 For the last few minutes, I want you to look into your crystal ball. I know you’re doing a lot of clinical trials. What type of things on the horizon are you most excited about in ovarian cancer?

 I think it’s obvious to all of us that the topic of immunotherapy is front and center in most clinical trials, introducing it into all of our solid tumor treatment. I think over the next decade, we’re going to see frontline immunotherapy introduced into ovarian cancer as well, whether it’s in the maintenance setting or with chemotherapy. It doesn’t just have to be checkpoint inhibitors; we have vaccine trials that are being conducted now to sensitize, or to make the ovarian cancer cells more immunogenic. We have a frontline intraperitoneal GEN-1 construct trial that we’re doing here with getting interferon on the cell surface to attract white cells. FLORA-5 is a GOG [Gynecologic Oncology Group] partners trial that’s going on around the country with oregovomab, which is an antibody construct that goes from the cell surface, CA-125 [cancer antigen 125], to make it more immunogenic. It’s a phase 3 trial; the phase 2 was very positive, as you know. We’ve been working with oncolytic virus to reverse platinum sensitivity and make cells more immunogenic here. I think we’re about to hopefully present a phase 3 trial to GOG partners.

I’m a very big enthusiast, and if you’ve seen what’s going on in lung cancer, you know, for certain lung cancers, pembrolizumab is now frontline therapy with carboplatin-based therapies. I wonder if we’re not going to select out the relative minority of patients who are PDO [patient-derived organoid] positive or have tumor infiltrating lymphocytes—whatever the marker is going to be—and add pembrolizumab with our frontline therapy or some other checkpoint. Or, are we going to find a way to manipulate the immune microenvironment for our patients and add checkpoint inhibitors? I think that’s where we’re going.

 Well, you have been on the forefront of clinical trials for many years now, and I’m a huge proponent. I think that’s our gateway to all of these advances that we see. I take every opportunity to make a pitch to folks to continue to look for clinical trial opportunities for enrollment. This is how we got to where we are with maintenance therapy, and it’s how we find tomorrow’s best treatment.

 I appreciate your time. We’ve had a great conversation today. I look forward to talking to you about the advances that we see in the next few months.

 It’s been great. I really appreciate the conversation and the opportunity. Thank you.

Videos

Oncologists contemplate what ovarian cancer treatment will look like in the future and exciting clinical trials in progress.

The Future of Ovarian Cancer Treatment

 Do you have any clinical pearls or tips in your experience for providers who perhaps haven’t used maintenance therapy or are thinking about incorporating maintenance therapy into their practice?

 I do have several, but it’s an interesting observation that, I still think the majority of patients with ovarian cancer in the United States may not be offered maintenance therapy. Maybe we’re passing over the 50/50 mark, but when we speak to our colleagues, like you and I, who have been using these maintenance therapies, we are kind of in a silo and think that all patients with ovarian cancer are offered these drugs. But as you know from referrals that you get, out in the community, a lot of patients don’t get offered maintenance therapy. It’s probably from days of old where our maintenance therapies were pretty limited and were cytotoxic, and there was a clear question about quality of life and benefit with cytotoxic agents, and wearing the bone marrow out. I think some of the hesitancy is that question about quality of life. There is more than one clinical trial that has looked at that and shown, despite what our bias would be, that if you’ve got adverse effects such as nausea, fatigue, and anemia, that the quality of life indexes are not measurably different. That’s because the control groups in these studies are having symptoms from their disease, so quality life for the population does not diminish on maintenance therapy.

The way I discuss it with my patients is that we have ways we can control fatigue, nausea, and loss of taste. Many of these adverse effects, as you know, tend to go away after a couple of months, but what we can control is progression of disease, pain, and bowel obstruction. By keeping patients off cytotoxic therapy, we’re hopefully preserving their bone marrow reserve. I tell them that their progression-free time, their maintenance time, is really time for them to travel, to get their life back, to exercise, and to get their physical endurance back, because we’re kind of trying to keep them in good shape to fight another battle another day for many of these patients. So, I really encourage them, if they’re coming out of chemotherapy weak, to get back into physical therapy. I tell them it’s time to join the YMCA again, start exercising, and enjoying life again. I can usually maintain patients and get them through their adverse effect profile.

