Introduction: The Incidence, Pathogenesis and Prognosis of Ovarian Cancer

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice, and welcome to “What I Tell My Patients.” This is Part 7 of a 10-part series we’re doing here at ONS this week. Tonight, we’re going to talk about the management of ovarian cancer. We have a great faculty today, and actually our faculty, we have the nurse and doc work together at the same institution. So it should be a lot of fun to hear, particularly about the patients that they are taking care of.

So as always, in all of our programs, we will be bringing up nonapproved agents and indications; check the package inserts for more information. For those of you here in the room, all the slides are on your iPad. There’s a survey for you to take as well. You can also ask questions or submit cases. Clinicians out there on Zoom, hey, how’s it going? And same functions for you in the chat room. In both of these, there’s a1-minute pre- and postmeeting survey. If you take that, you’ll get a lot more out of this experience. We also are video and audio recording all these programs. We’ll let you know when they’re available in the next week or two and for your colleagues not able to attend here tonight.

So this, we are doing 10 programs here, and we are focusing on specific cancers, for example, ovarian cancer tonight. But we’re also trying to take a step back and really just think about being in oncology, and oncology nursing in general, and also being involved with clinical research in general. To try to enhance this year’s meeting, we tried kind of a new experiment, and over the last few weeks I chatted with 8 nurses who participated in previous ONS programs. We weren’t able to get them in this year. They weren’t available or we weren’t doing their tumor. But we chatted with them and asked them a bunch of similar questions. By the time we got to the end, we were just so struck by the content. Our original thought was to put a couple of these in the meetings, which we’re doing, and tonight we’re going to show you 3. But we actually ended up producing 85 videos. They’re all under 90 seconds; we’ll be distributing by social media over the next few weeks as well. I’ll be really curious to see what you think about what we can do with this. But you’ll see, you’ll get a little bit of a taste of it here tonight, and curious about where it might head.

Okay, ovarian cancer. So we’re going to start out and spend a lot of our time on the newly diagnosed patient, where a lot of advances and important changes have occurred, and a lot of nursing implications. So maybe just to take a step back, why don’t we just start with a patient? We haven’t tried that. I’d like to do a little improv here. So Jaclyn, why don’t you tell us about a patient, actually came to see you?

MS SHAVER: Yeah, this is a patient that I’ve recently seen, interviewed several weeks ago. Patient came in with presumed to be ovarian cancer. We did take her back to the operating room and had a successful cytoreductive surgery with no gross residual disease. So that’s really important. And when you’re talking about ovarian cancer, we do our best to try to remove all of that disease that we can visibly to have the best outcome that we can. And so we were successful at doing that, and during this time we also have to think about the genetics of the patient now. It’s a huge part of our treatment for these patients. And so during that time we discussed the reasons why behind getting genetics, not only for medical treatment, but also from a family history stance point to see potentially, is there family members at risk of having this deadly cancer as well, and potentially even getting those different other cancers?

DR LOVE: So this is a patient who’s a new patient.

MS SHAVER: Yeah.

DR LOVE: We’re going to use this as an example as we go through this meeting. She’s 64?

MS SHAVER: Sixty-four.

DR LOVE: So if you didn’t pick up on some of the things, we’re going to analyze everything as we go along. But she’s a newly diagnosed patient, and she still hasn’t had her treatment determined. Floor, one of the things that I know is sort of cooking with her, she just had her surgery and all, are genomic tests. Why do we do genomic tests in this situation? What kinds of genomic tests do we do? And how does it affect how we treat the patients?

MS SHAVER: Yeah, so there’s a —

DR LOVE: Sorry, that was for Floor. Trying to move it around a little bit.

DR BACKES: She knows it all, she’s fantastic. So you don’t really need us over here. But no, this is a great opportunity for our patients, so different reasons. The first reason really, for the patient herself, is that if we see that there’s a genomic underlying problem, that we have also targeted drugs that we can use in these situations. So really having that information early on will be helping us to figure out, what are we going to do for maintenance to try and keep these patients cancer free? And Dr Moore was the primary investigator for probably the most impressive trial, for the SOLO-1 trial, that did olaparib in up front in BRCA patients and really has paved the way to an impressive overall survival difference here for these BRCA patients. So I think that’s huge for the patients themself, but also for the family members. Oftentimes this doesn’t get picked up, and it may not be evident yet that there is breast, ovarian, pancreas, maybe even male breast cancer. This may be the first contact with a provider that’s looking at it, hopefully not, but oftentimes it is. And this is an opportunity to get the patient screened and see if there’s any mutations that put them at risk for ovarian cancer, but also breast cancer and other cancers. And then if that’s present, then also to get their family members screened and do that cascade testing. And so then, once we know all that information, we can do preventative. We don’t have to deal with the ovarian cancer anymore.

DR LOVE: So — and as you were mentioning, that really things changed dramatically with the so-called SOLO-1 trial that Katie led looking at the PARP inhibitor olaparib. And then that’s going to be a key question here in this woman who’s just getting the treatment that we had been using before chemotherapy. Is she already starting that now?

DR MOORE: Yeah, she’s on cycle number 2, so we’re paclitaxel/carbo and we’ve added in the bev.

DR LOVE: Right. And that was kind of where we were 5, 10 years ago before we started new studies to look at PARP inhibitors. And so this woman is going to have genetic testing, and also testing of the tumor. And again, we’re going to go through all this. But Katie, the things as Floor just sort of alluded to, the whole treatment of patients in this situation — incidentally she’s 64, which I guess is a pretty typical type of age, Katie, for this presentation? So you know, prior to this, we really just had chemotherapy, and then you led the so-called SOLO-1 study. Now, that was restricted just to patients I believe with BRCA1 and 2. Is that right?

DR MOORE: Correct.

DR LOVE: So they theoretically would be the ones who would respond the best. Can you explain a little bit first of all, prior to the actual, this study, what had been done to understand how PARP inhibitors work? And when you started the study, what did you think you were going to see?

DR MOORE: Sure. So SOLO-1 started accrual in 2013. And prior to that, there had been — it’s pretty, in the history of drug development, it’s a pretty rapid ascension to FDA approval. The first approval was in the recurrent setting, in BRCA1 to 3, or actually 3 or more priors recurrent disease. And the response rate and the duration of response in that setting was so profoundly better than what was a historical benchmark that it gained accelerated approval in 2014, and then sort of started entering these large, randomized Phase III studies as a maintenance. Prior to that was all of the preclinical work and early Phase I work, to really understand the dosing and scheduling of this first oral medication in ovarian cancer. And it really came to understanding. And there’s not enough time in this session to give enough gratitude to the early investigators and scientists who develop PARP inhibitors, but there’s several who really saved this medication. Really, the efficacy of PARP inhibitors really hinges on the fact that PARP inhibitors inhibit PARP. PARP is poly(ADP-ribose) polymerase, which is a protein, so that’s all you need to remember. And that protein’s really important in fixing DNA. So right now, you’re all sitting here, and your cells are dividing, and your DNA is replicating, and it’s some miracle that it happens and we’re not all just goo, because we have this really beautiful surveillance system and proteins that fix the DNA errors that we have normal cells, which is great for normal cells, but not great for cancer cells. Like if a cancer cell’s really good at fixing its DNA, it just keeps living. PARP is one of those key proteins.

Ovarian cancer through BRCA, and through many other modifications that we’ll probably talk about, has a lot of vulnerabilities in how it fixes its DNA as it’s replicating, so it really struggles to do it. So if you take out the PARP protein and it’s vulnerable, through these other mechanisms, the cells die. And that’s really how PARPs came to be in the ovarian space first. We’re not getting breast leftovers. Like PARPs were developed for our patients first, and then very rapidly moved into these maintenance settings, and then finally into SOLO-1 where we are likely curing about 25% more patients than prior.

DR LOVE: So yeah, that was really revolutionary. So I’m kind of curious. Prior to this, Courtney, before we had PARP inhibitors, people mainly were getting surgery and chemotherapy. What would a patient like this typically, after she’s finished her adjuvant chemotherapy, would she normally get some kind of a maintenance, prior to —

MS ARN: Prior to the PARP inhibitors, no. Sometimes patients would get like bevacizumab as a maintenance therapy, but the PARP inhibitors have definitely changed our maintenance strategy.

DR LOVE: How do these people usually present? How did this woman present?

MS SHAVER: She presented with bloating, nausea, vomiting, early satiety.

DR LOVE: Typical. Right. Is that typically what you see, Courtney, and what are some of the other presentations you’ve seen of ovarian cancer?

MS ARN: Sometimes it can be generalized just like fatigue, but a lot of times it is the GI symptoms, like the early satiety, weight loss, nausea. Oftentimes, they’ll have some abdominal or pelvic pain. Frequently, we’ll see patients go through several workups before they come see us with a cancer diagnosis. So their primary care doctor kind of does a general workup. And sometimes they’ll refer to GI. Sometimes they’re referred to several different specialties before the cancer is identified, because the symptoms can be so vague.

Genetic Testing for Newly Diagnosed Advanced Ovarian Cancer

DR LOVE: So Floor, can you talk a little bit about the type of testing a patient like this is going to be going through? She’s actually having it done now. You’re waiting for the results. Really, the main purpose is really to assess the possibility she may benefit from PARP inhibitors. Can you explain kind of the types of tests, and what somatic testing is versus germline, and then the types of mutations, and how that corresponds with PARP?

