Advanced Endometrial Cancer: Optimal Sequencing of Therapy


Insight on the optimal sequencing of therapy in patients with advanced endometrial cancer based on MMR and MSI status.

Case: A 70-Year-Old Woman With Endometrial Cancer

Initial Presentation

  • A 70-year-old postmenopausal woman presents after experiencing abnormal uterine bleeding for about 3 months. She has a grown daughter, underwent menopause at 52 years of age, and her father had prostate cancer in his late 60’s.
  • PMH: Unremarkable
  • PE: Notable for large uterus and tenderness upon 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, 15 negative pelvic nodes, invasive 1.9 cm of 2.4 cm myometrium
  • Molecular testing shows MSI-high, MMR proficient, and HER2-


  • Postoperative radiotherapy: vaginal cuff brachytherapy to a dose of 21 Gy in 3 fractions
  • 12 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


  • 15 months later the patient has disease relapse with metastases to the paraaortic lymph nodes
  • She is now treated with pembrolizumab


Michael Birrer, MD, PhD: Before, it was easier: carboplatin, paclitaxel, and that’s it. We’d debate whether we wanted to use doxorubicin. It’s gotten more complicated, but that’s good for our patients because there are choices. In this case, with a tumor in the outer 50% of the uterus, a grade 2, I probably would have given the patient adjuvant chemotherapy rather than radiotherapy. But I tend to be very aggressive because I’ve never had a patient get into serious trouble with carboplatin-paclitaxel. That might have been slightly different.

Let’s say the patient was treated with radiotherapy and then, when the tumor recurred, we use carboplatin-paclitaxel. It’s perfectly reasonable. But it recurs, and we move on to pembrolizumab. I completely concur with that. Given what I just said about KEYNOTE-158, it’s hard to imagine that re-treatment with chemotherapy, let alone with any of the agents that I have outlined, would be anywhere as near as effective as pembrolizumab as a single agent. I agree on that.

What you find for endometrial cancer is that there are patients who will get adjuvant chemotherapy or treatment for metastatic disease and, for whatever reason, have a long disease-free interval. Let’s say you have a patient—with grade 3 endometrial cancer, for example—who gets adjuvant chemotherapy and then 2½ to 3 years later recurs. There are individuals who will re-treat with carboplatin-paclitaxel. The reason they do is because the platinum-free interval is so long. But I have to point out that the field is contaminated a little because most patients who treat endometrial cancer treat ovarian cancer. In ovarian cancer the platinum-free interval is clearly defined. When patients recur with a long platinum-free interval, re-treatment predicts for a reasonable response. There are no comparable data in endometrial cancer to correspond on that. The molecular reason is because ovarian cancer has a homologous recombination deficiency; most endometrial cancers do not. So I’m not sure that analysis makes a lot of sense. In this case, given that you had an MSI [microsatellite instability]–high tumor, going on to pembrolizumab makes a lot more sense than re-treating with carboplatin-paclitaxel.

A lot of people won’t count adjuvant chemotherapy as a line because it’s not a line for a metastatic disease. You’ve removed everything, and you’re just treating the patient. I think that’s nonsensical. The tumor is being exposed. Any tumor that’s left is being exposed to chemotherapy, so that’s a line to me. If they recur, then you’re into second line, and a lot of the indications for pembrolizumab are second-line indications. What are the scenarios? A patient gets surgery like this patient, radiation occurs, nothing else, and then it recurs and the patient gets chemotherapy. That’s the first line and then, pembrolizumab is coming in as the second line. If this patient had gotten it instead of radiation and adjuvant chemotherapy then recurred, the adjuvant would have been counted as first line, and the recurrence would have been second line. I would have used pembrolizumab at that point. I hope that’s clear. Because we have choices, it’s gotten a little murky. Just remember that when you give chemotherapy, it doesn’t matter if you can see the tumor. You’re treating tumor, so that’s a line.

There are patients on KEYNOTE-158 who are almost flattening the curve for overall survival. A lot of us feel for those patients who have microsatellite-unstable endometrial cancers, because for a subset of those, the tumor does not come back within 2 to 3 years and they’re likely cured. It’s not everybody. As I said, the response rate is only 50%, but there’s a percentage of patients who don’t respond and so the tumor progresses. I’ll keep my fingers crossed that she’d be in the group that did really well, and then the tumor would disappear—which I’ve seen—and wouldn’t come back. If she’s not in that group, then she falls into an interesting group of patients for whom there’s a lot of research ongoing. When patients who have microsatellite-unstable tumors either respond or don’t respond to pembrolizumab, what’s the mechanism to resistance? We don’t know that, but within about 5 years we’ll have a much better idea. And if this patient fell into that group, one could think about the other agents I’ve talked about. The mTOR inhibitors would be there. Even though this isn’t a stable tumor, there’s no reason why one couldn’t add lenvatinib to pembrolizumab, just as you do with microsatellite-stable patients. You also have bevacizumab as an antiangiogenic agent, so there are options for that patient.

Transcript edited for clarity.

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