For some of the basic tips as you had asked about, I do premedicate my patients the first week or two. Nausea is one of the common adverse effects for most PARP inhibitors, and I think if you’re going to start a patient on a new drug and they have a horrible experience the first week with vomiting, it’s hard to keep them on the horse, so to speak. They’ll tell you they just can’t take the drug. I will use prophylaxis with antiemetics for the first 1 to 2 weeks and then tell them to use it as needed. I put all patients on antacids, and I tell them to take it with food. For niraparib in particular, I tell them to take it after their evening meal, so that if they do get nausea, hopefully they’re sleeping through it for at least a significant amount of that time. And for the fatigue issue, which is also very common, I really encourage everyone to start aerobic exercise. For most of our older patients, that just means getting out and walking 20 minutes once or twice a day, and trying to establish that habit and getting their muscles back in shape so that they’re not feeling so fatigued.

 I may steal some of your advice to patients. Those are great thoughts to help patients understand why they’re on the medication and to tolerate it better. On the flip side, when I think of it, I have a lot of community physicians who are geographically remote from where I am, so I’ve had the experience of seeing firsthand some of our challenges with getting the information out there about these changes and advances in ovarian cancer. We have great community oncologists who are treating multiple different disease sites. It’s really been a challenge the past couple of years to get out and talk to people about what’s happening in ovarian cancer. Some folks may see just a handful of patients a year, whereas like you mentioned, we’re in a silo, immersed in these changes. It’s really been a struggle to get that out to communities, particularly in places that are somewhat geographically remote from the cancer centers. It’s been a conversation for me with those providers who refer in to me.

The first step is making sure that the genetic testing is done, both germline and somatic. Then we have a conversation about why the somatic testing may be important, and then really encouraging folks to jump in. I usually treat my own patients with the surgery and chemotherapy, but I do partner with a lot of people out there who treat with chemotherapy when my patients live a good distance away. Like with every newer drug, I say to jump in, and we learn very quickly how to manage the adverse effects of it. We learn very quickly how to help patients get through it. In a lot of ways, the medical oncologists who are out there may be more familiar with some of these drugs, just not as familiar with them in ovarian cancer. I think the folks I’ve talked to have been very receptive to it, but there has been a gap in getting the information out there about it, and sharing the excitement we’ve had as a specialty about the advances that we’ve seen in maintenance therapy over the past few years. I think it’s a matter of time, and I see it gradually increasing. I think we just have to continue to make that push to get the information out there both to patients and providers, and help both groups learn how to manage the medications and adverse effects better.

Robert W. Holloway, MD, and Chad A. Hamilton, MD, provide clinical pearls for community physicians using maintenance therapies for ovarian cancer.

Ovarian Cancer Maintenance Therapy Clinical Pearls

 I won’t throw this as a question to you, but for my folks that maybe have come out of their primary chemotherapy and have a lot of bone marrow toxicity and their platelets are low, maybe that’s a group that I would lean more towards the olaparib [Lynparza] side of things. What other things make you differentiate 1 versus the other?

 You hit on it with a toxicity issue with bone marrow. Clearly, you have to consider how they tolerated their cytotoxic therapy and how their bone marrow reserve was. If you’ve got a patient that had repetitive episodes of thrombocytopenia, then I would be a little more concerned about niraparib [Zejula]. But if you’re going to use it, then you’re going to be waiting 6 to 8 weeks before you start it, most likely, which in a setting like this with a partial response, I’d be a little concerned about. I want to get them onto something and keep them maintained as quick as we can to not allow them to progress. This patient is most unusual, and obviously, these are made up examples, but if I really had a patient like this who had persistent disease, I’d be asking why they weren’t completely resected and where was the disease. If I did the surgery, I would know that, but if I didn’t do the surgery, I’d want to know. If I was told that it’s distal small bowel, and if that’s really her site of residual disease in a patient who’s 

 mutated like this, it’s going to inhibit their ability to take any kind of maintenance therapy, so I would almost consider thinking about going back and correcting our GI [gastrointestinal] issue to make her quality of life better, and then get on with more effective therapy if we could. Now if it’s multi-site disease, I certainly wouldn’t do that. And she’s just a nonresponder or less than optimal responder who’s got a poor prognosis, unfortunately, even though she is 