DR BACKES: Yeah. So you mentioned those 2 main types, so the germline, so if there’s something in the genes, that could be passed on between family members also, and then the tumor. So for the germline, there’s much, a lot of different panels. And we’re very fortunate that we have genetic counselors embedded in our clinic also. But that’s not the case for everybody. But it’s more than just BRCA. There is RAD51, there’s other, BRIP. There’s other mutations too. And so most of the patients will get a pretty extensive germline panel, with somewhere between 50 and 75 genes that will be tested for inheritable diseases. So that’s the one part. If that is negative, we still want to go a little bit further. We want to test the tumor too, because you can also have a BRCA mutation in your tumor that still can make you sensitive to the PARP inhibitor drugs, and to the same level as if you have it in your germline also. So really important that you test both the germline as well as the tumor to get those results. And also, if you find something in the tumor, if you do it the reverse way and you get your tumor results back first, you have that BRCA mutation in tumor, that does not mean that somebody has a germline mutation and that their family members are at risk. So by doing then the subsequent germline testing for that same patient that had the BRCA mutation in their tumor, and it’s negative, then you can reassure their family members also that they’re okay. But it can also be a way to actually pick up that you should do germline testing. You may find somebody in their family. But it should be a combination of both.

DR LOVE: Roughly, what fraction of patients present with BRCA germline, who are BRCA germline?

DR BACKES: So about 15%, as high as 20%, 25%. And then the other part that I didn’t mention yet also is that there’s another tumor test that can indicate if you’re sensitive to PARP inhibitors, which is homologous recombination deficiency. So there’s a couple different ones on the market. Some are a combination of 3 different factors that are combined into the genomic instability score. Some of them just have 1 component of it, and that’s oftentimes called LOH, or a loss of heterozygosity, a term that you may have heard. And that can also, if the score’s above a certain number, that can be an indication that also you’re more likely to benefit from PARP inhibitors.

DR LOVE: So we’re saying, this woman, we’ve been talking about her all week long, and we always talk about the patient is newly diagnosed with cancer, regardless of what kind of cancer it is, how upending it is. And so this woman now is confronting — she’s had surgery, she had chemotherapy, and on top of all of that, now she has potential consideration of her kids. Because she’s getting germline testing, she’s got a 15%, 20% chance. What is her family situation? Does she have children?

MS SHAVER: She has 1 child, a daughter.

DR LOVE: Interesting. And of course there’re a lot — one of the things I hadn’t thought about, we do a lot of programs on PARP in prostate cancer. And of course breast cancer, PARP inhibitors are used in many different places. But I was actually thinking about the fact that if you see say, the son, the daughter has it, okay well you could do bilateral mastectomies, almost completely reduce the risk of breast cancer. You could take out her ovaries. But like, what do you do if it’s a man, in terms of getting prostate cancer? There’s not — I don’t know. You can tell me, but they said there’s nothing you can do, so they don’t even want to tell them. But in any event, so theoretically now, in addition to this she might be thinking, wow, my daughter maybe is going to have a high predisposition.

Any comments on sort of how this works out as the patient’s first confronting a diagnosis, and now they’re worrying? And we had a case of a prostate patient who had 4 daughters who all were BRCA. I mean, it’s a very devastating thing. Any comments?

MS ARN: Yeah, I think it adds a whole other layer to their new diagnosis. So they’re already dealing with the stressors of being told they have cancer, they need chemotherapy. But then they’re dealing with the guilt of, did I give this to my children? And that adds a lot of stress to the patient. And then I’ve also seen the opposite side of it, where I have like younger patient population and they have told me from their perspective is their mom treats them differently because they felt like they gave them the cancer. And so I think it changes the family dynamics in many ways.

DR LOVE: So we’ve had a theme in this ONS meeting, we’ve been coming here — I’m sorry, Floor?

DR BACKES: Let me add to that. So I totally agree that that is a lot of stress. I actually have a very interesting patient also who was diagnosed. She was 35 when she was diagnosed, Stage IVB ovarian cancer. She tested. She was BRCA positive, BRCA2 positive. And then we tested the rest of the family, and actually didn’t know where it was coming from. Her mom turned out to have BRCA2. I did the risk-reducing surgery for her mom then.

DR LOVE: Wow.

DR BACKES: We did not have a diagnosis yet until we did her risk-reducing surgery and found a Stage, early Stage II, like microscopic in her tube.

DR LOVE: Wow.

DR BACKES: This is the other side of the story. Like the daughter helped her mom from the diagnosis.

DR LOVE: How old is her mom?

DR BACKES: The patient was 35, the mom was, I think 60? So yeah, so she — crazy story, but yeah. Usually, we don’t see it that way.

DR LOVE: Well, I’ll just drop in and say, while we’re talking about it, any thoughts, Katie, about giving PARP to somebody who’s got the early-stage disease? Your patients in the trial were kind of later, more advanced than this patient, because she got picked up early. But would you still want to give her PARP? I mean, she has a risk — I don’t know, what would you say her risk of recurrence is, Floor?

DR BACKES: Thirty percent or so.

DR LOVE: Yeah, maybe you cut that back, way back. Katie, is that outside the indication, or can you do it?

DR MOORE: It is outside the indication. So we do have to say it would be off label. However, and we’ve actually talked about this a lot at the National Cancer Institute level, trying to figure out how we can study this in clinical trials, but it’s just difficult because of the numbers. But some of our colleagues, like Dr Elizabeth Swisher, Barbara Norquist at University of Washington, who have very large high-risk screening populations, have published retrospectively. And even in Stage I cancers, the ones that are found kind of in risk reducing surgery, they do seem to have a higher risk of recurrence than a Stage I serous, high-grade serous that’s BRCA wild type. And that makes sense, because you had a genetic predisposition, so you probably have some risk in the other cells. So based on that retrospective data, I have definitely offered PARP to patients post adjuvant treatment for early-stage disease, with very careful counseling that it is off label and there are risks.

DR LOVE: So yeah, in breast cancer, we were talking about this Wednesday night, they kind of evolved differently because they had these huge metanalyses they did and they had just thousands and thousands of people and they eventually came into a thing where even though they were demonstrating in the high risk patients that the treatment worked, they demonstrated it. You saw the same relative risk reduction going all the way down. So even people with lower risk tumors would benefit, it’s just they don’t benefit as much. But they, you may go from 30% to 15%. That’s, like, (1), you know, 15% chance you’ve avoided recurrence. That’s a very significant benefit.

The Role of PARP Inhibitor Maintenance for Newly Diagnosed Advanced Ovarian Cancer

DR LOVE: But let’s continue with the case. And again, over the years here at ASCO — ASCO, that’s in 1 month. We do 10 programs at ASCO, too, but anyhow. So yeah the theme here is a lot different too than ASCO because one of the themes here, has been a very strong theme over the year. I want to ask you about this patient, is why was it different to take care of this patient than another patient, in the same oncology situation, ovarian cancer, same age, everything the same, except it’s a different person. Different attitude, social situation, comorbidities, age, et cetera, et cetera, et cetera. In your mind, as she sort of began walking through the door and you sort of began to assess her, those first few interactions, what was coming out that was important for her?

MS SHAVER: So during her initial interview, not only getting the medical history is important, but also the social history is very, very important to these individuals. And so one of the challenges that she had was she had financial insecurity. And so she lived multiple hours away from the treating facility, did not have a lot of good social support in regards to getting her to the office visits, even having some food insecurity and things like that. And so it’s very important, especially as nurses, to make sure that you are diving into that social aspect and giving the support that they need, giving them the resources that they need. We fortunately have some really good resources at the cancer center where we work at, me and Dr Moore. We have financial aid assistance, we have social workers, we have nutritionists that can help come alongside of the medical aspects and provide that care to the life of the patient that we actually don’t see. They have a life outside of the clinic where you see them, and that really is impactful of actually completing the treatment and getting hopefully the cure that we want for these patients. They have to come to the visit, right? And so that’s a very important part of the whole picture of the patient. We try to do holistic care for these patients, not only treat them medically, but treat them as a whole person.

DR LOVE: So interesting, kind of geographically, Katie. You’re there in Oklahoma, a little bit more rural than Washington, DC, for example. Any comments again on some of the social issues you encounter in your patients?

DR MOORE: Yeah. I think Jaclyn hit it, kind of hit the nail on the head. And I think I would say to this audience is that my nurse, who is Christie Sawyer, who is worth her weight in gold and platinum, she’s usually the one that’s bringing these to my attention. Because I’m coming in and I’m really like focused on a CT scan, and the physical exam, and the moleculars, and what clinical trial I have, and talking about these things. And then Christie will come in and say, “Hey, you know, Mrs Jones didn’t want to tell you, but she wants to go on a cruise and doesn’t want to start for 3 weeks, but she was nervous to tell you.” And I’m like, oh, well, of course she can go on a cruise, because that’s important. So it’s even like those sorts of things that our nurses in the office like get a sense of what’s important to our patients, things that are important for their families, but also things that are important in terms of their care, like they are home without electricity, they are having trouble with food insecurity, they are taking care of their 90-year-old mom, that happens a lot, domestic issues. We have the run of it. So it just all impacts our ability to really provide holistic care to our patients. And we’re really, I feel blessed because we have so much wrap around resource at our big center, and most places don’t have that. But I think it just comes down to sort of asking the questions and trying to meet our patients where they are and go from there.

DR LOVE: So let’s move a little bit farther. We’ll see what happens with this lady over the next few weeks and what direction she’s going to head. And as we go through this meeting, you’ll see how important the results that she’s waiting for are going to be, not only to her family, but also in terms of her treatment.

And Floor, you have a 78-year-old woman. Interestingly, she had a different type of mutation called RAD51D, but has kind of similar implications for BRCA. She actually got neoadjuvant chemotherapy that’s commonly used in ovarian cancer. You might comment on when it’s used. And then she did get a PARP inhibitor on a trial, niraparib, which is also approved in these situations. Can you talk a little bit again about how she presented and kind of what happened with her?

