Expert Discusses Recent Endometrial Cancer Research

Rebecca C. Arend, MD

Several abstracts presented at the 2017 ASCO Annual Meeting shared the latest significant data in endometrial cancer research.

OncLive: What endometrial cancer abstracts drew your attention at this year’s ASCO annual meeting?

In an interview with OncLive during the meeting, Rebecca C. Arend, MD, assistant professor, UAB School of Medicine, UAB Department of Obstetrics and Gynecology, UAB Comprehensive Cancer Center, discussed highlights from the ASCO meeting and other key developments in endometrial cancer.Arend: There is an abstract out of my lab, which is basically about molecular profiling of high/intermediate risk endometrial cancer patients who all underwent observation after surgery and looking at those who recurred and did not recur. So, trying to find a molecular signature to tell us who should receive adjuvant treatment in that cohort of patients, which we still don’t really know about.

The most recent trial that we did compared chemoradiation with observation, brachytherapy—most people around the United States do brachytherapy. Most of us observe them due to the fact that adjuvant treatment enhances progression-free survival but not overall survival. But, there seems to be some subset of patients that do recur—so can we identify those patients upfront instead of histologically on a molecular profile level. We used a next-generation sequencing panel, the Caris Panel—their non-commercially available panel that is about 550 genes. And then for RNA, I used NanoString which is 770 genes.

The first abstract that was presented was PORTEC-3, which looked at advanced endometrial cancer. So, it did include some high/intermediate risk but only grade 1 that were stage 3 that had LVSI and deeply invasive disease, and the rest were grade 3/4. And those patients either got radiation or radiation plus chemotherapy. I felt like the take-home point there was that if you have stage 3 endometrial cancer, you need chemotherapy—and that is what that trial showed.

What is the current landscape looking like for patients with endometrial cancer who are MSI-H?

Then GOG-258 was presented, which had chemotherapy alone, so that had chemotherapy versus chemotherapy plus radiation. And I felt like that took it to another level by saying that you for sure need chemotherapy in stage 3 endometrial cancer patients, but you probably don't also need radiation.We just saw an approval for all solid MSI-H tumors. So, that is also very exciting because we’ve started about, a year and a half ago, doing a personalized medicine initiative within my division, so we do panel sequencing on recurrent tumors. When we started, it was almost exploratory. Obviously, a lot time, there isn't a targetable mutation, or if there is there is not a drug available or it is too expensive, etc. But now, we know if you have a BRCA somatic mutation then you are available for rucaparib, as well as MSI testing. So now, if you are MSI-H you have a drug available, which is immunotherapy. This is exciting because it is personalized medicine that is not grasping at straws, even though the number of patients that it is going to help is still pretty small.

Where we are going with all of this research is figuring out how to get more patients to respond to immunotherapy and how can we get the BRCA wild-type patients to look more like BRCA-positive patients, so that they respond to PARP inhibitors. And that is sort of what everyone is trying to. It is really exciting that we have PARP, and it is a home run if you have a germline mutations.

For your patients with endometrial cancer, do you have a time point of when you would test them for MSI-H?

What other targets are you finding in endometrial cancer that we may not have drugs for yet?

The durable responses that we are seeing with immunotherapy in MSI-H patients are exciting. But again, those numbers are small—so being able to increase at 20% of ovarian or 20% of endometrial up to 80% by using combinations is where we are headed.Yes, at the time of first recurrence—that is what we have been doing for all gynecologic patients. It may not change out management at that time point, but if and when a phase I trial is opened that has an FGFR inhibitor and my patient has an FGFR mutation, I will put a couple patients on that trial. There have been other things that look at mutations that could predict if the patient would respond to a BET inhibitor, now we have a phase I BET inhibitor trial. I work closely with the phase I unit to make sure that I am aware of the phase I trials that are available. So, I could pull a patient back, look at her next-generation sequencing data, she may be coming up on her third- or forth- line, so now could be a time that she could use this. It is an IRB-approved protocol where we can send the patients at the time of recurrence.Patients with PI3-kinase mutations and mTOR mutations. We have 1 patient that is on an mTOR inhibitor in combination with everolimus and letrozole, and there was a gynecologic study that showed that this combination worked in a patient with an mTOR mutation with a prolonged benefit. Again, these numbers are small, but when you find it, it is really significant for the patients involved.

The other area of interest is looking at ARID1A mutations and looking at EZH2 inhibitors, which are in the pipeline. We do know that this could potentially be a synthetic lethality interaction, similar to what we have seen in BRCA somatic mutations and PARP.

MEK inhibitors, specifically in low-grade pap serous, are something to consider. But, the issue is that most MEK inhibitors do not work well as single agents, so having more trials with MEK inhibitors, even in combination with PARP or immunotherapy in KRAS mutant, is a direction that we are headed in as well.

SM De Boer, ME Powell, LR Mileshkin. Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and radiation therapy (RT) versus RT alone for women with high-risk endometrial cancer. J Clin Oncol 35, 2017 (suppl; abstr 5502).