 We had we just had to throw you a little bit of a curveball here. We couldn’t just have the standard textbook case for you. I think your point about not all these mutations are the same and not all these patients are going to behave the same is really salient. I think that, particularly in terms of how the HRD [homologous recombination deficiency] test is really looking for evidence of these DNA editing challenges in the patient’s tumor, so we’re not really getting either “yes” or “no” for if it’s there. I think our friend Dr. Coleman [Robert L. Coleman, MD, FACOG, FACS; Chief Scientific Officer, US Oncology Network] described it well that the HRD testing, in a lot of ways, sees the smoke and doesn’t necessarily see the fire that’s there. So I do think we have a little way to go in refining our HRD testing to determine better ways of acquiring this information. Is our LOH [loss of heterozygosity] score going to be equivalent to genomic instability, or equivalent to the other testing that’s out there? I just don’t know. I think it continues to evolve, and I think what we do in 2 and 5 years is going to be a little bit different from what we do now. Hopefully, we will continue to get better and better biomarker guidance as to how to treat these patients. I’m just glad that we have something at this point that is so remarkably different than we did 5 years ago to help us guide treatment in these patients. It has been, certainly for ovarian cancer, one of the most dramatic changes that I’ve seen in my career. I am a big proponent of testing, and for a good number of patients, I think maintenance therapy is the appropriate treatment.

Key opinion leaders discuss how they decide between two regimens for ovarian cancer maintenance therapies.

Ovarian Cancer Maintenance Therapy: Olaparib vs. Niraparib

 The second case is a 64-year-old who received frontline chemotherapy with the carbo [carboplatin]/Taxol [paclitaxel] for a stage IIIC high-grade serous epithelial ovarian cancer. This is our kind of bread-and-butter patient. Initially, she presented with abdominal bloating and decreased appetite. She had a mass in the right ovary and evidence of peritoneal carcinomatosis. Cytology confirmed that it was high-grade serous ovarian cancer, she was HRD [homologous recombination deficiency]-positive and 

 mutated, CA 125 [cancer antigen 125] was elevated, and there was good performance status. She underwent a primary surgical debulking with gross but minimal residual 1 cm disease. She achieved a partial response to her chemotherapy. Unfortunately, she had pretty severe GI [gastrointestinal] toxicity with diarrhea, often multiple times a day, and a lot of nausea with chemotherapy. How would you approach treatment, and specifically your considerations for maintenance therapy, in this patient?

 This is really kind of an unusual case example, and why I say that is because she has a 

 mutation in her germline. I would expect that the vast majority of these patients are going to be R0 resected, and his patient actually had 1 cm residual disease. It would make me wonder why and why it wasn’t resected.

 And a partial response. I think this brings up the point that, unfortunately, not every patient with a 

 mutation gets a CR [complete response], or if they do and they go into maintenance therapy, we still see patients relapse on PARP [poly adenosine diphosphate-ribose polymerase] inhibition. So there’s more to this story. There is more investigation that we need to do to try to find out in real time what’s going on with PARP inhibition or HRD for patients. Not everybody plays by the rules, and this is a patient who’s not playing by the rule. As it stands, she’s having quite a bit of nausea with her chemo, so the next thing makes me wonder that she has some degree of carcinomatosis on small bowel, a functional obstruction, or even mechanical obstruction, from adhesions. She had upfront debulks. I’d want to investigate that as we’re going into maintenance, try to understand why she’s having so many problems with her chemotherapy and her severe nausea. Assuming that we don’t find a surgical issue and it’s just a disease issue or tolerance issue to her therapy, what are her options? Well, clearly, she’s 

 mutated, so get her onto a PARP inhibitor. She could either go on olaparib [Lynparza] twice a day from SOLO-1, or she could go on niraparib [Zejula] from PRIMA. She could even go on bevacizumab [Avastin] plus olaparib from PAOLA. Again, this GI toxicity issue makes me a little concerned about the bevacizumab. Is this one is going to perforate with disease on our small bowel? She has a partial SBS [short bowel syndrome], so I’d be really wanting to think about that one; I probably go more with a PARP. Looking at the 2, of course, you’d have a discussion about the 2 different PARP options, toxicities, and side effects. I think, obviously, the advantage of the niraparib would be once a day rather than twice a day, so if she’s having nausea with these drugs, that might be a better fit for her. But I think either 1 could be used.

 I would agree with you on that. For the patients that are having a lot of GI toxicity, I do sort of lean to the niraparib option in those folks. Since it’s once daily, you can treat them at night and add on an antiemetic in the evening, and I think I think they still do pretty well with that. Olaparib would certainly be a reasonable choice in that group and we probably will never have something that will tell us efficacy difference between those 2.