DR BACKES: Yeah, so this is a very healthy, at that time, I think around the time that I met her, she must have been just early 70s. Very healthy, prior flight attendant. Came in kind of with all those vague symptoms that we previously described and ended up being diagnosed with Stage IV disease with pleural effusions, couldn’t breathe very well, short of breath, had a chest x-ray. The chest x-ray showed some more fluid on her lungs, turned out to have a belly full of fluid and the ball started rolling with her ascites. But ended up having neoadjuvant chemotherapy because she had so much disease that we would not be able to completely surgically resect it, so. As you’re probably aware, like, we do combination of surgery or chemotherapy, but the question is, what do we start with? And so that depends on ideally, you would like to start with surgery and remove everything if we can. But if we cannot remove everything, then the risk is too high and there’s no benefit of starting with surgery, risking those complications. So we start with chemotherapy first for 3 or 4 treatments and then do surgery in the middle of the treatment, and then do another 3 or 4 treatments of chemotherapy afterwards.

So that was her paradigm. And she responded really nice and had a good surgery afterwards. We were able to remove everything, got more chemotherapy. And during this time also she got her genetic testing and that turned out to be RAD51, RAD51D. And so she regardless, was eligible to go on a clinical trial with a PARP inhibitor, and so she enrolled on that. It was PARP versus placebo. So I don’t even know for 100% sure that she got the drug, but she did have some side effects that suggests that she probably did, although we don’t know 100% sure. She never had to be unblinded.

DR LOVE: Well, not to mention that she survived. That’s probably the best reason.

DR BACKES: Yes, because now 7 years later, she’s just coming to see me weekly. Sorry, weekly? Annually.

DR LOVE: Annually.

DR BACKES: I just saw her a week ago. But yes, she just comes for an annual visit and she is still cancer free. She’s off her PARP inhibitor, she’s done with maintenance, she is so happy. She’s travelling again and has been able to travel with this, also. So she did really well, but she also had a very positive attitude. She’s like, I’ll do whatever and I’ve done all this. Sure, I’m not — maybe I feel a little bit more fatigued, but I’ll just take a nap and then I’ll go do my other things again. She adjusted her life and did really well to a point where she didn’t want to come off of her maintenance pills, and like, don’t take away my security blanket here.

DR LOVE: So Courtney, in a second I’d like to hear kind of what you say to patients who are about to begin PARP inhibitors, whether you say different things to people who get niraparib versus olaparib, for example.

But I have to ask Katie, when you hear a case like this, here’s a woman who’s alive after having very advanced disease many, many years later, really a result of your study. And I’m just kind of wondering what you thought about the first time you saw those curves.

DR MOORE: Oh my goodness, that was like one of the highlights of my career, to be honest. And it was one of those — because I got to see it before anyone else did, and it was sort of just like, how is this even possible? And honestly, it’s just gotten better because that was the progression free survival, which was just so much better with PARP versus placebo.

DR LOVE: Yeah, we were talking about hazard rate was like 0.3.

DR MOORE: 0.3, so a 70% reduction. Yeah. So just like you could stand between the curves, like it was just so amazing. And that was important. But in front line ovarian cancer, up until this point, we never had talked about cure. Like we don’t talk to our patients about cure. The long-term cure rate for chemotherapy alone sits at about 15% at 10 years. That’s when you can call cure. It’s not 5 years. And so, you just don’t talk about that. It’s sort of disingenuous, as much as I hate to admit it. But now we are.

And so for BRCA-associated, at least, patients, with BRCA associated cancers, the cure rate with chemo alone is about 20%, maybe a little less. And so there are some in that group and we are overtreating them, I will acknowledge. I hope someday we can figure out who doesn’t need anything, but we cannot yet. But an additional 25%, we’re sitting almost at 8 years, have not recurred, and they’ve been off their PARP for 5 years. So most of them are cured, which is not something we’ve ever talked about. And so I think for me, and for all of us, like it’s not just for me, but for all of us to have a patient just get treated, until we can screen or early intercept for this thing, which really is what we need to do. But until we do that, to really move more patients into this cure fraction, so they can just treat and live their lives, that’s sort of the goal. So that’s the best outcome I think from SOLO-1, and also is the bar for every other molecular subgroup now. Like now we need to catch everyone else up to that point with different drugs. It’s honestly not going to be with PARP. It’s going to require some other things.

DR LOVE: So you know, as we've been saying all week, you can understand why people want to present incredible stories like this. And we’re not trying to say every patient that gets a PARP inhibitor has a story like that, but just the fact that they’re out there. And again, thinking about that curve, a lot of people are benefiting. But it also is not a free ride. A lot of times people think oral medications, no prob, not necessarily. So maybe just begin the discussion of some of the things you talk about with patients about to be in PARP. And again, is it different? We have niraparib, olaparib, and talazoparib also, different with different agents. Or I’m sorry, rucaparib.

MS ARN: So I think —

DR LOVE: Forgot where I was.

Side Effects Associated with PARP Inhibitors

MS ARN: One of the most important things is starting the conversation early, helping the patient understand the treatment plan. Once they finish their chemotherapy, we’ll most likely plan a maintenance therapy. And once we get their genetic results back, determining what that maintenance therapy looks like. Once identified if a patient is going to be on PARP inhibitor maintenance, start talking to them about the expectations. One of the first things I talk to them about is how to take the medication. We’ve been giving PARP inhibitors for so long, it’s kind of second nature to us. And so we just order it, have them — expect them to start taking it. But it’s really important to make sure they know how often to take it, how many pills to take at a time, when to take it, the potential side effects, going over all that education with them. I also want them to know expectations, you know, how often are we going to be seeing you when you’re on maintenance therapy, how often are we going to be checking labs, what to expect with the lab results. Those types of things I think are really important to help the patient have a better understanding of what their maintenance therapy will look like.

And then I talk about the specific side effects depending on which PARP inhibitor they’re on, which can be different depending on the PARP inhibitor. And then I talk to them about signs and symptoms to be looking for, reasons they should be calling our office. And then I briefly touch on reasons we might need to hold treatment or even dose reduce their PARP inhibitors depending on their side effects.

DR LOVE: So we want to continue this discussion. This is one of the most important themes of the whole week. We’ve talked about this, there are oral medications in almost every cancer now that are not that easy to give, and there are a lot of considerations. We were talking about this extensively Wednesday in breast cancer. Let’s take a look at one of the nurses who actually is a Gyn nurse. If we can bring — yeah. So Kimberly is actually a Gyn nurse also not too far away from y’all, but out there in, I think, Alabama. Here’s what she has to say about using medications like PARP and adherence, and also the issue of dose modification.

MS SPICKES: So I’ll always start out, I’ll say just because it’s oral, it’s not a benign drug. Because people really have that false sense of thinking I’m not coming in for an infusion, I’m going to feel okay. For pretty much all oral, especially PARP, I always tell 'em if you can give us 4 weeks to see how you’re going to tolerate it, but you’ve got to take it every day. If you don’t take it every day, we can’t guarantee it's going to work. But if you can give us 4 weeks, we can talk about are you tolerating it. Because you really need that 4-week period to see are these side effects going to kind of stabilize because it takes about that long to say yes or no, I’m tolerating it. And the same thing with the long term. I’ll say you’ve been on it for this long, we can talk. Do we need to reduce it? Is it worth it? It’s always that risk and benefit conversation. And once they get through that first couple of months, they tend to be okay and they’ll take it every day for the most part as long as they’re feeling okay.

I like to use the example of same thing with the blood pressure medicine or diabetes medicine, we always change the dose based on is your blood pressure too high, too low, is your A1C too high and too low. If you kind of explain it that way, they tend to understand because a lot of them have some other comorbidity where medications have had to be adjusted accordingly.

DR LOVE: So Jaclyn, just kind of curious. We hear that a lot of times, patients get uncomfortable when you want to do dose reduction. Are they going to lose control of the tumor? Any thoughts, again, about using PARP inhibitors and encouraging adherence?

MS SHAVER: Yeah. So I think it’s important to listen to your patients, listen to their fears that they have, expel the fears that they have and kind of redirect them, acknowledge that they do have those fears. But just kind of it’s important just to say, yes, you do have these, but how can we help you meditate those or correct those? And the biggest thing really is, a lot of times, the fatigue. They’re very fatigued in the first few months. And if they can get through the fatigue, like she said, usually that 3-month timeframe, the fatigue will slowly be going away and they’ll be able to function as they normally did before. And so I think a lot of it is just listening to them, redirecting them, giving them the advice that they need, giving them and making sure they’re taking their pills correctly, like you said. Are they taking antiemetics with their PARP inhibitors? Because they can have nausea. So nausea and fatigue and anemia are one of the top side effects with the PARP inhibitors. So ensuring they are taking the nausea medication. And like she said, dose reducing if we need to and checking those labs on a weekly basis in the very beginning. So the first month or so, we’re checking to ensure they’re not having profound anemia, or then we would need to stop the drug and we need to give them blood transfusion and things like that. So I think it’s, again, just giving them expectations upfront, when to call the clinic, and then intervening when we need to and giving them that support that they need at home to kind of alleviate those side effects.

DR LOVE: So yeah, Kimberly is at Little Rock, Arkansas. So Floor, your colleague from Ohio State, Dr O’Malley, was here yesterday morning talking about endometrial cancer. But he also talked a little bit about PARP, and the issue of fatigue came up. And he kind of brought up the issue of methylphenidate. I’m curious how you handle fatigue. And also, can you talk a little bit more about cytopenias, thrombocytopenia, the weights and plates story with niraparib, and anemia, transfusions?

