 Surgery is important. Anatomic, typical FIGO [International Federation of Gynecology and Obstetrics] staging is important. The molecular biology of the tumor is important. Dave, bring us back to practicality. I do a robotic hysterectomy as I did yesterday. What does the pathologist do with that tissue? What are the typical biomarkers that are the global standard in endometrial cancer?

 First of all, we need to assess the nodes. Most of us are doing sentinel lymph nodes at this point, and we think that adds to this dividing into stage III, which obviously is a higher risk. We have that. Let’s get the information we need surgically with the hysterectomy and at least sentinel lymph nodes, at the very least, mismatching pair proteins through IHC [immunohistochemistry] at the time of diagnosis. At this point, I would advocate—based on prognostic factors and potential treatment options, as well as identification of people with Lynch syndrome potentially or families with Lynch syndrome—that we do that as a baseline.

What is an evolution? Even though the NCCN [National Comprehensive Cancer Network] Guidelines changed last year, looking at this molecular classification based on the PORTEC trial that is still having a difficult time getting payers to reimburse and thus having my pathologist do these extra tests. What are some of the other things? Well, MSI [microsatellite instability]. Should we be doing that PCR [polymerase chain reaction] test if the MMR [mismatch repair] proteins are all intact? We’re not doing that yet, but that’s something I do on recurrence. How about the IHC for 

 that Katie and Brian have mentioned? That should probably be done routinely, but we need to make sure the payers are paying that. As we look at the 

 and the next generation sequencing, as well as additional mutational analysis, there are some other subgroups that maybe will identify their predictive in the future.

But at diagnosis, particularly in early stage disease, that’s not routinely being done, and we’re having trouble getting reimbursed. We really need to look and work with our pathologists as well as the payers to make sure these things are reimbursed so that we are able to perform those tests. I personally don’t think PD-L1 testing should be done. I see that frequently, especially in patients who are coming in for a referral, because we really haven’t seen that it is a marker in endometrial cancer. Don’t do a test if you don’t know what to do with the results.

 [human epidermal growth factor receptor 2] and ER [estrogen receptor], PR [progesterone receptor]?

 Great question. As we look at these, as 

 moves from the serous cancer where we have data, where it makes the clinical significance, clearly it should be done in all advanced-stage serous cancers. We’re not doing it at our institutions for the local or stage I or II disease, but it’s a consideration as we move forward. We’re not doing ER-PR routinely, but it’s really interesting information. I would argue that anybody with a grade 1 is going to be ER-PR positive. For that grade 2 and 3, you may bring a new set of treatments in that you otherwise wouldn’t use.

 I called you my brother when I introduced you. That’s way too complicated. If you tell your pathology what you just said, it isn’t going to work. Krish, I need you to boil it down here. Then I’ll get Brian. Boil it down—just a bite size. Go ahead. What biomarkers do you want done?

 I want TILs [tumor-infiltrating lymphocytes]. That’s what I want to know. Because that’s going to make a difference in whether immunotherapy is going to be effective for advanced disease.

 All right. Brian, help us. Come on, man.

 I appreciate that earlier you said we come from esteemed universities and that we’re all really smart, but I like to keep it simple. The advantage of molecular profile in these tumors is that 1 of the things we haven’t mentioned is that it makes it more reproducible for pathologists to come up with the same diagnosis.

: Prior to molecular profiling, it’s subjective. Here you get endometrial cancer, and No. 1, you do a 

 positive, you follow it up with a HER2/neu, regardless if it’s serous or endometrioid, because the pathologist could be wrong. If it’s 

 negative, you do ER-PR. It’s simple and straightforward. Anyone can do it.

 positive—in other words, mutated—then you do 

. If you’re not, you do ER-PR. You do immunohistochemistry on those—basically all patients. It’s basically the nonserous, but they might be wrong.

 We just made a very complicated subject matter very simple.

 All right. That’s rare for you guys. Wow. Hopefully we can keep the momentum going.

I don’t mean to insult my good friend, Dave O’Malley. But there’s a real ability here to be astute and smart, and you’re that, Dave. Thank you. I’m so glad to have you here.

Videos

Role of Biomarker Testing in Endometrial Cancer

 I was asked the other day, “Brad, what’s the No. 1 word used to describe endometrial cancer?” One word. I said, “Heterogeneity.” It is a constellation of diseases. Brian, Dr Slomovitz, tell us a little about how we’re classifying these tumors at the molecular level.

 Sure. Thanks for that, Brad. Historically we’ve classified these primarily by traditional factors—histology and endometrioid being the most common—followed by serous and clear cell, which are some of the more aggressive histologic subtypes. We still classify them by stage and grade. But of all the cancers we’re treating, the molecular subtypes have really been well defined in endometrial cancer. Ever since Doug Levine published the first TCGA [The Cancer Genome Atlas] article on endometrial cancer, dividing endometrial into 4 distinct subtypes, we’ve really been able to define clear categories for disease and also come up with better treatment plans based on those categories.

Briefly, there’s MSI [microsatellite instability] high, and there’s the 

 mutations. The MSI high make up about 40% of endometrial cancers. 

 is in the single digits—not that common, with a good outcome. There’s the typical low copy number, we call them, endometrial cancers. Then finally, the most aggressive type, the type that are most likely to be ovarian cancers, the 

 subtype. But they’re really well characterized. Not only can we easily divide the cancers into those groups, but those groups really are prognostic and can determine outcome.

