Metastatic Endometrial Cancer: What to Ask

Endometrial cancer is no longer sorted by appearance alone. Molecular classification splits it into four groups. NCI states that this testing is encouraged in all patients with endometrial cancer where it is available and feasible. Laboratory capacity and whether enough tissue was taken can decide whether you get the full panel, so ask what was actually run on your sample. It shapes risk grouping and decisions about drug treatment.

The four groups and what they signal:

• POLEmut, a pathogenic POLE mutation. Good prognosis. NCI notes that adjuvant therapies are avoided in this subtype.
• MMRd, mismatch repair deficient, sometimes reported as MSI-high. Intermediate prognosis, and it predicts immunotherapy response.
• NSMP, no specific molecular profile. Intermediate prognosis.
• p53abn, abnormal TP53. Poor prognosis.

Two practical points follow. The classification can be done on a biopsy. If it is, it need not be repeated on the hysterectomy specimen. And in FIGO staging, a known molecular class is written with an "m" and a subscript. An example is Stage IIm p53abn. NCI notes that this applies to early stages only: stage III and stage IV are not modified by molecular class, though the class is still recorded.

Ask which of the four your tumor is. If it has not been tested, ask whether it can be, using tissue already in the laboratory.

Some types are high grade by definition, regardless of how they look under low power. NCI lists these: serous adenocarcinoma, clear cell adenocarcinoma, mesonephric-like carcinoma, gastrointestinal-type mucinous endometrial carcinoma, undifferentiated carcinoma, and carcinosarcoma.

For endometrioid carcinomas, grade rests on how much of the tumor is solid rather than glandular. Grade 1 is 5% or less. Grade 2 is 6% to 50%. Grade 3 is more than 50%.

Grade 3 endometrioid carcinoma is the group NCI singles out. It calls this type mixed in prognosis, in behavior, and in molecular makeup. It also calls it the type that gains most from molecular classification. Without that testing, NCI says, these cancers cannot be properly assigned to a risk group.

Two large trials define first treatment when the cancer is stage III, stage IV, or recurrent. Both add an immunotherapy drug to carboplatin and paclitaxel, and both split results by mismatch repair status.

KEYNOTE-868 enrolled 810 people. All received six cycles of paclitaxel and carboplatin, with pembrolizumab or placebo, then up to 14 cycles of maintenance.

• In the 222 people with dMMR tumors, 1-year progression-free survival was 74% with pembrolizumab and 38% with placebo.
• In the 588 with mismatch repair proficient tumors, median progression-free survival was 13.1 months versus 8.7 months.

RUBY used dostarlimab instead. It went in by vein every 3 weeks for six cycles alongside chemotherapy, then continued as maintenance at a larger amount every 6 weeks for up to 3 years. Unlike the pembrolizumab trial, some people without measurable disease could enroll.

• Across the whole group, the risk of progression or death fell by 36%.
• In the dMMR group, it fell by 72%.
• Overall survival improved in both, with a hazard ratio of 0.64 overall and 0.30 in the dMMR group.

The pattern is consistent. Both drugs help everyone somewhat and help dMMR tumors dramatically. That is why the mismatch repair result is the single most important number to ask for.

Study 309, also called KEYNOTE-775, tested a two-drug pair. It was pembrolizumab by vein every 3 weeks for up to 35 cycles, plus lenvatinib capsules by mouth daily, at the trial's full 20 mg starting strength. The comparison was chemotherapy chosen by the physician. Everyone enrolled had progressed after a platinum-based regimen. All cell types were allowed except carcinosarcoma and sarcoma.

Median progression-free survival was 7.3 months with pembrolizumab and lenvatinib, against 3.8 months with chemotherapy. Median overall survival was 18.7 months versus 11.9 months. NCI notes the benefit held regardless of mismatch repair status.

Lenvatinib is a daily pill with real side effects, and dose reductions are common — plenty of people never sit at the trial strength for long. Ask what you would start at, and what the plan is if blood pressure rises. Whatever your oncologist writes on the prescription is your dose, not the trial figure.

Endometrial cancer that has spread is not one situation either. The word covers disease in pelvic and abdominal lymph nodes, deposits on the lining of the abdomen, and spread to the lungs, liver, or bone.

Those patterns are treated differently. Nodal disease may still be approached with radiation to a defined field. Widespread disease is managed with drugs. A single new spot may be treated on its own.

Ask which pattern your scans show. Ask whether radiation to a specific site is part of the plan, or whether the whole approach is systemic.

About testing:

• Which of the four molecular groups is my tumor, and what does that change?
• Was the classification done on my biopsy or on the surgical specimen?
• If I am dMMR, does that raise a question about Lynch syndrome for my family?

About treatment:

• Which trial does my recommended regimen come from, and did that trial include people like me?
• Is my cell type one of the ones excluded from a given trial?
• What is the maintenance phase, and how long does it run?

About the sequence:

• If this stops working, what comes next?
• Does starting this now affect eligibility for a trial later?

Advanced endometrial cancer brings symptoms that need attention on their own timeline. Bleeding, pelvic pain, leg swelling, and fatigue are the common ones. Palliative care manages those alongside cancer treatment. It can start at the first visit.

Ask who coordinates your care. Several clinicians are usually involved: a gynecologic oncologist, a medical oncologist, and your primary clinician. Unclear ownership causes more delay than any single decision.

For how stage is assigned and what tumor testing adds, see cancer staging and biomarker testing. For the disease overview, see endometrial cancer.

• Call 911 or go to an emergency department if vaginal bleeding is heavy and will not slow, especially with dizziness, fainting or a racing heart. Go too for sudden breathlessness or chest pain, or for one leg that is newly swollen, hot and painful. Go for severe cramping belly pain with vomiting and no gas or stool passing, which can mean the bowel is blocked. Go as well if your temperature is 100.4°F (38°C) or higher, or shaking chills come on, while you are having chemotherapy: with your counts down a fever is an emergency, not a phone call, and CDC says to be seen straight away. On dostarlimab or pembrolizumab a fever can instead be the drug inflaming an organ, which still needs looking at the same day.
• Call your care team the same day if you are on dostarlimab or pembrolizumab and have diarrhea several times more often than usual, or blood or mucus in your stool, and for a new cough or breathlessness. Call the same day if you are passing much less urine than usual, or have new pain in your side or back, which can mean a ureter is blocked. On lenvatinib, call for a bad headache with home blood pressure readings that are much higher than your normal.
• Call your care team within a day or two if a leg or the lower belly is slowly swelling, if pelvic pain is building, or if you feel unusually tired, cold or heavy in a way that is new. Immunotherapy can affect the thyroid and other hormone glands, and that is treatable. Do the same for numbness or tingling in your hands or feet on paclitaxel, and for mouth sores that stop you eating.

• National Cancer Institute, Endometrial Cancer Treatment PDQ, health professional version, updated May 14, 2025; accessed August 6, 2026
• National Cancer Institute, Immune Checkpoint Inhibitors; accessed August 11, 2026
• National Cancer Institute, Infection and Neutropenia During Cancer Treatment; accessed August 11, 2026
• National Cancer Institute, Gastrointestinal Complications PDQ, health professional version; accessed August 11, 2026
• CDC, Watch Out for Fever (Preventing Infections in Cancer Patients); accessed August 13, 2026