 Let’s go to our third case. This is a 64-year-old post-menopausal patient who presented with a big uterus. She’s tender, she has a bunch of blood, and she’s feeling unwell. With an 18-cm uterus, we did an exploratory laparotomy on her, and because of our visualization, we also did a full bilateral pelvic lymph node dissection.

 We got 12 out. She had a 44% invasion; I hate these grade 2 tumors. Grade 2 tumors, let’s call it 54%.

 It’s a big tumor, a bunch of blood, and a lot of symptoms. Molecular testing shows mismatch repair proficient. They did checkHER2/neu [human epidermal growth factor receptor 2], though I normally wouldn’t check in a nonserous cancer. We talked to her, sat down, and guess what we recommended, Brad?

I agree with that. The pelvic sidewall is clear.

It’s definitely not crazy, but the way pelvic radiation is delivered today, through IMRT [intensity-modulated radiation therapy], bladder and bowel sparing, it’s almost tougher to do vaginal brachytherapy. It’s more lucrative for the radiation doctor. I don’t mean to imply that’s why they do things, though. It’s a controversy. However, the PORTEC-2 trial was randomized, so the data would support vaginal brachytherapy, and that’s fine.

 These grade 2 tumors drive me nuts. There are some data that show about two-thirds of them are going to act like low grades, but maybe as high as one-third are going to act like a high-grade, more aggressive tumor. Unfortunately, about 17 months later, the patient recurs—a big right pelvic sidewall recurrence—and we took out those 12 pelvic lymph nodes, but maybe we missed the sentinel.

 Seven percent will be outside the usual boundaries, which is something to keep in mind. She has a right pelvic recurrence, we give her a carboplatin with paclitaxel, and she gets a nice response, with a little disease left at that point. Brad, what are you going to do with any recent data that may help us here? Do you complete the 6 to 8 cycles of carboplatin, paclitaxel?

 Both of you have been passionate advocates of maintenance PARP inhibitors in ovarian cancer. You get a response and you know that the risk of recurrence is very high. We have multiple 

 papers showing maintenance, and bevacizumab in maintenance. We have addressed that same question in endometrial cancer, where you’re going to recur; you get your 6 doses, and go ahead and get maintenance therapy. There’s a study that was reported on February 8th through a press release that will be presented very soon at a scientific meeting, called SIENDO, which stands for selinexor in endometrial cancer. This is a randomized 2:1 maintenance trial, once weekly of the selinexor, 80 mg, and it improved progression-free survival. I can keep talking about it, but I know, Dave, you’ve done a deep dive here. Tell us about the results of this trial and what you think about it.

 What’s interesting is it’s an XPO1 inhibitor. We have this novel target. We saw a hazard ratio of 0.7, so about a 30% improvement in all populations. With what we’ve reported, we’ve only seen the press release, 

 wild type seemed to benefit the most. The observation arm was right about 3.8 months improvement in progression-free survival, so that makes sense in national history.

 The results are the same whether it’s 

 Great point. When we looked at all-comers, not quite double, it was about 5.7 versus 3.8 months. But in the 

 wild type, there was about a 3-fold improvement in the median progression-free survival.

 Yes, 0.38, precision is important. This is another positive phase 3 trial, run through GOG Partners.

 The GOG-3055 trial, thank you. When we’re looking at this group, we know the FDA loves biomarkers. Ultimately, what will the approval look like? Will it look like the 

wild type, or will it be all-comers? I don’t know.

I don’t know. Think how novel this is. In the 

 is known as the guardian of the genome. 

 causes G1/S arrest and allows DNA mutations to be repaired, so that works in the nucleus. XPO is an export of

 stays in the nucleus and does its job. The wild-type functional 

This is so exciting; we’re going to be ordering 

 testing on all our patients with endometrial carcinoma. Are we going to order it up front or are we ordering it later?

We’re going to need to traffic through this, but this is here to stay. I’m going to give you the medians now. This is 6 cycles in stage IV recurrent of carboplatin, paclitaxel, then maintenance, once weekly, with a low discontinuation rate. You take 1 weekly fixed dose of 80 mg, and if you’re 

 wild type, which can be assessed by immunohistochemistry staining, you go from 3.7 to 13.7 months, a 10-month improvement in progression-free survival. Bingo. This is exciting, and the mechanism of action, a nuclear pore inhibitor, is amazing. I don’t care what mutated 

 does. I can’t turn it back on, but I can relocate the 

that’s functional and keep it in the nucleus where it can maintain the integrity of the genome and help patients in the long run.

 We have another phase 3 trial that is positive. We have the KEYNOTE-775 trial, we have, what did you say?

 SIENDO stands for selinexor in endometrial cancer. I love it. It’s another phase 3 trial. We have at least 4 phase 3 trials that are going to read out within the next 1 to 2 years with regard to metastatic recurrent disease looking at immune [I/O] therapy, and does it help the backbone of carboplatin and paclitaxel? Then we have the adjuvant setting for locoregional disease. Then we have high intermediate risk, patients with MSI [microsatellite instability] high or MMR [mismatch repair] deficiency. Can we or should we add I/O therapy too to improve their outcomes? We know their recurrence rates will be 25%-plus. We’ve already talked about how hard it is it to salvage in recurrent settings.