DR BACKES: Yeah. So just continuing on, on the fatigue. It usually starts with kind of what was brought up already with exercise, good sleep, good sleep hygiene, keeping a good rhythm, getting good nutrition, kind of doing all those things first. But then, there’s some patients that are so debilitated or can’t do activity. I can’t make it to my grandson’s ballgame on Sunday because I’m so fatigued. Well those are moments that you may want to use something like methylphenidate to get them, and they can try that out at home. And if that works for them, and starting that at the low dose. And then, they may make it to that event. I never get to go with my girlfriends for lunch or for a dinner anymore because I’m so tired. To get them through that period but usually, not as a standard. If you’re needing to take that every day because the fatigue is so bad, you need to start holding it, see if they get better. Is it really the PARP inhibitor that is causing this fatigue or could there be something else medically or something else? Mental health, medical issues can all contribute to that. So if it’s not improving with the PARP, if they’re off for a week maybe or even sometimes a little bit longer or even a few days, then, yes, a dose reduction may not help. But otherwise, sometimes we do have to do a dose reduction for fatigue also.

DR LOVE: In terms of anemia, do you typically transfuse and keep them going at the same dose or dose reduce?

DR BACKES: Yeah. The anemia, so we expect all our patients to be slightly anemic, I would say. Most of the time, like oh my lab is not good. It’s like well your hemoglobin is over 10. That’s pretty good. We’re excited about it, but the patient is like it’s red. It is not, it’s highlighted. But we’re happy with that. And we’re probably happy with it if it’s over 9. And if they’ve been on it a while, maybe even over 8. But typically, we want to get them, keep them around the 9, 10, of course, or even higher. Did you want to say something?

DR MOORE: Can I make a comment?

DR LOVE: Sure. Katie?

DR MOORE: Just I think there’s — so for those of you in the audience, how many of you are ordering the pre-chemo labs for starting someone, you’re in charge of ordering things to get your patients set up? Yeah. So just to Dr Backes’s point, when you’re starting somebody on any of the PARP inhibitors, and this may just depend on your part of the world, this is my little crew right in front of me, my Oklahomies. Our patients have a lot of nutritional deficiency, so just tremendous. Actually, I just gave someone ferric carboxymaltose 2 days ago because I need to get her up so she can get on a trial. So much iron deficiency, so much folate deficiency, and then, again, we have just food insecurity. So we test that, that’s part of our baseline labs. So that may be something that you consider doing. Because as Dr Backes said, a lot of times, patients are coming in with a hemoglobin of 9 or 10 and we’re like, yay. But that’s still anemic. And you may just be like, well that’s just from the prior chemo, which is true, but they may also have nutritional issues that are contributing. And so if you just replace those as you’re starting the PARP, you can, not eliminate the anemia, but you can mitigate the severity so you can try and avoid the transfusions and things. So we’ve found that to be particularly helpful. If you just do it upfront and just be aggressive with your replacements, that can help just prevent some of the Grade 3’s that you might need to transfuse for.

DR LOVE: So there’s another issue we need to bring up here in terms of the potential increased risk of acute myeloid leukemia or MDS. But I’ve got to say, I’ve been sort of flashing a little bit on the idea of your patient with food insecurity without electricity driving home with pills that are extremely, extremely expensive and how much we invest in the technology of their healthcare but yet, they don’t have electricity. Interesting comment on our times.

What about AML and MDS, Floor? What do we know about it? You can see this with chemotherapy in 1%, for example, with the doxorubicin. It’s not a huge surprise. We know that these PARP inhibitors are working inside the DNA. What have we learned? And particularly, one of the things that we were curious about is the risk of AML and MDS in patients who Katie talked about in the beginning how, of course, everything was in people way far down the line. They had already had a lot of chemotherapy, which increases that risk. And then now, and we put this slide up just to kind of give you an idea. And, Katie, in a second, maybe you can talk about that. But now, again, we sort of have seen this sort of move forward. And now, with several PARP inhibitors potentially available, also bevacizumab. But Floor, what do we know about AML and MDS?

DR BACKES: Yeah. So we’re really talking more about the front-line now. We saw more when we were doing PARP inhibitors in the recurrent setting, so patients that went on maintenance treatment after having a platinum sensitive recurrence and finishing their chemotherapy. So it was at least a second, if not, fourth-line of platinum-based chemotherapy, so multiple risk factors. But there, we saw numbers going up to 4% to 8%. In some select populations, maybe even a little bit higher than that. But that’s pretty high. Now, in the front line —

DR LOVE: But the 4% was without PARP. The 4% was just chemo, that went to 8%. But this thing, 4% is pretty high to start with just from chemo.

DR BACKES: Yeah, yeah.

DR LOVE: Am I right, Katie? Have I got the numbers right, 4% and 8%?

DR MOORE: In the recurrent setting.

DR LOVE: Yeah, in the recurrent setting.

DR MOORE: In the recurrent setting, yes. That’s true.

DR LOVE: Right. Exactly.

DR MOORE: Yeah.

DR LOVE: But now what do we see earlier? Less chemo.

DR BACKES: Yeah. So in the recurrent — in the front-line, we see around 1%, 1.5, somewhere around there, 0.5 to 1.5% or so. We typically quote about a 1% risk. So relatively, yes, it’s a scary diagnosis, but so is recurrent ovarian cancer. And that’s how I counsel my patients, at least. You have about an 80% chance of your ovarian cancer coming back that we can bring down by about 70% by taking a PARP inhibitor in a BRCA-mutated population, for example. But yes, we do have to monitor your blood counts. Why do I have to get my labs done? Because we still want to make sure that if your counts are not coming up or I have to hold your drug and have delays or you’re always low and your white blood cells, your platelets, they don’t recover, hemoglobin, all of the lines can be affected with MDS also, so myelodysplastic syndrome. So we really want to keep monitoring those patients and watch them closely.

DR LOVE: And is that why you sort of tried to encourage your patient to stop therapy even though she wanted to keep taking it, Floor?

DR BACKES: Yes. At some point, yeah. If we see the benefit, at 2 or 3 years is what the front-line study showed, so for one, we want to use it earlier. We want to give the opportunity to use a PARP inhibitor where it works best, where the risks are the lowest because the risks have not gone up. But we also don’t want to go past what the working time is. We think that with more exposure, that there is a higher risk of developing side effects rather than still having the benefits. We may have already done the best work upfront. I hate to say the C-word but I agree, I’d love to hope that we at least have that part under control.

DR LOVE: So Jaclyn, second cancers are not new, as we mentioned. We know chemotherapy can do that. The most recent example was last December. CAR T, so much excitement about that. Now, they’re seeing T-cell lymphomas, but very, very few. But people just get freaked out when you hear about second cancer. As Floor alluded to, in many situations, CAR T, these people are getting cured, and there’s 17 cases out of thousands and thousands. But for a patient, I think it’s not easy to hear that kind of information. So Jaclyn, any thoughts? How do you talk to patients about this? And how do they react?

MS SHAVER: Yeah. So I recently was seeing another one of my partner’s patients. And this was actually even in the front-line maintenance. One of her concerns was, you know, if I take this drug, am I going to get another secondary cancer? And like it’s been kind of said before, yes, that’s a very possibility but it’s very small. In regards to your risk of having a recurrence of your ovarian cancer is higher than that. And so I think you have to, again, put in perspective, talk through with the patient and kind of let them know risks and benefits. And ultimately, it’s up to what they want to do. Our job is there to present that information to them. But I think it’s just being there to give the support that they need and the education that they need and, again, just putting it in the right perspective. Because sometimes, they have this horrible diagnosis and they went through all of this chemotherapy and I had all these side effects from the chemotherapy. And now, I’ve got to go on this maintenance drug that may give me a secondary cancer. And they have all these different fears. And so I think it’s best just to do the best that you can and just talk through those with those patients and, again, be there to support them throughout the process however we can.

DR LOVE: So Katie, one of the themes here, and we talked about it, remember, again on Wednesday, in terms of CDK inhibitors in breast cancer where there are 3. And they haven’t been compared, so people have to decide sort of indirectly. Here, again, we have several. But one in particular, and actually Floor’s patient was on niraparib, it seems like all of these drugs can cause some kind of cytopenia, some kind of GI issues, AML, all these sort of class effects. But maybe some a little more one thing than the other. You hear more about anemia with olaparib, but thrombocytopenia with niraparib. Can you talk about sort of where niraparib came in that was sort of after the SOLO-1 study was, how that trial compared to the SOLO-1 trial, and in what situations right now we use niraparib? And in particular, the so-called weights and plates idea of how you dose it.

DR MOORE: Sure. Niraparib, actually, niraparib was the first PARP inhibitor to enter Phase III or at least complete their Phase III clinical trial in the platinum sensitive setting. That was the NOVA study that was all-comers. It’s a little more complicated study to present, but it’s the first study that really showed the benefit of PARP in the maintenance setting, there, platinum sensitive recurrence. And then olaparib came after with SOLO-2, and then rucaparib as well. In the front line, SOLO-1 readout followed by a study called PRIMA.