Experts review the potential maintenance therapy approaches for a 64-year-old woman with stage IIIC high-grade serous ovarian cancer.

Case Scenario: Stage 3C High-Grade Serous Ovarian Cancer

 You mentioned several of these pivotal trials that we’ve seen in the past few years that led to the registration FDA [Food and Drug Administration] indications for these maintenance therapies. You had mentioned earlier that we all do these cross-trial comparisons. I’m thinking specifically of PRIMA, SOLO-1, and PAOLA-1 that got us the frontline indications. The thing I do remind myself about is, as you mentioned, that the PRIMA population did seem to be a higher risk, higher volume disease initially, and that was an all-comers population. Where SOLO-1, not to be hyperbolic about it, kind of blew us all away having shown a 70% reduction in progression of disease. That’s something we haven’t seen, and I haven’t seen in my career. Then, to have PRIMA follow-up with an all-comers population, granted a little bit heavier disease burden and a little bit higher risk population, PRIMA also had fairly dramatic decreases in progression and death in those patients. Forgive me if these numbers are off, but I think it’s in the high 50s-60s range based on HRD [homologous recombination deficiency] or 

status. Those are pretty remarkable results, and even in the PRIMA exploratory analyses in the patients that were HRD positive, maybe not without 

 and also the proficient population, we saw activity of the PARP [poly adenosine diphosphate-ribose polymerase] inhibitors there. Those are things that have really stuck out in my mind and in my practice, things that I talked to our colleagues about. Regarding PAOLA-1, I agree with you. When I’ve started a patient on bevacizumab [Avastin], then I usually will stick with it, and I’m a pretty strict constructionist when it comes to guidelines and FDA approval. If I’m going to layer on a part, I layer on olaparib [Lynparza] with that, and I do think there’s a benefit there. I think a lot of it is probably driven by the by the PARP inhibitor in that circumstance just like you alluded to. I’m sort of a big picture guy. Those are the big picture sort of things that I think of when I think about these various trials that got us the first-line indications and has really had a dramatic impact on our patients. Is there anything I’ve missed or anything I’ve skipped at a sort of broad level that you think about when you think about PRIMA, PAOLA-1, or SOLO-1?

 I don’t think so. I think I practice very much the same way. I think the difficult group we haven’t mentioned in the examples here is the wild type, HR [homologous recombination]-proficient patient. What do you do for them? I wish we had something better. There is a benefit with PARP in the PRIMA trial with niraparib [Zejula], as you mentioned, and there is a benefit with bevacizumab. Unfortunately, that didn’t work out in PAOLA-1 for that combination. It didn’t provide a benefit over bevacizumab alone, so the benefit is relatively short compared to what we see in the HRD population. It’s a tricky calculus, which I think you have to kind of look at the side effects, complications, and quality of life, and then individualize if you’re a patient and have that discussion about “here are your options.” Recognize that whichever path you take, you’re probably going to use the opposite one when they relapse. Hopefully you get a platinum-sensitive relapse, and you’re going to have the opportunity to use the other one. So that’s the tricky calculus, I think in the proficient patient group.

 As we started wading into this field of maintenance and got more and more indications, I started asking myself and others, “Should everybody get maintenance therapy of some sort at this point? Are we at that point in our practice?” I think maintenance is right for a lot of people. In that proficient population I have a little bit more of a conversation with the patient about the potential pros and cons of maintenance therapy for them. I have some patients that are proficient that I have treated with part maintenance, and I have others that I have not. I guess that’s the population that I really tried to individualize, and that may be the toughest group to educate on the pros and cons of PARP. I do worry about the cost of maintenance for everybody, especially this proficient combination, until we have some better indicator of who is going to benefit. A little bit of that goes with the bevacizumab/olaparib combination as well, if we get most of the bang for the buck from PARP. It hasn’t changed my practice, but it’s in the back of my mind when I think about these things.

Dr. Chad Hamilton explains pivotal data from several important clinical trials in ovarian cancer.

Ovarian Cancer: Significant Clinical Trials

 What is your time frame for starting your maintenance therapy after you finished your adjuvant chemotherapy? Let’s say she’s on carbo [carboplatin]/Taxol [paclitaxel] and bevacizumab [Avastin], and she’s completed 6 cycles total. How soon do you start the olaparib [Lynparza]? Or do you layer the olaparib onto the bevacizumab at that point? Is there any eyeballing the patient? Do you have sort of a fixed time frame in your mind?