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Oncologists debate the proper treatment of a patient with a grade 2 endometrial carcinoma tumor.

Endometrial Carcinoma: Clinical Case Scenario 3

 Krish, tell us about your case. What was the chance of recurrence? You’re probably going to tell us she recurred. What was the probability of that? What did you do?

 The probability was pretty high; it’s about 60% that this patient with nodal metastases would recur. She did recur and had already been treated with chemotherapy plus carboplatin-paclitaxel. What are the treatment options available for a patient who’s been previously treated for advanced-stage disease who then relapses?

 The molecular signature matters. Essentially, every second-line patient, including those who got adjuvant therapy like this 1, needs pembrolizumab in the second line. The only question is, do they need lenvatinib when pembrolizumab is not going to work very well?

Brad, I’ve got to interrupt you. She’s platinum sensitive. She’s recurred 8 months.

 8 months. But that doesn’t apply to endometrium, right?

I’ve got you, Krish. I hate that. There’s no data in 6 months. She’s platinum exposed! Those patients need pembrolizumab, exactly as what Brad said.

 Dave, what you said—people say that. As much as we think no one ever would, they do. That’s part of the value of this conversation. Dostarlimab was FDA approved on August 17, 2021. We can use pembrolizumab or dostarlimab if the patient is MSI [microsatellite] high or mismatch repair deficient, or theoretically 

 hypermutated, with TMB [tumor mutational burden] opportunity for pembrolizumab. Then everybody gets pembrolizumab-lenvatinib. We’ve had that opportunity for a long time based on the September 2019 accelerated approval. In July it got full approval. You’ve seen the publication in the 

 that randomized patients, just like this, to chemotherapy vs pembrolizumab-lenvatinib, and it showed a survival advantage that was not only statistically significant but clinically meaningful in this patient.

Physician-researchers discuss the risk of recurrence in endometrial carcinoma and the available treatment options after relapse.

Treatment Options for Advanced Stage Relapsed Endometrial Carcinoma

What biomarkers do you test at diagnosis? What are you asking your pathologist to do? Is 

I’ve been fairly frustrated. I love my pathology colleagues. The group in molecular pathology is wonderful, but we haven’t adapted in being able to practically check POLE, and we’re not routinely getting 

. For which patients are you going say, “I want that.” Is that going to change what we do on most of these patients? With some of the evolving data, it could change.

Tell me about some of the evolving data. Brad, do you want to take this, with respect to 

Let’s tell our audience the right way to work up a newly diagnosed endometrial cancer for biomarkers. It’s pretty simple. You do the IHC [immunohistochemistry] for the 4 MMR [mismatch repair] genes. 

 is easy; it’s an IHC as well. There are 2 scenarios where 

 is mutated. It’s overexpressed because the gene is mutated and the protein accumulates, or it’s 

 mutated. The dark is overexpressed, or the light is nodal. The model in between is 

 wild type, so that’s routine. If you’re a believer that estrogen and progesterone receptor are important, you should do that. Finally, if it’s a uterine serous cancer, you should do 

/neu [human epidermal growth factor receptor 2]. It’s mismatch repair deficiency, 

. That’s the way you do it. Let’s talk about 

 as a target when we get into the recurrent setting, in which case mutation still is the adjuvant.

It will be exciting to share some of the news then. Any other biomarkers you’re interested in, Dave?

I’m interested in seeing what the PORTEC-4a trial turns out. Outside clinical trial we’re not quite ready for those. As we evaluate this, Brad, you brought up a good point: what are the things we should absolutely check?

What if they’re MSI [microsatellite] stable? Do you go further and order a tumor mutational burden on these patients?

I don’t in the early-stage disease. Should we begin next-generation sequencing looking for POLE, knowing that that’s an important risk factor? Should we go to the PORTEC-4a trial, which looks at CTNNB1 as well as L1CAM? We’re not doing that. Outside a clinical trial, I’m not ready to do that. But that’s something we need to consider in the future.

 That’s in the adjuvant setting, but I’ll bet that when you get stage IV recurrent, that’s when you’re doing the POLE. That’s when you’re doing the tumor mutational burden and some of these other targeted opportunities. It’s important to separate the 2 buckets where chemotherapy is used: adjuvant and stage IV recurrent. All the studies we’re doing except for the KEYNOTE-B21 trial adjuvant are in stage IV recurrent disease.

That’s a really important point. We’re not there with regard to significantly changing our adjuvant setting based on the molecular markers. That may be 

. You’ve got a grade 3 endometrioid deep invasion. Are you going to give chemotherapy to that patient vs other observation vs vaginal cuff brachytherapy? That’s the biggest question mark.

An overview of biomarker testing in endometrial carcinoma.

Bradley Monk, MD, FACOG, FACS

Articles

Endometrial Carcinoma: Clinical Case Scenario 3

Treatment Options for Advanced Stage Relapsed Endometrial Carcinoma

Biomarker Testing in Endometrial Carcinoma