PRIMA was different than SOLO-1 in that it allowed not only patients who had BRCA, but also all-comers. So any patient whose tumor was high-grade serous or high-grade endometroid was eligible to come on. And then the statistics were done in such a way that the comparison was benefit of PARP versus placebo maintenance in biomarker positive tumors. They were called homologous recombination deficient, which includes BRCA but also includes some tumors that were not BRCA, we call that BRCA wild type, but had other vulnerabilities to how their tumor fixed their DNA. So they’re termed HRD. And then if that looked positive, then the study looked at the whole population, which was called intention to treat or ITT. You’ll see that. And so niraparib showed benefit in the primary endpoint, which was progression free survival, which is the time the patient enters the study, so it’s after chemo, so they had to respond to their chemo, they start, they get randomized to placebo or niraparib until they progress. That’s progression-free survival. And so in the biomarker-positive group, the HRD-positive group, it was very much a positive study. The hazard ratio for BRCA was very similar to PARP. It was about 0.3 and it was about 0.45 overall. And then the whole group including that HRD group also benefited, which is why niraparib currently has an FDA indication for any patient irrespective of biomarker in the maintenance setting as long as they have responded to their front-line chemotherapy. So that’s how that came about and that’s its current indication.

DR LOVE: And there are a lot more patients like — there are a lot of patients like that.

DR MOORE: A lot of patients like that. More patients like that than there are patients with BRCA.

DR LOVE: And niraparib is approved for that but the other PARP, olaparib is not.

DR MOORE: Olaparib alone is only approved for BRCA. Olaparib plus bevacizumab is approved for HRD-positive, and there’s reasons for that.

DR LOVE: But not the wild type that you’re talking about?

DR MOORE: But not the wild type.

DR LOVE: So you just have niraparib.

DR MOORE: Right, right.

Dosing, Adherence and Other Issues with PARP Inhibitors for Ovarian Cancer

DR LOVE: So what happened with your 45 — because I want to hear about this weights and plates thing, sort of the weight and platelet count adjusted initial dose. Your 45-year-old lady, it looks like she got the weights and plates strategy, so she had a reduced dose. Can you explain kind of what those numbers are?

DR MOORE: Sure, sure. So when we start PARP inhibitors, they all have a different starting dose. Olaparib — the 2 most common in the front-line are olaparib and niraparib. Olaparib is dosed twice daily, and it’s a starting dose of 300 mg twice a day, so 600 total. And then you can dose reduce to 250 and then 200, although most just go to 200, but you could do both. So there’s, you can see there’s a number of dosing strategies there, which is good.

But a lot of times, patients don’t like taking things twice a day. I can’t even take things once a day, much less twice a day. Our patients are amazing. Niraparib, when niraparib was developed, one of the true benefits of it is that it’s once a day. So it’s once-daily dosing. You heard about the nausea with all of the PARPs. It’s no different between the PARPs. And so you can take it once a day, you can take it with an antiemetic and go to bed. Those are very good aspects of that medication.

But it is a different medication in that it’s a more potent PARP inhibitor in terms of its PARP trapping. And it may, because of that and other reasons, have more of an effect on platelets. And we wish it had been developed a little bit differently, but it only really has 3 doses, 300, 200, 100. So when it was developed in the NOVA trial that I mentioned to you, that platinum sensitive study, which I worked really well, but we had a lot of patients with big drops in platelets. We can tolerate someone who comes in and their platelets are 75,000. You’re like, you’re okay. Don’t floss your teeth, good. But patients are coming in with, like, 8 platelets. And then you’re like, you know, go straight to the emergency room for platelets. So that’s a no. You cannot have that. And so they did a lot of analyses as to why that was happening. And in a retrospective analysis that has been validated, it looks correlated with the baseline weight of the patient and the baseline number of platelets the patient has. So if the patient’s platelets are 150,000 or less, or the baseline weight is 77 kg or less, not both, either/or, that patient is at risk for severe thrombocytopenia. And so that patient, if you’re starting a patient on niraparib and you have either of those, then you start at 200. And it cuts the rate of severe thrombocytopenia but also, anemia and neutropenia by about half. It takes it down to about 13% Grade 3 or 4 thrombocytopenia, which is still a little higher than olaparib that sits about 6%, but better than 30%. So that’s where that came from. It was validated in the PRIMA upfront. And that is the recommended dosing in the United States for niraparib, is to start 300 if they have neither risk, 200 if they have either risk, weekly labs for at least a month, if not 2, to make sure the platelets are stable, and then dose modify if you see the platelets start to drop. If they start to drop at all, you hold. And then you have to wait for them to come back up, and modify. So it is a little tricky initially. But once you’re on the right dose, it doesn’t happen again and you sort of cruise.

DR LOVE: So your lady started 200 and with cycle 1, she was thrombocytopenic? How low were her platelets?

DR MOORE: They were low, like, 10. She had, like, 10 platelets.

DR LOVE: Ten platelets? Interesting. Sounds a little scary. How about once she got down to 100? Everything okay?

DR MOORE: Yeah. Once she went to 100, she was fine. And it’s so interesting. It’s beyond the point of this but with patients, like you said earlier, patients get worried. They’re like well I’m only on 100, I’m at the lowest dose. Am I even getting a benefit? They really do get nervous about that, especially when there’s only 3 doses. But there’s been studies done of the amount of drug in someone’s, like, the exposure, we call it exposure rates in 100, 200, 300 just based on the dose modifications. And really, the patient’s body tells us how much they need. It’s sort of interesting because the dose levels across the 3 dosings in the different patients look the same. So you’re getting the right dose for your patient, so you should just pay attention to what they need and drop it. And it’s still an efficacious dose. You don’t lose efficacy by appropriately dose modifying.

DR LOVE: Floor?

DR BACKES: Yeah. I think this is so important that you pointed this out. The other thing I’ve seen, I think this is also where it’s important for our nurses to be on board with all of this, and our nurse practitioners, to provide that education. Yes, it is safe to restart. Because sometimes, it can be a very effective drug, and then the patient’s like well, I had this episode. My platelets went down to 10. I had to get transfused, I’m so scared. I’m not going to take this again. But it doesn’t mean it’s going to happen again. Actually, most of the time, it happens within the first week or 2, and at least during the first cycle. That’s why the first cycle is such intense monitoring. But then once you do your dose reduction, it oftentimes doesn’t happen again. And they do just fine and they can stay on their treatment. But same for other providers. I’ve seen patients, and I’m sure we’ve all seen that, from coming back, oh 1 episode of thrombocytopenia that was pretty severe, and never restart it. And we take away that opportunity to cure patients. So really important that we educate our patients and reassure them. With good monitoring, we can work this out.

The Potential Role of PARP Inhibitors in Combination with Anti-PD-1/PD-L1 Antibodies for Advanced Ovarian Cancer Management

DR LOVE: So Courtney, we’re going to move into recurrent disease in a second. I would like to hear about your 48-year-old patient who was BRCA positive who recently lost her sister to ovarian cancer. Before we hear about that, though, just a couple questions back to the docs in terms of where we might be heading. Floor, one, of course, everybody always wants to add checkpoint inhibitors onto anything just to see what happens. Sometimes it works. Sometimes it doesn’t. How about here in ovarian cancer? Do you see any future? There are some hints that this may be a good strategy. What are you thinking, Floor?

DR BACKES: Yeah. Nothing big yet. There’s been 1 study recently presented about immunotherapy and PARP inhibitor. But it’s kind of hard to tease out, is it just the PARP inhibitor? Is it the immunotherapy combination? But the studies where it was chemotherapy with immunotherapy in ovarian cancer followed by immunotherapy maintenance, or even with bevacizumab combinations, have not really panned out that it adds any benefit. We’re certainly waiting for another study that will be presented in the near future, hopefully, with immunotherapy and a PARP inhibitor to see if that worked in the upfront situation as a maintenance treatment. So that study actually had 4 different arms. And so 2 have been reported. The other 2 still we’re waiting for. So maybe we’ll see a signal there. But immunotherapy and ovarian cancer have not done very well yet.

DR LOVE: So we were saying this morning that the abstracts for the ASCO meeting were just published today. And just a little bit of hint, this is the big oncology meeting of the year in the beginning of June in Chicago, so we were just checking out some of the papers. A lot of follow-up on these studies we’ve talked about. But I was just mentioning to Katie a couple cool ones I saw. One, neoadjuvant PARP. Neoadjuvant olaparib. I was curious because there was a study in breast cancer that they did in BRCA. I think it was, like, 50 people or something. It had a very high response rate. And then I never saw it again. You guys are using the chemo and all, it sort of makes sense. Any thoughts? Do you know anything about neoadjuvant PARP, Katie?

DR MOORE: A little bit. And what I know, I know from Dr Shannon Westin at MD Anderson who has led the NOW study, which is neoadjuvant, so it’s for patients with BRCA-associated cancers who are getting neoadjuvant chemo. And they get 2 cycles of olaparib leading in and then they’re assessed for surgery. And so the endpoint was really, it’s a small study, just to look at feasibility. Would patients be interested in this? Would they respond? Because the responses to platinum are quite high. You don’t want to compromise that. And then, what was their outcome at surgery? So Dr Westin presented the preliminary results of that at the Society for Gynecologic Oncology last year. And thus far, I think there were 14 patients. It still looks preliminary, but very feasible with very successful surgical output — outcomes.

DR LOVE: Responses?

DR MOORE: With responses, which you would expect.

DR LOVE: Sure.

DR MOORE: So the question is, and it will be difficult to know from that small study, what does it look like long term? Does it change the outcome long term? So the short-term outcomes, which was the point of the feasibility study, look quite promising. And now, Dr Stefanie LaRue at Princess Margaret, she and Shannon are, like, competing for smartest women. Actually, just smartest doctor. Not even gender. But they compete because they both are doing just groundbreaking work in ovarian cancer. So it sounds like Dr LaRue has a study, so I’m excited to see the abstract when it, they haven’t been released yet, just the titles.