 I obviously have to see how the patient is healing. I’m a little concerned about adding bevacizumab too quickly if they’ve had GI [gastrointestinal] surgery. So if a patient had a low rectal, I’d probably wait until she’s at least 6 weeks before I’d start this regimen and maybe even a little longer, especially if she was R0 resected. The olaparib is a big driver in an HRD [homologous recombination deficiency] patient and won’t have a problem with the GI surgery. So that’s all about bone marrow, and she’s already been off chemotherapy probably 4 weeks before you went to your interval size reduction. So within a month, you could clearly start the olaparib and then maybe later the bevacizumab and do it the other way, if you had GI surgery. With no GI surgery, you’re just looking at the wounds and vaginal cuff and probably get going within a month is what I would typically do. And then of course, you’re going to look at your toxicity that you had with your chemotherapy coming up to that. If their bone mass still seems a little fatigued, you could layer on the olaparib a little bit later.

 I’m going to adjust this case just a little bit. Let’s say you did a primary debulking on a patient that didn’t get down to R0 and had residual disease, so you decided to start her on bevacizumab but then shortly after you got testing back, it demonstrated she was HRD-positive. Would you ever bail out on the bevacizumab early on, knowing that you’re going to have part maintenance on the back end? Or I know you talked about the hazard ratio, does that give you enough impetus to continue with the bevacizumab in that scenario?

 I think it’s really patient-dependent. If they’re tolerating the bevacizumab well—not having hypertension or proteinuria problems—that would certainly be 1 issue. If it’s difficult for the patient, if they’re traveling a little bit, or if they express to you that they’re weary, asking “Are we really going to do this for a year? You’re going to come in and take infusions every 3 weeks?” Then I wouldn’t feel it terribly difficult to back off on the bevacizumab and go with single agent niraparib [Zejula] in that setting; switch maintenance, we’ll call it. Or a patient, if they started out on a PAOLA [clinical trial] treatment and they said after 6 months that they just didn’t want to take any more bevacizumab and they were completely resected, and they really don’t seem to be the type of patient who derive the best maintenance benefit from the bevacizumab, then I could even see dropping it. I realized that would be out of guidelines maybe, but probably not. That probably happened in the study, too. They were started on it, maybe they got off the bevacizumab for some reason and they continued the olaparib, so I think you’d have those choices. I think if you look at the hazard ratios with SOLO-1 and PAOLA, they’re rather similar, and it suggests to me, and these certainly 

 and HRD populations, that the benefit is largely driven by the PARP [poly adenosine diphosphate-ribose polymerase] inhibition.

Robert W. Holloway, MD, details how he decides to start maintenance therapy after first-line ovarian cancer treatments.

Starting Maintenance Therapy for Ovarian Cancer

 Let’s jump into a case. I’ll get your perspectives on how some of this plays into your management of this hypothetical patient. Let’s say you have a 57-year-old woman who received neoadjuvant chemotherapy, and you give her carbo-Taxol [carboplatin, paclitaxel] and bevacizumab for what was a stage IIIA high-grade epithelial ovarian cancer. She initially presented with abdominal pain and unintentional weight loss. She had a left ovarian mass on exam confirmed by imaging. A CT scan also demonstrated the mass with some pelvic and inguinal adenopathy but not extensive disease and no pleural effusion. She had a paracentesis for some ascites that confirmed high-grade epithelial ovarian cancer. Germline molecular testing demonstrated HRD [homologous recombinant deficiency]–positive BRCA wild type and an elevated CA-125 [cancer antigen 125]. She had an excellent performance status. After completion of neoadjuvant chemotherapy, she had platelets of 125,000 per mm3 and hemoglobin of 9.0g/dL, which recovered a couple of months after chemotherapy completion. Then she underwent surgical debulking with complete resection of disease and had a complete response to treatment.

That’s a lot to package into that case. Let’s go back to our original thoughts. We talked about frontline treatment in the abstract. How do those things we talked about play into this case?

