapy decisions in endometrial cancer now depend on MMR status alone.

MMR-deficient (dMMR)

A dMMR result has two main implications that your care team will act on together:

Immunotherapy is likely to be an important part of your treatment. Multiple immunotherapy drugs are now approved specifically for dMMR endometrial cancer, both as single agents for recurrent or advanced disease and in combination with chemotherapy as first-line treatment. The options have expanded significantly in 2023 and 2024 (see the treatment section below).
Lynch syndrome needs to be evaluated. Further testing will be done to determine whether your dMMR result is due to Lynch syndrome or a spontaneous, non-inherited change in the tumour. This process involves additional tests on the tumour tissue and may lead to a referral for a blood test (called germline testing) and a meeting with a genetic counsellor. A dMMR result does not confirm Lynch syndrome — it means the possibility must be investigated.

Distinguishing Lynch syndrome from sporadic dMMR

The most important follow-up question after a dMMR result is: Is this inherited? The answer usually starts with looking at which proteins are missing on the IHC test.

Loss of MLH1 and PMS2 together is the most common pattern in endometrial cancer and is usually caused by sporadic MLH1 methylation — a chemical change in the tumour itself that is not inherited. An additional test for MLH1 methylation can confirm this. If methylation is found, Lynch syndrome is much less likely. If it is not found, a referral for germline testing is recommended.
Loss of MSH2 and MSH6 together is strongly associated with Lynch syndrome and should always lead to a referral for genetic counselling and germline testing.
Loss of MSH6 alone or PMS2 alone is also associated with Lynch syndrome and warrants genetic evaluation, though the likelihood varies somewhat by pattern.

In many centres, MLH1 methylation testing is performed automatically whenever MLH1 and PMS2 loss is found on IHC — so the process often proceeds without you needing to request it separately.

Lynch syndrome and endometrial cancer

Lynch syndrome is a hereditary condition caused by an inherited mutation in one of the MMR genes — most often MLH1, MSH2, MSH6, or PMS2. People with Lynch syndrome are born with one faulty copy of an MMR gene in every cell of their body. When the remaining healthy copy of that gene is also damaged over time (which can happen randomly), the repair system fails, and cancer can develop.

Endometrial cancer is actually the most common Lynch syndrome-related cancer in women. Depending on which MMR gene is affected, the lifetime risk of developing endometrial cancer with Lynch syndrome can reach 40 to 60% — compared to about 2 to 3% in the general population. This is why endometrial cancer is often the cancer that first reveals Lynch syndrome in a family.

Lynch syndrome is passed through families. Each child, sibling, or parent of someone with a confirmed Lynch syndrome mutation has a 50% chance of carrying the same mutation. Those who do can begin regular cancer surveillance — more frequent colonoscopies, gynaecological monitoring, and other tests depending on which gene is involved — which can detect or prevent cancers early, when they are most treatable.

If your MMR test result raises the possibility of Lynch syndrome, you will likely be referred to a genetic counsellor. They will explain what further testing is needed and what a positive result would mean for you and your family. This does not need to be resolved before your cancer treatment begins — both processes can move forward at the same time.

Treatment implications of dMMR in endometrial cancer

The treatment of dMMR endometrial cancer has been transformed by immunotherapy over the past few years. A series of large clinical trials has shown that immune checkpoint inhibitors produce strong, durable responses in dMMR tumours and have led to multiple new drug approvals. The options now available are substantially better than what existed even five years ago.

Single-agent immunotherapy for recurrent or advanced disease

Both pembrolizumab (Keytruda) and dostarlimab (Jemperli) are approved as single-agent treatments for previously treated dMMR recurrent or advanced endometrial cancer — meaning patients whose cancer has come back or progressed after prior chemotherapy. In the studies that led to these approvals, response rates in dMMR endometrial cancer were approximately 45 to 57%, with many responses lasting well over a year. For a disease where second-line chemotherapy had response rates of around 14 to 27%, these results marked a major step forward.

Immunotherapy combined with chemotherapy is used as first-line treatment.

In 2023 and 2024, three large phase III trials showed that adding an immune checkpoint inhibitor to standard first-line chemotherapy (carboplatin and paclitaxel) dramatically improved outcomes for patients with dMMR advanced or recurrent endometrial cancer. All three trials — NRG-GY018 (pembrolizumab), RUBY (dostarlimab), and DUO-E (durvalumab) — showed a roughly 70% reduction in the risk of cancer progression or recurrence in the dMMR group when immunotherapy was added to chemotherapy.

As a result, three combination regimens are now FDA-approved for dMMR primary advanced or recurrent endometrial cancer:

Pembrolizumab (Keytruda) plus carboplatin and paclitaxel, followed by maintenance pembrolizumab, was approved in June 2024 for all advanced or recurrent endometrial cancer regardless of MMR status, with particularly strong benefit in the dMMR group.
Dostarlimab (Jemperli) plus carboplatin and paclitaxel, followed by maintenance dostarlimab. Approved July 2023 for dMMR primary advanced or recurrent endometrial cancer; expanded in August 2024 to all advanced or recurrent endometrial cancer regardless of MMR status.
Durvalumab (Imfinzi) plus carboplatin and paclitaxel, followed by maintenance durvalumab, was approved from June to July 2024 for dMMR primary advanced or recurrent endometrial cancer.

For patients with dMMR advanced or recurrent endometrial cancer, the current standard of care is one of these combination regimens. Your oncologist will discuss which option is most appropriate for your situation, taking into account your overall health, treatment history, and goals of care.

Early-stage disease

For early-stage endometrial cancer (cancer that has not yet spread beyond the uterus), dMMR status is increasingly informing decisions about how much treatment is needed after surgery. This is an evolving area — research is ongoing to determine whether immunotherapy has a role in early-stage dMMR disease, and clinical trials are underway. For now, decisions about radiation, chemotherapy, or observation after surgery in early-stage dMMR endometrial cancer are based on stage, grade, and the full molecular profile of the tumour, and your oncologist will walk you through the recommendations for your specific situation.

What happens next

If your MMR result has just come back, two things will happen in parallel:

If your result is pMMR, immunotherapy based on MMR status is not the priority. Your treatment plan will be based on stage, grade, p53 status, POLE status, and other findings. Chemotherapy with or without immunotherapy may still be discussed for advanced disease.
If your result is dMMR, your oncologist will discuss immunotherapy options. At the same time, your care team will begin evaluating for Lynch syndrome — starting with any additional tumour tests needed (such as MLH1 methylation testing) and, if appropriate, a referral to a genetic counsellor for a blood test. These two processes move forward together.

If you have just received a dMMR result and have not yet spoken with your oncologist about what it means for your treatment, or with a genetics team about Lynch syndrome, it is completely appropriate to ask for that conversation. You do not need to navigate this alone, and you do not need to understand everything at once.

Questions to ask your doctor

Was my endometrial cancer tested for MMR/MSI status, and what were the results?
Which proteins were found to be missing — and does the pattern suggest Lynch syndrome or a sporadic (non-inherited) cause?
Has MLH1 methylation testing been done to help distinguish these?
Based on my MMR result, which molecular group does my cancer fall into — and what does that mean for my prognosis and treatment?
Am I a candidate for immunotherapy, and if so, which drug or combination is recommended?
Should I be referred to a genetic counsellor for evaluation of Lynch syndrome?
If Lynch syndrome is confirmed, what does that mean for my long-term surveillance and for my family members?
Are there clinical trials I should consider based on my MMR result?