DR LOVE: Right. We don’t even know how many patients are in it. Yeah, interesting.

DR MOORE: Yeah, I want to see what’s in there. Yeah.

DR LOVE: So the other one that caught my eye, it wasn’t just in ovarian cancer, it looks like multiple cancers. We’ve been talking about bispecifics, both immune bispecifics and then at lunch, we were talking about EGFR hitting 2 parts of the target. So this is a paper here. It’s a bispecific targeting PD-1 and CD137 combined with systemic IO, pembrolizumab. Do you know anything about that, Katie?

DR MOORE: I don’t know about that particular combination. I don’t think that that is — I have to look at 137 for ovary. But bispecifics in ovary are actually kind of hot right now. There’s a number of them in clinical trials, several of them in combination with either PD1 inhibitors or with chemotherapy. So we’ll kind of see. So it’s an interesting strategy. We think of an antibody like a Y. One arm of the antibody grabs a target. Usually, thus far, it’s been something called CD3. That’s an immune cell. And then it grabs something that’s on the tumor, like a tumor associated protein like MUC16, which is a CA-125 protein, or PRAME or a number of others, and then tries to bring them together so that the tumor — the immune cell recognizes the cancer cell protein and says, hey, I should kill you. I’m going to make a bunch of me that are programed to kill this thing and make the person create this army of programmed T-cells. It’s the goal to, like, wake up the immune system. So they’re pretty cool. Tebentafusp in uveal melanoma, that’s completely immune inactive. It’s like on the curve of things that are reactive like cutaneous squamous cell to immune checkpoint inhibitors. It’s like the very bottom. It’s the worst possible thing that could ever respond to an immune drug. And yet, you have this bispecific that works amazing. So they’re cool. Whether or not they pan out in ovary I think remains to be seen.

DR LOVE: Well, last night, we were talking about them in lymphoma. And they’re cool because they work, but they also cause cytokine release syndrome, which you all are going to have to kind of get used to.

DR MOORE: Yeah.

DR LOVE: Now the general oncology, they’re already getting used to it because they’re using it in myeloma and they’re using it in lymphoma. But it’s kind of interesting that then we get to the solid tumor people, there’s a really cool bispecific in small cell. Not approved yet, but looks very active. CD3, causes CRS. And the lung people are like, what’s CRS? Already, we’re out there with it. So interesting, we’ll see where some of these things head.

PARP Inhibitors for Relapsed/Refractory Ovarian Cancer

DR LOVE: But let’s get back to the reality of clinical practice. And as you can see there are quite a few people who relapse with this disease. And Katie referred earlier to the fact that those were the initial trials that looked at these agents in the relapsed setting. And we wanted to just hear about a case first and then talk about what’s happened, particularly the fact that the FDA has actually pulled back the approval of some of these agents in certain situations, again, because of concerns about excess deaths in the metastatic setting. We’ll talk more about it. But let’s hear about your 48-year-old woman. What happened?

MS ARN: Yeah. So this kind of goes back to our earlier conversation about genetic testing. She was diagnosed at age 46. She had a family history of breast and ovarian cancer, and the family had BRCA mutation. So she had genetic testing, and she was found to have a BRCA1 mutation. And so she, at age 46, had a prophylactic mastectomy. And then, she went to her gynecologist and had a prophylactic BSO for her BRCA mutation, and at that time, was found to have high-grade serous carcinoma. So she was referred to our office for management of her ovarian cancer that had already been diagnosed. She received neoadjuvant chemotherapy with paclitaxel and carboplatin, and then had interval debulking surgery. So actually, when she did present, she had large-volume ascites and pleural effusions too. She had a history of colitis, and she was kind of being worked up for all of her GI symptoms as colitis related, and I think missed the cancer related symptoms. So had neoadjuvant chemotherapy, had a debulking surgery, and then adjuvant chemotherapy. We did not give bevacizumab because of the history of colitis and her current symptoms. And then, we treated her with maintenance PARP inhibitor. We actually started her out on olaparib, and she had pretty profound dizziness. So we ended up switching her to niraparib, and she did great. We did have to decrease her dose from 200 to 100 mg because of the platelets, but she did fine on that. She was on that for a while, but then recurred.

Conversations about recurrent ovarian cancer have definitely changed. I’ve been working in Gyn oncology for 10 years now. And when I first started, it was a very grave discussion where we had limited treatment options for these patients, and it was a tough conversation to have with patients. I’ve definitely found over the years with some of these new treatment options that we’ve had, these better progression free survivals, better response rates, it’s an easier conversation to have and a more optimistic conversation, but it’s still challenging. And this patient thinks that, in her mind, she has a better perspective of things because her sister had died from ovarian cancer prior to her being diagnosed, so she knows kind of what to expect. But in my eyes, every time I have a conversation with her, she knows where this is going, she knows the outcome. And so it’s almost a little bit more challenging to have these conversations. Even though she’s kind of prepared for what to expect, it makes it harder because she’s been through this before with a family member.

DR LOVE: Did she share with you what happened to her sister?

MS ARN: She was treated —

DR LOVE: And did she have specific concerns about what happened that caused her to be anxious?

MS ARN: She hasn’t really gone into many details. But interestingly, she has limited support at home, and her one support person is her sister’s husband. So he comes to all the visits. And he talks about the sister a little bit more than she does, but just that she, you know, she did do chemotherapy locally, but I don’t know how long she was on treatment or what treatment she received.

DR LOVE: So Floor, I don’t know if this surprised you, but it sure surprised me when this started to happen with the FDA. And we could spend a long time talking about it, but can you kind of capsulize what happened?

DR BACKES: Yeah. So this was a sad year. And I think it was sad for all of us that these drugs were taken away. So the FDA started looking, as we were getting more data, started looking at some of the overall survival outcomes. Now mind you, the trials were never designed to really look at or were powered or had enough patients to really truly look at the difference in overall survival. So they started looking at that in the patients that had recurrent disease initially. We didn’t have a lot of data yet from the front-line studies, and still are waiting for some of those. But for the recurrent setting, they looked at overall survival, and in some of the trials, saw some differences. So, for example, with niraparib, we saw differences. The overall survival was around 31, 30, 31 months from starting the niraparib with the maintenance pills until death. And then with the placebo pills, they saw actually that was slightly better. But the number of months was 1, 2, maybe 3-month difference. So really, really small differences, not statistically significant differences, not powered for it. But still, it trended the wrong direction.

So the FDA started pulling some of those off the market. And tell me if I’m explaining that wrong. But then, they started looking at the next study and the next study. And so some of these studies were differently designed, they had different populations in them, that you really couldn’t truly look at it. But there was concern that patients were not living significantly longer if you were on a PARP inhibitor maintenance, in the recurrent setting at least. So really important that we think about the recurrent setting. So in some subsets though, the benefit was greater. We saw a benefit in patients who had germline BRCA mutations. And so for those patients specifically, we can still use it in the recurrent setting, whether it’s BRCA in the tumor or in the germline, depending on which PARP it is. So they’ve become much more restricted.

DR LOVE: Basically, right now, where can —

DR BACKES: The HRD or PARP inhibitor for everybody, those days are gone.

DR LOVE: But right now, what’s the main group that you’re thinking about using a PARP inhibitor in the relapsed setting? Is it a platinum-sensitive patient, for example?

DR BACKES: Yeah. Yeah, it’s still — platinum-sensitive disease, one of the things also that we think that indicates, it’s probably one of our best biomarkers to say that you’re going to respond or benefit from a PARP inhibitor. So yes, it is for the platinum-sensitive population. If they have not had a PARP inhibitor yet and they have a germline or somatic BRCA mutation, those patients would still be on label, and we can use it. There’s some patients that we may consider it outside of those guidelines, but it would be off label in that case.

The Current Role of Mirvetuximab Soravtansine for Ovarian Cancer Treatment

DR LOVE: So Katie, we actually did an entire program on antibody-drug conjugates. Was that yesterday? I’m totally forgetting what day this is. But anyhow, we did an entire program on antibody-drug conjugates. And we were talking a lot about breast and lung cancer because there’s so much to talk about. But we referred to the fact that ADCs are being used all over oncology, including ovarian cancer. What’s mirvetuximab?

DR MOORE: So let’s just define ADCs just in case everyone doesn’t know, because I imagine there’s some younger nurses in here. So ADCs, we use all these abbreviations, stands for antibody-drug conjugate. And, again, it’s a Y antibody. It targets something that’s on the surface of tumor cells that is either only on the surface of tumors cells or so overexpressed on the tumor cell as compared to normal that your drug is going to hone in on tumor. Different than the bispecifics or bevacizumab, though, is the fact that these antibody-drug conjugates have these very elegant linkers that allow us to stick highly potent molecules of chemotherapy.

And I was just at AACR. We’re going to be putting more things on them than chemotherapy, so stay tuned. But really, really potent molecules of chemotherapy. So not gemcitabine or paclitaxel or PLD, these are really potent chemos that if you gave as a free drug to a patient it would indeed kill their tumor, but it would cause so much toxicity to their bone marrow and everything else that you might kill them. But when they are on these antibody-drug conjugates, they circulate in the blood and let — if they don’t find their mark, you just pee them off. If they find their mark on the tumor, the proteins that we design these for, when they bind, they think it’s a friend and they kind of give them a big hug and bring them inside like a Trojan horse. And then once inside, they’re encased in these, we call them lysosomes. But the pH changes and the molecules of chemo pop off and they kill the cell. And then, sometimes, depending on the characteristics of the molecule, they can secrete into surrounding tissues, even if those cells don’t have the protein that you’re looking at, and kill those too. That’s called bystander effect. So this is a way of, this is targeted chemo, targeted super-potent chemo, and it allows us to have a much better therapeutic index than chemo where you’re limited by how much you can harm the normal cells. So that’s how these work so far.

