A 64-Year-Old Woman With Advanced Endometrial Carcinoma - Episode 2

Mismatch Repair Defects and Endometrial Carcinoma

A discussion on risk factors associated with endometrial cancer and the role of molecular testing to help evaluate for mismatch repair abnormality.

Robert L. Coleman, MD, FACOG, FACS: The risk factors for endometrial cancer aren’t completely elucidated. One of the features that we recognized early was a connection between an estrogenic environment and the development of growth inside the uterus, ultimately turning into cancer. We noticed this because postmenopausal hormonal replacement was being utilized without a compensatory balance of progestin—this was unopposed estrogen therapy—and this was associated with an increase in the incidence of endometrial cancer back in the mid-1970s.

We knew that there was a connection between this tissue on the inside of the uterus that’s normally responsive to hormones and was part of the menstrual cycle, and the development of the genetic mistakes that could lead to cancer. But the exact mechanism for how and why it happens in patients who don’t have these characteristics is still unknown. We know that if you look at the disease from a molecular standpoint, there are a number of abnormalities. One of the more interesting and critical ones now that we have drugs available is the representation of the tumor cell to have this inability to fix these small mismatches in the DNA. This mismatch repair process is critical for normal cell survival, and when it’s mutated, altered, or disabled in any form, that leads to a higher probability for cancer development.

We know that endometrial cancer is one of the index cancers associated with Lynch syndrome, which is also associated with colon cancer and others. Early on, we learned that endometrial cancer can run in families associated with this syndrome. And now we know that this syndrome is associated with the imperfect productivity of the mismatch repair proteins and genes that regulate the expression of those proteins. Mismatch repair deficiency is a very important part of the evaluation of patients with endometrial cancer.

In this case, this patient had molecular testing, which isn’t clear in terms of exactly what was done. But what’s most frequently done is looking at the expression of the proteins in the tissue that are oftentimes associated with mismatch repair. Those are MLH1, MSH2, MSH6, and PMS2. This is now part of a routine evaluation of endometrial cancers, in particular endometrioid endometrial cancers, to evaluate for the potential of up to 30% of our endometrial cancers that might have an abnormality.

This is important because about 6% of patients with endometrial cancer who have this will have a germline mutation, which would be important to rule out. As I mentioned, this could be associated with Lynch syndrome. We test for that if we find the absence of these proteins by checking for promoter methylation of MLH1, and if we rule that out, then this would be a case that would at least need further evaluation for a germline mutation that would associate with Lynch syndrome. But the vast majority of these patients just have an alteration in these proteins, and they can also be assessed by the microsatellite loci by a number of tests.

With this patient, we described both tests. We usually do one or the other unless there’s concern that we’re missing the small fraction of patients who might have a positive hit on one vs the other. The last thing I’ll mention is that this patient had HER2 testing. We look for amplification. We see this in mostly our nonendometrioid tumors, particularly the serous subtype. But this patient had a shotgun approach of all these molecular tests, which may not have been done routinely for a grade 1, or in this case a grade 2 locally contained endometrioid endometrial cancer.

Transcript edited for clarity.

Initial Presentation

  • A 64-year-old postmenopausal woman presented with abnormal uterine bleeding for about 2 months. She has two grown children, underwent menopause at 57 years of age, has no known family history of cancer.
  • PMH: BMI is 32, and she has hypertension that is controlled with medication
  • PE: Notable for large uterus and right lower quadrant abdominal tenderness on palpation

Clinical work-up

  • Endometrial biopsy: endometrioid adenocarcinoma, FIGO grade 1
  • Surgery: ELAP TAH BSO with bilateral pelvic node dissection
  • Pathology: grade 2 endometrioid adenocarcinoma, 18 negative pelvic nodes, invasive 2.1 cm of 2.3 cm myometrium
  • Molecular testing shows MSS, MMR proficient, and HER2-


  • Postoperative radiotherapy: vaginal cuff brachytherapy to a dose of 21 Gy in 3 fractions
  • 14 months after completing radiotherapy, she presented with new RLE edema and right hydroureter
  • She then was treated with carboplatin/paclitaxel chemotherapy which was well tolerated
  • Nine months later the patient has disease relapse with metastases to the paraaortic lymph nodes and lung
  • She is now treated with lenvatinib/pembrolizumab