 One point you brought up was in frontline therapy, making a decision whether you’re going to use bevacizumab. In this case, I wonder about the decision because they didn’t describe a lot of bulky disease. With the inguinal nodes making it extra peritoneal, kind of a stage IV patient, I didn’t know if that’s why we did it. I typically use bevacizumab in instances where we have bulky upper downward disease, parenchymal, lung or liver. Clearly, it’s been show in stage IV in neoadjuvant chemotherapy that being as aggressive as you can makes a difference. In this case it was used. My only hesitation with bevacizumab in a neoadjuvant approach is potentially wound healing, and I’ve had some issues with vaginal cuff dehiscence, or just slow healing of the cuff, and I’ve had to reclose a cuff or 2 along the way.

If I use a neoadjuvant, there are a couple of problems: No. 1, if you put a subclavian port in, you can’t use a defer cycle. You have to let them heal, so you’re going to go without it. That leaves you with cycle 2. If I give cycle 3 and then I operate in 28 days, you’re right on the cusp of that. I’ve had the experience with probably 4 or 5 patients with whom I’ve had slow-healing, ischemic-looking vaginal cuffs. I don’t usually see that on open surgery, so I’m wondering about that. Then there’s the issue of having a slow-healing cuff. If I’m doing a low rectal anastomosis, am I compromising that? I haven’t had any leaks, knock on wood, in those patients, but it does worry me a little. In this case, everything went fine; she got a complete response.

I have a saying with the fellows: I don’t get off the horse that’s winning. It looks like she got a great response with this combination with bevacizumab. We’ve gotten her down to maintenance therapy. What are the options? She’s HRD wild type, so she could go on to bevacizumab plus olaparib from the NCCN [National Comprehensive Cancer Network] Guidelines and the PAOLA-1 trial, or she can go on single-agent niraparib within the guidelines. Either would provide a benefit for this patient, but I tend to not alter from what got us here. I wonder if bevacizumab didn’t drive a lot of the response with the platinum. I’d be inclined to consider that she’s healing from her surgery, reinitiating bevacizumab while the bone marrow is recovering and then add olaparib at some point.

I took the time to look at the hazard ratios in this HRD and BRCA wild type and do a cross-study comparison, which I know is fraught with problems. The PRIMA trial with niraparib had higher-risk patients for failure than PAOLA-1 or SOLO1. But if you look at hazard ratios, and they’re supposed to correct that thing, the hazard ratio for this HRD and BRCA wild-type group was favorable for bevacizumab plus olaparib. The problem is that it’s cross studied with 2 different populations, higher risk and niraparib. But because you got the patient here into remission, it’s rational to use bevacizumab with carbo-Taxol [carboplatin, paclitaxel] to continue that in your maintenance phase and add the olaparib because she’s HRD positive.

 What I was hearing from you early on in the case is, that typically, you reserve bevacizumab for our most challenging patients: those with bulky disease and pleural effusions and who we have less of a chance of completely cytoreducing. If you start them with bevacizumab, and they end up having a homologous recombination deficiency, then stick with that regimen—layering on the olaparib with PAOLA-1 that’s got the indication for maintenance—and do prolonged bevacizumab-plus-olaparib maintenance.

Chad A. Hamilton, MD, and Robert W. Holloway, MD, review the case of a 57-year-old woman with stage IIIA high-grade epithelial ovarian cancer.

Case Scenario: Stage 3A High-Grade Epithelial Ovarian Cancer

 Do you have genetic counselors that are in the mix with you, or do you do most of that out of your office? You mentioned that you have midlevels help out with it.

 Yes, I might be a bit of an outlier. I don’t know. When I hear from most of our colleagues, it’s often stated in talks how important genetic counseling is. We have a volume of patients in central Florida, so it would be difficult to say that every patient with ovarian cancer could get in to see a genetic counselor. Given that the guidelines are clear that every patient with ovarian cancer needs germline testing, I don’t think they need to see genetic counselors. I know that’s been a standard in many large cancer institutes around the country. I wonder if they haven’t adapted so the provider is getting the frontline germline testing. We have genetic counselors available, and some of the testing companies have online counseling available. But I use them in circumstances where patients have uncertain family histories. I need someone to spend more time with the patient to figure out if they are at risk in those situations.