Mirvetuximab is an antibody-drug conjugate. The protein it targets is folate receptor alpha, which is just a protein. It’s not that active folate molecule that regulates folate levels in your body. It’s a different folate. We don’t really know what it does, but it’s there on ovarian cancer. And, like, 80% of high-grade serous has some folate, but about 30% has what we call high. There’s a test for that now. And on the tail of this conjugate are really potent molecules of a microtubule toxin. So it’d be most closely aligned with paclitaxel. That’s how I explain it to patients. But it’s not paclitaxel. And if that tumor had previously progressed on paclitaxel, it has nothing to do with if this drug will work or not. But it’s most similar to that. So that’s the drug. And then it’s been through — do you want me to talk about the trials?

DR LOVE: No, let’s — yeah, sure. Talk about it in terms of side effects and benefits that we’ve seen in the trials. And then, we’ll see how it all plays out in practice.

DR MOORE: Okay. So I’m going to just summarize. We put the first human being on this study — on this drug in 2012 at my site, and we got full FDA approval about 3 weeks ago based on the MIRASOL trial. The MIRASOL trial was done in platinum resistant ovarian cancer, 1 to 3 prior lines of chemotherapy, you could have prior bevacizumab or not, and folate receptor alpha-high. And in that clinical trial, the progression free survival, the hazard for progression was about 37% lower with use of mirvetuximab. The response rate went from 16% to 44%, and that’s RECIST response. The overall tumor shrinkage was about 70%. And for the first time ever in the history of ovarian cancer in the platinum resistance setting, we improved overall survival by 30%. So this is now fully FDA approved and screening tumors for folate receptor. It’s kind of like BRCA now, we must know so that we can decide whether or not this medication makes sense. But it’s in the, FDA approved in the recurrent resistant setting in clinical trials in earlier lines now.

Toxicities with Mirvetuximab Soravtansine

DR LOVE: So let’s get a little bit of a picture of how this actually plays out in patients, particularly related to toxicities, which are pretty interesting with this drug. So Floor, it looks like you have a 72-year-old woman. She got mirv?

DR BACKES: Yeah. She had one of those rare toxicities. She was on it long enough that she started to have some side effects. But overall, actually, the drug is relatively well-tolerated. I don’t see a ton of nausea/vomiting. Some abdominal pain sometimes. But blurry vision is probably the most common and what also is most impactful as we’re counseling our patients. Gosh, if somebody is going to tell me, you may have blurry vision, that’s pretty scary. So we monitor really closely at the beginning and during treatment also, every other cycle, to get their visit with an optometrist or ophthalmologist to take a look at their eyes and specifically at their cornea. And what we also tell the patients that get this inflammation, sometimes a little cyst on their cornea or keratitis, but the cornea also sheds just like our skin does. So when you hold the drug, then also you give it a little bit of time. It typically improves and it’s very, very rare that you get permanent changes in vision. But it’s a really important one to manage. So as long as you use the lubricating eye drops and prophylactic steroid eye drops and you hold the drug on time before it can get really bad, you can mitigate that.

So we’ve gotten much more used to it. It was very scary too, I think, for all the providers also. And how do we assess this? And for patients alike. But we got a good handle on that now, how to manage that with the drops. That was probably one of the — my patient ended up developing it slowly over the trend of time. And I’ve now had 2 actually most recently, that after cycle 7, 8, which is rare that they get that far on any other drug that they get 7, 8 cycles in a platinum resistant setting and they’re still on. So that’s a good sign. But then, their liver function started to trend up. Their bilirubin went up, their LFTs slowly started to go up. And ultimately, got too high where I couldn’t give it anymore. And so they ended up getting, both of them had a liver biopsy ultimately that confirmed that it was toxicity from the drug. That’s quite rare. That was actually the first 2 incidences that I had seen, and we’ve been participating in the trials. And I don’t know if you’ve seen it more often, but it’s mostly the blurry vision probably that’s the most common thing.

DR LOVE: So we recently did a CME program with an ophthalmologist from Memorial that was 90 minutes long because there’s so many things right now. All of a sudden, we’re seeing ophthalmologic issues. ADCs particularly. Erdafitinib, a drug used in bladder cancer, causes central serous retinopathy. It’s like all on. You had a patient who got mirvetuximab. How do you find patients respond when you bring up the visual thing? And what happened with this patient?

MS ARN: So just like Katie, we’ve been using mirvetuximab for 10 years. We started with the initial trial too. So I think our institution is much more familiar with it. So I think our conversations are a little bit more comfortable. We’ve had enough experience with it to know what to expect. The patients are kind of caught off guard because it’s not something that they’ve seen before with chemotherapy side effects. But really, it’s just talking to them, making sure they’re aware of what to expect, talking about the symptoms that they might have, when to expect them. We usually see it between cycle 2 and cycle 3. And just like Dr Backes said, generally, these symptoms start to improve or resolve as soon as we stop the treatment. So it’s not something that’s going to cause permanent vision loss. And I think when patients hear vision changes or ocular toxicities, they immediately think they’re going to lose their vision or have significant impact on their quality of life. And for the most part, it’s dry eyes, blurry vision and things that we’re easily able to improve with using more consistent lubricating eye drops, sometimes we need to change the dosing of the steroid eye drops, those types of things. But it’s not severe vision loss or sever ocular symptoms.

DR LOVE: And Katie, we’ve been talking about in oncology, we start out late and we start moving treatments earlier. Is mirvetuximab moving up?

DR MOORE: Yes. So there’s an ongoing Phase III clinical trial right now to evaluate mirvetuximab with bevacizumab as a maintenance in the platinum sensitive recurrent setting versus bevacizumab alone, which is only right now in folate receptor high. We all wish it were in medium and high. And then there’s a few studies that are done that we expect to readout hopefully, this year. One is called the PICCOLO study, which was use of mirvetuximab monotherapy for platinum sensitive recurrence just instead of chemo, but in patients who have had 2 or 3 lines of platinum and they’re still platinum sensitive. But it gets harder to use platinum 4 times, and so they use mirvetuximab. And I believe Dr Alvarez Secord will be presenting that at a meeting later this year. That’s in the platinum sensitive setting.

And then there’s a front-line neoadjuvant study that’s currently enrolling led by Dr Rebecca Arend at University of Alabama. So this is definitely moving up. And behind it, when something succeeds, excellence breeds excellence, so there’s just a pipeline of second and third-generation folate targeting antibody-drug conjugates coming down the pike.

DR LOVE: And did you say that there was, before when we were talking, there was a trial substituting mirv for paclitaxel?

DR MOORE: That’s the front-line study that Dr Becca Arend is leading. So it’s for patients who are getting it neoadjuvant chemotherapy, so you have to do really rapid testing to know if they’re folate receptor alpha medium or high. And then, they get mirvetuximab and carboplatin instead of carboplatin and paclitaxel. And we’ve tested that combination actually pretty robustly in the platinum sensitive setting, and it works quite well. It’s very well tolerated.

DR LOVE: I was going to say, it must be a lot better tolerated than paclitaxel.

DR MOORE: No hair loss.

DR LOVE: Yeah.

DR MOORE: Less, but not no neuropathy.

DR LOVE: Really?

DR MOORE: So we still have to deal with the neuropathy. But we do have to contend with the ocular disturbances that you’ve been hearing about. So there’s always trade-offs. But if we can get rid of alopecia for our patients, I think —

DR LOVE: Absolutely.

DR MOORE: And maintain, either maintain or exceed efficacy, I think that would be a win. That would be progress.

The Incidence and Management of HER2-Positive Ovarian Cancer

DR LOVE: Absolutely. So Floor, again, we did a program yesterday focused on antibody-drug conjugates. And one of the big issues there was the very recent approval of an antibody, a HER2 antibody-drug conjugate, trastuzumab deruxtecan or T-DXd. Pan-tumor, any patient with a solid tumor who has run out of options who has HER2 positivity is eligible to receive this antibody-drug conjugate. Can you talk a little but about what your thoughts are, Floor, in terms of this agent, which seems to be very, very effective in many tumors? But also, has some interesting complications.

DR BACKES: Yes, absolutely. It’s a great new, or new to gynecologic oncology, I should say. The breast cancer world is much more familiar with this drug, but we’re starting to learn. And as we started to go through these kind of growing pains with mirvetuximab and some of the other drugs that we’ve seen, we’re also going through some of the growing pains now with this antibody-drug conjugate. So the response rates in overall and all tumors, if you were not present yesterday, is around 57% or so across the board for all tumor that expresses HER2, or is a high expressor. So even up to, in endometrial cancer, one of the higher response rates, in the 80s, which is unheard of, but still based on a small population. So we want to see the bigger studies. But it’s very, very promising.

Actually, in fact, that patient that had liver toxicity on mirvetuximab is recurrent ovarian clear cell. She’s been doing this thing for over 4 or 5 years now. She did okay with the mirvetuximab. She just started. She hadn’t responded to some things before. And she’s now on the T-DXd. And her CA-125 has gone from 1,200 to 800 to 500, and now was 300 most — on Wednesday.

DR LOVE: Wow.

DR BACKES: So she’s thrilled. She was so cachectic. Really, we dragged her through the first cycle. Her family basically said please, please, please try. And she did for her family. And every cycle, I said you don’t have to do this again. And now, she’s cycle 5. And she’s like, I want to go to Florida in 2 weeks. I was like this is great. This is what we do this for, and get these new drugs. So that was fantastic.