 It’s interesting. As gynecologic oncologists, we use the FIGO [International Federation of Gynecology and Obstetrics]staging system. We don’t use the TNM [tumor, nodes, metastases] system. Stage I is limited to the endometrium, stage II in the cervix, and stage III is in the nodes. But Katie, I’ve heard you talk about the molecular staging—maybe this is what Brian said—that there may be a molecular way to look at prognosis rather than disease spread. Tell us about that.

We still have work to do with that characterization. But certainly, alluding to what Dr Slomovitz just mentioned with the TCGA, there have been other interesting studies done in Europe that are consistent. When you look at endometrial cancers that have loss of 

, which we are very used to seeing in ovarian cancer. But in endometrial cancer, we’ve known about it for a while. It’s mainly those patients with uterine papillary serous or very undifferentiated grade 3 endometrioid cancers can have this 

 signature. They’re serous-like and they have a poor prognosis, even when you are controlling for stage.

A stage I, which is all confined to the uterus, endometrioid vs 1 of the loss of 

 tumors, that latter tumor is going to have a much different prognosis if left untreated. How best to treat it—we’re going to talk about it in this session a little later. But we know that they’re much higher risk for recurrence. They make up a much higher percentage of those patients who present with advanced and recurrent disease, so are high unmet need. On the flip side, Dr Slomovitz also mentioned POLE. That’s an interesting group and we don’t understand it really well yet.

We have a sense that even though they are commonly found in undifferentiated tumors, they still have maybe a better prognosis. There’s been some retrospective looks that they do better than they should histopathologically. But it really hasn’t impacted how we treat them. More to come on that.

Risk Classification of Endometrial Cancer

® titled “Advanced Endometrial Cancer.” This is 

®’s first endometrial cancer discussion. I am so excited to be here. My name is Brad Monk from the University of Arizona and Creighton University, both in Phoenix, Arizona. I’m also part of the US Oncology Network. My hospital is St Joseph’s Hospital and Medical Center in downtown Phoenix. I am joined today by 4 experts in the field from very prestigious academic medical centers. First is Dr Kathleen Moore. I’m going to call her Katie. Dr Moore is at the University of Oklahoma Stephenson Cancer Center. Katie, hello.

 Thank you. Dr Dave O’Malley from The Ohio State University Wexner Medical Center in Columbus, Ohio. Dave, welcome my brother.

 Excited to be here for this inaugural endometrial cancer discussion.

 Thank you. Dr Brian Slomovitz from Florida International University Herbert Wertheim College of Medicine and Broward Health in Fort Lauderdale, Florida. Brian, welcome.

Thank you very much for having me, Brad. It’s really an honor.

 You look very smart with all those plaques behind you, Brian.

 Thank you. Dr Krishnansu Tewari from the University of California, Irvine. I’m going to call you Krish. Thank you. Welcome, my friend.

 This is exciting. As I think all of you are aware, there have been several important advances in understanding endometrial cancer, both from a biologic standpoint but also from a novel therapeutic standpoint. We’re beginning to define frontline treatment, and now we have options in recurrent disease. We’re going to review these options, from a surgical, regional, and systemic opportunity. I’d like to get started on our first topic, and that is to consider the biology and the prevalence and incidence of endometrial cancer or uterine corpus cancer.

Krish, why don’t you go ahead and start about the increasing incidence of endometrial cancer and how that has affected your practice.

 Thank you, Brad. In 7 to 8 years we’ve seen about a 30% increase in the incidence of this disease in the United States. There are about 65,000 new cases anticipated for 2020. Maybe 8 years ago there was 45,000. So it’s an increased incidence. It accounts for probably 30% to 40% of my surgical practice, doing surgery for endometrial cancer. We’re not sure why the incidence is increasing. Certainly, for patients who are overweight, obese, and morbidly obese, not only has that been holding stable, but those conditions have been rising.

Diabetes is pretty stable, but what’s interesting is that ever since the Women’s Health Initiative was published in 2002, there’s been a decrease in the use of combined hormone replacement therapy. There’s a possible association between lack of progestins and the rise of endometrial cancer. Also, there are fewer hysterectomies being done for benign disease. Those 2 things need to be looked at in more detail. But predominantly, the obesity crisis in the United States is driving the higher incidence.

 It is the most common operation that I do. Virtually all these operations are done minimally invasive. Katie Moore, your partner, Joan Walker, did that pivotal trial called LAP2.

 Do you ever make an incision for an endometrial cancer? There’s been this evolution in cervical cancer that minimally invasive is not good in cervical cancer. But it’s still OK in endometrial, right?

 Right. Yes, occasionally make an incision, certainly if we can’t do it laparoscopically or more accurately robotically, we get the uterus out the old-fashioned way. But it’s pretty uncommon.

 It’s still not outlawed, but maybe someday open hysterectomy for endometrial cancer will be outlawed.

 It’s really interesting that you’re bringing that up, Brad. Dave can probably comment on this. Actually, all of us can as fellowship directors. When I do the numbers for the fellows now, they do not have a lot of open notes.

 That’s right. With sentinel lymph nodes now…

 Even more common lymphadenectomy is rare.

David M. O'Malley, MD, The Ohio State University

Articles

Role of Biomarker Testing in Endometrial Cancer

Risk Classification of Endometrial Cancer

Overview of Endometrial Cancer