With our midlevels in the clinic who take a very active approach with this counseling, it doesn’t take much time to give the patient their germline report and ask them about how many siblings and how many daughters, and if the male siblings have children, and explain to them the 50/50 transmission rate of 

 and that everyone needs to get tested. We mention that male cancers that are associated with 

. We can do that in 3 minutes, and we’ll mention it at follow-up visits. “Have you given this to your family?” I oftentimes hear things like, “My brother doesn’t want to be tested and my sister does.” Then we’ll again ask them, “Would you like to get your brother in to see a genetic counselor? Would you like to get more information to convince your brother?” That’s how we triage patients. This is for 

-associated genes. It’s pretty straightforward, and we handle that in our office. What do you do at Ochsner [Cancer Institute]?

 We have genetic counselors available, but the volume far outstrips the immediate availability, so it doesn’t help us a lot if the genetic counseling visit is 3, 4, or 6 weeks down the road. We like to get things rolling because we know that this information does impact how we plan for treatment in the near term. We’re doing most of our counseling in house in the clinic. If they become more complicated or we have other cancer involved, then we get our formal genetic counselors involved.

Don’t get me wrong: the work that the genetic counselors do is phenomenal. When I read their notes, and they’ve gone through everything with the patients and their pedigrees and the implications of X, Y, Z, I wish we could have immediate access to that for every patient. But it’s not feasible with the way things are set up. We had a shortage of genetic counselors before we ran into all the shortages we’re seeing with health care personnel. That’s a long-winded way of saying that my practice reflects yours pretty closely.

I have 1 more question for you on this. It came up the other day for us. How are you working tissue testing, somatic testing, for your patients who are getting neoadjuvant chemotherapy? Do you try to send something from your first core biopsy or cytology, or do you wait till the interval procedure?

 Great question. We always get the germline testing up front with the diagnosis. If it’s a laparoscopic event, then we get a biopsy to determine whether we’re going to do primary debulk or interval debulk. I can usually get more tissue. If it’s a core needle biopsy, knowing that I’m probably going to get more tissue. I don’t need the next-generation sequencing, so immediately I prefer to wait till we go to interval debulking and get more tissue.

I’m afraid of wasting time with the core needle. They’d get the slides and say, “There’s not enough here. Can you send more?” So I’ll wait. However, some of these patients, especially the 

-mutation carriers, will get such a great neoadjuvant response that we don’t have much tissue when we get to the interval debulking. I’ll fall back on the core needle biopsy to get tissue. I try to get tissue on every patient and not rely on cytology for that reason if we’re going to do neoadjuvant.

Oncologists debate the need for genetic counseling for ovarian cancer patients and how to approach molecular testing alongside neoadjuvant chemotherapy.

Genetic Counseling for Ovarian Cancer

 What are you doing these days? I’m curious because I talk to so many people, and there are many little variations.

 It’s an interesting topic. I look at what the NCCN [National Comprehensive Cancer Network] Guidelines say about tissue testing and next-generation sequencing for ovarian cancer. It’s not in the guidelines, but there’s a position paper attachment that covers the territory that you mentioned. With all the members of the NCCN Guidelines committee, there was a wide variation of practice and opinion. They couldn’t come to a consensus statement for exact guidelines, to the best of my understanding, for tissue testing. Some people, like you, do HRD [homologous recombination deficiency] testing along with germline testing. Others do next-generation sequencing and use the loss of heterozygosity scores that are attached to the various companies that do that testing.

Like many people, I’m doing this testing earlier and earlier for a variety of reasons, recognizing that the vast majority of our patients recur and recognizing that we do have frontline maintenance options. It’s more imperative to us to get this testing going earlier and then go to treatment so we can be prepared to discuss at 3-week visits with our patients. This is on an ongoing basis, about what we’re going to do for maintenance therapy. Make that plan early so we don’t get to the end of the process and then have to wait another month to get tissue testing and then have that discussion. That’s part of it, recognizing that majority of our patients eventually recur.

I’ve been more of a fan of a broad-panel next-generation sequencing approach and LOH [loss of heterozygosity] scores. I use Caris [Life Sciences] mostly, so I also get IHC [immunohistochemistry] testing on a variety of factors and look at PD-L standing. I have patients for whom I’ve used immunotherapy and who are perhaps MSI [microsatellite instability] stable but PD-L positive, and I’ve been able to incorporate that. I have clinical trials that require that we test early to stratify patients, whether they’re 

 mutated or not, so that’s also gotten my whole office system used to getting this diagnosis. We have midlevel providers in our clinic who stay on top of that with me so people don’t fall through the cracks. We get down to an interval debulking, and we still haven’t tested. We’ve morphed to get it earlier, and I have a team approach with midlevels who keep us on track getting everyone tested early. That’s been our approach.