But I’ve also seen the flip side of patients. And pneumonitis is a very new finding for us. And with mirvetuximab and with the immunotherapy, we see pneumonitis, but they get a little bit short of breath, they have some changes on their CT scans, and it’s okay, we still treat them as long as they’re not needing oxygen or it’s not really too symptomatic or really symptomatic. But now, this is different and we really need to be on high alert for this pneumonitis because they can go from oh, I’m doing fine, fine, fine, to I’m on the ventilator.

And I think Dr Moore and I both share some of these experiences. And I recently had a bad experience with this too where a patient was doing just fine. Had a cold a month ago. Did fine, recovered, did fine, did fine. Imaging, was doing fine, recovering from a cold on imaging. And within 2 days, she was on a ventilator and she never made it off the ventilator, unfortunately. So what I have started sharing with our staff also is we work through these and we talk to our experts around the country and we talk with our pulmonologists and also with our staff of the importance of the screening. And the nurses are going to be such — triage, especially the triage nurses. If they complain of any kind of cough, I feel a little bit more short of breath, I can’t get up the stairs anymore that I could do a week ago. It’s not just nothing. This is where you say you need to go in right now. And we need to get imaging. We need to figure this out. And really re-educating our staff where it’s like oh, we’ll see you next week for your visit. No. Right now, to prevent these things from happening. Because we need to hold the drug, we need to potentially give steroids, we need to get our pulmonology colleagues on board. Really important that we’re going to educate everybody, all teams, not just — yes, doctors but absolutely front line, which is what our nurses oftentimes are, those phone calls, and even the staff at the desk. No, this patient does need to be worked in the schedule or the patient does need to get ahold of the nurse to talk about it. Absolutely.

DR LOVE: So Katie, I see you had a patient also, 70, who got T-DXd. It’s interesting. With this pan-tumor approval, all of a sudden, everybody outside breast has to all the sudden start finding out what’s happening. And they’re talking to the breast people, you know, like what do you do? And the breast people have it down.

DR MOORE: Yeah.

DR LOVE: I’m not saying they don’t see lethal, but they know how to do it. And they’ve got the system. They do a lot of CAT scans, very aggressive. And they’re not seeing very much. Certainly, not serious issues. What happened with your patient, Katie?

DR MOORE: Yeah. So this was — I said T-DXd, she was on a trial that actually Dr Backes and I both are leading, but it’s a very similar medication. And she had ovary cancer and was platinum resistant. It’s actually one of Dr Walker’s patients. Came on really with not a lot of options, was HER2 3+, which is kind of about 10% of our ovarian patients. Right now, we don’t really know because we haven’t been testing ovary. We’re kind of going based on historical data, but maybe 10% 3+, maybe another 18% 2+. But she was 3+ and went on this very similar medication and had a beautiful response for about a year, 4th or 5th line. And the things you have to be alert for and just that are common is that these are highly emetogenic medications, so they need triplet antinausea medications. Don’t mess around. Just start it. Don’t wait and see. Because they’re really emetogenic. If you treat it aggressively, they do great. It’s really uncommon for them to have a lot of problems after, but some do. But that’s not unusual, so just be on high alert about that. And then, they feel really good. You do see some cumulative hematologic side effects even though it’s targeted chemo. Once they’re on cycle 6 or 7, you’ll see them come in with some drift in their counts. And you have to hold here and there and potentially dose modify in later lines of therapy for that, so don’t be surprised about that. My patient was doing great. She did end up, on the scan that took her off, she had progressed just a little bit. She feels so much better though. She’s a different person than she was a year ago, so it’s opened up all sort of other options for her on trials. I think that’s why our patients are living longer, because these things work for a long period of time and then they can go on something else. But on her last chest CT, she had some new ground glass opacities. She’s totally asymptomatic. Her O2 sat is 98%.

DR LOVE: Perfect.

DR MOORE: And so we’re having her worked up. And pulmonology may say it’s not consistent with pneumonitis. But I think the message, and just to reiterate what Dr Backes said, for gyn onc practices, mirvetuximab, we saw ground glass opacities all the time. I don’t even think I called it pneumonitis. We see in Oklahoma waxing and waning things on these CTs all the time. We did not pay attention to them. It’s just you’re blind to them. You have to unblind. And you’re going to hold more than you want to. But these drugs work so well that your patient’s like, don’t hold my drug, oh my God, I’m at 300, don’t hold my drug. I’ve held patients for months, and their tumors just stay the same. You have grace. So don’t feel pressured to keep a patient going while you’re working something up. Stop, work it up, and then restart. You’re going to be fine. Because when these patients get sick, they get sick fast. And breast learned that. We’ve got to learn it fast.

DR LOVE: So a couple of final thoughts. You sit here tonight, you sit here in all of our programs, and you realize oncology is such a deep field. There’s so many aspects to the human experience of oncology. So many facets to it. Here’s some other thoughts from, we call these the agnostic nurses because we just ask them about stuff that applies to every tumor the same way they said T-DXd applies to every tumor. Here’s Jessica Mitchell, a GI nurse from Mayo Clinic, talking about spirituality and religion in patients.

Spirituality and religion.

MS MITCHELL: Yeah, that’s another big one. I think in many senses that is underaddressed in the medical community because it makes people feel uncomfortable. But I think if we can talk about it, patients are usually the ones that bring it up first, which I think is appropriate. People who have a higher, like, level of belief in a higher power, I’ve found seem to be more at peace with their diagnosis and any changes that might happen, so I really feel like it’s a huge benefit.

Unfortunately, here we only involve chaplains or rabbis when patients usually are hospitalized at end of life, but I think a more comprehensive cancer place would address spirituality earlier. I think talking beyond like organized religion is important too, right? People don’t always follow those paths, and I think that’s really an important component of just the comprehensive person, right? Spirituality is a big part of that.

People ask me to pray with them. I do that if they want me to.

DR LOVE: Courtney, any thoughts?

MS ARN: I think she hit on a lot of good points. I do think it’s kind of underserved for a lot of our patients. We’re fortunate at Ohio State, we do have a chaplain on site even in the outpatient setting, which has been great. Because regardless of the provider, the nurse, or the doctor, whoever is seeing the patient, what’s important to the patient is important to the patient. And we have to make sure that the patients are getting the resources that they need. And so if it’s meeting with the chaplain or setting them up with support groups, things like that to help with their spiritual religion beliefs, then we do that. I think when it comes into play with healthcare is if they have specific beliefs of not getting blood transfusions, things like that, it’s important to know upfront because that might adjust the medications that you’re putting them on or adjusting the dose that you’re putting them on. But making sure that you do acknowledge your patient’s spiritual or religious beliefs and making sure you’re adhering to those.

DR LOVE: So another theme that we’ve gotten into is taking care of yourself in oncology. Obviously, this is a challenging field, a wonderful field. But we’ve talked about this forever, since we started coming here, about that and how people try to avoid burnout. Here’s Kathy Burns who is a GU nurse.

Taking care of yourself and avoiding burnout.

MS BURNS: This is a big topic. I’ve always kind of been on the border of burnout, but that’s where I live, and that’s what I — it sounds crazy, but that’s what I enjoy. My job is incredibly important to me. I can tell, I think a little bit, if I need to take a step back. And I think learning that as you go along and finding a balance, I’ve always been able to find a balance. We need some sort of physical activity, some friendship with teams and families and all, but my MO has always been really put yourself in both feet first, and it will give back tenfold.

DR LOVE: So Jaclyn, we’ve always thought about people new to oncology when we do these programs. We know maybe one quarter of the people in this room have been in oncology less than 5 years. What would you say to them about sort of taking care of themselves?

MS SHAVER: Yeah, I think it’s really important. Like she said, if you feel like yourself is getting to that point where you are being more short with your fellow staff members or you’re being more short with your family at home, to take a step back like she said. It’s very important to take care of yourself, whether that is making sure that you’re taking off some time that you need. We all have to take off time from work. We all are dedicated to our job, but we also have to make sure we’re dedicated to ourselves. And just taking that time away and finding that thing that you like to do outside of work, finding that hobby that you like to do. If you like to travel, take the weekend off, take Thursday, Friday off. That’s very important to do because then, when you get back to work, then you can really be able to focus more on your patients, be able to maybe hear them a little bit different, maybe to be able to hear your coworkers a little bit different and have that perspective to really go in, like she said, full force, and put all of that energy into those patients that you may not be able to do if you’re so overwhelmed. So it’s just really important for you to do, especially when you first start but also, the people that have been in it like us, decades. And we also have to remember to do that. And so it’s just extremely important for our patients really.

DR LOVE: Final comment?

MS ARN: Yeah. I think in our profession, it’s easy to get burnt out. And I think we all know, we hear it from our family, friends, you need to take care of yourself, you need to exercise, you need to eat right. But something that’s really hit me hard is I’ve often had patients or my patients’ spouses say I need you there to take care of me or I need you to take care of my spouse. And if you’re not taking care of yourself, you can’t be there to help them. And we really form relationships with our patients and our patients’ spouses. And I think that’s a different way to look at it. They need us. And if we’re not taking care of ourself, if we’re not getting enough sleep, we’re not making good decisions, if we’re not taking care of our health, we’re not going to be alive to take care of them. And so just looking at that perspective, it’s not a selfish thing to take time to yourself to exercise every day. You’re actually helping yourself so that you can be helping others.

DR LOVE: I think everybody here is so grateful to the 4 of you for what you’ve shared with us tonight. Thank you for coming. Come on back tomorrow morning, 6:00 am, HCC.