 It almost becomes like a quality metrics that you can look at as far as the number of patients that you’re testing.

Dr Robert W. Holloway explains his typical approach to ovarian cancer biomarker testing and sequencing.

Sequencing of Biomarker Testing for Ovarian Cancer

 program on ovarian cancer. I’m Chad Hamilton, a gynecologic oncologist and an associate research director at the Ochsner Cancer Institute in New Orleans [Louisiana]. I’m pleased to discuss approaches to the management of patients with ovarian cancer along with my colleague Dr Robert Holloway, who is the medical director of and a gynecologic oncologist at AdventHealth Cancer Institute in Orlando, Florida. Let’s get started. We’ll have a little discussion about context first, Dr Holloway, and then we’ll talk about some cases and how we would manage those. From a broad landscape approach, what do you see as some of the greatest challenges in treating patients with ovarian cancer? Specifically touch on frontline ovarian cancer. What are the greatest challenges there? We’ll get into more detail in a bit.

 It’s well known that our greatest challenge with ovarian cancer is that most of our patients still present with advanced-stage disease, which requires multimodal therapy to get the disease under control. We’ve made great advances in the past 30 years with new drug therapies and new supportive therapies for getting patients into clinical remission, but what hasn’t changed much is that the vast majority of our patients relapse with symptomatic disease at some point in their lifetime, at least 75% to 80%. Of course, we’ve had recent advances in maintenance therapies to maintain or prolong that disease-free survival, but at the end of the day, most of our patients relapse and succumb to their disease, and I view that as the single biggest challenge to improving overall survival. We’ve made some bumps in that during my tenure as a GI [gastrointestinal] oncologist over a few decades, but we’re not hitting home runs yet. We’re getting on base, though.

 Yes, I agree. Absolutely. Thinking a little about first-line treatment for ovarian cancer, because that’s where our focus is today, the challenge for me is that it almost comes as a series of choices that we have to make in the front-line setting. Maybe the first is [whether] this is a patient for primary debulking surgery or if this is a neoadjuvant chemotherapy patient. Once we make those decisions—do we layer in bevacizumab with that treatment? Which patients are appropriate for bevacizumab?—and then continue it as maintenance, how do other biomarkers help us determine treatment in the front line and of course maintenance therapy. I’m happy it’s gotten a lot more complicated and confusing; frontline therapy wasn’t that long ago. There was carbo-Taxol [carboplatin, paclitaxel] and maybe a couple of derivations of that, but it’s evolved a lot and changed in the past 5 years.

To touch on that biomarker question a little more, and the landscape of that, we’ve seen a dramatic evolution. We were initially testing folks guideline based for germline 

 mutations. That’s evolved as we’ve learned more about this homologous recombination landscape and all these factors playing into the machinery of DNA editing and how we test for that. Can we test for that? Whom should we test for those things? To be honest, I’ve done it a number of ways, and even in the past year, how I layer those things has changed.

The first challenge is to discuss biomarker testing with patients. It’s hard enough in a short 15-minute appointment to teach them what germline testing is vs somatic testing, and they’re both very important parts of ovarian cancer treatment when deciding on first-line treatment. I introduce that into the discussion at 1 of the first visits after the patient has started to digest their disease and what’s going on. In the context that we need to start treatment, these are some things that may help us with decisions now and down the line. I’ve done it a couple of different ways. I’ve done germline testing first and the reflex into somatic testing.

The question of HRD [homologous recombination deficiency] testing has come into play a little more. What type of testing should we be doing for homologous recombination? Are they all the same? Are they all different? I’m testing for both germline 

 mutations and homologous recombination. I’m currently using the Myriad [Genetics] platform, and I’m doing those not in sequence but at the same time if possible, which is a bit of a challenge when neoadjuvant chemotherapy comes into play [because we have to] get the best specimen for those tests. That’s what I’ve evolved into. It’s an ongoing process, but I try to do both germline and somatic testing. My preferred in this up-front testing right now is the HRD platform, which uses a combination of factors to come up with a risk for patients.

Chad A. Hamilton, MD, and Robert W. Holloway, MD, discuss challenges clinicians face in treating ovarian cancer and review the current state of biomarker testing.

Robert W. Holloway, MD

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