There is no clear directive regarding the proper makeup of available treatment modalities in the recurrent setting of ovarian cancer, particularly when it comes to secondary cytoreductive surgery, explained Jeannie Chern, MD.
"There is some suggestion that doing a secondary cytoreductive surgery may be beneficial for patients, however there are data that have made it less clear whether or not cytoreductive surgery should be done," said Chern, a gynecologic oncologist at Moffitt Cancer Center.
However, there is a necessity for genetic testing in advanced ovarian cancer—a role that has been firmly established in the newly diagnosed setting.
In an interview during the 2019 OncLive® State of the Science Summit™ on Ovarian Cancer, Chern discussed developments with genetic testing in ovarian cancer and key trials in patients with recurrent disease.
OncLive®: Could you speak to the importance of molecular testing in ovarian cancer?
Chern: As the landscape of ovarian cancer treatment has changed, we've found that there are unique mutations in our patients. Most notably, BRCA1/2 and homologous recombination deficiency (HRD) genes which have an effect on the treatment of our patients. We use BRCA1/2 to help determine whether or not patients should get maintenance therapy and whether or not they should receive PARP inhibitors later on in treatment. The way we determine that is through genetic testing––whether germline or somatic is still being defined. Current recommendations state that we should be testing all patients [with a diagnosis of ovarian cancer], particularly for germline mutations.
What are some of the important germline and somatic mutations to be aware of in this space?
The high penetrance genes are the BRCA1/2 mutations. There are moderate penetrance genes, such as BRIP1, RAD51C, and RAD51D. Other mismatch repair genes like the Lynch syndrome genes are being looked at. The HRD genes play a larger role in this space right now. We're studying those a little bit more to see if they have a role in treatment.
How has our knowledge of these mutations evolved over the years?
The first preclinical data we had on PARP inhibitors came out in 2005. Now we have an indication to use PARP inhibitors. Identifying these gene mutations and their role in treatment has significantly impacted patients’ outcome. Recent approvals of PARP inhibitors in the frontline maintenance and maintenance settings has really changed patients’ progression-free survival (PFS). We don't have data on overall survival (OS) quite yet. As we understand these mechanisms better, the role of treatment will start to evolve.
What are some of the recommendations in place to support this testing?
Current guidelines from the National Comprehensive Cancer Network, Society of Gynecologic Oncology, and the American Society of Clinical Oncology all agree that any patient who is diagnosed with ovarian cancer should have genetic testing regardless of histology, grade, or family history.
Are these guidelines limited to germline mutations?
It’s not clear whether or not patients should have just germline testing or somatic testing as well. Right now, the landscape allows us to use somatic testing as an equivalent to germline testing, so patients who have a somatic mutation can still receive the treatment as if they had a germline mutation. Though, the gold standard at this time is still germline testing.
Are there any barriers to genetic testing?
One of the problems with genetic testing is the cost. Many patients may not be able to afford the cost of genetic testing when they're dealing with the burdens of chemotherapy treatments. There are ways to overcome that. Many companies will offer financial [aid] and will assist in [covering the payment] because they understand the importance and the impact of the results.
The other rate-limiting factor is we don't have enough genetic counselors to test and counsel patients on the results. That's very important because when you get a result, it can create high anxiety in patients. Patients have to have the support of a genetic counselor and resources to help them [process their results]. Additionally, having the baseline knowledge to educate not only the providers who are treating these patients but also the patients, so that they can understand what these mutations mean.
Would you say that adherence to testing remains low? What are some of the factors contributing to that?
Nationally, genetic testing is done about 30% of the time in ovarian cancer. This may be because it's new. When we're more educated about the utility of genetic testing and its impact on patient care, that will change. A lot of this also has to do with restructuring our pathways. One of the things we've recognized in our institution is we have to approach this in a multidisciplinary fashion. When we included things like genetic tumor boards and geneticists within our clinics, we started to see a rise in genetic testing which is helpful. In some cases, these resources aren't available, so we have to find other ways of providing patients with genetic testing or genetic counseling. That might be made possible with telegenetics or group sessions.
What are some of the key tests available for use that your colleagues should know about?
There are many companies that provide germline targeted tests and panel tests; these panel tests may be specific to a certain disease site, but there's also
these panel tests may be specific to a certain disease site, but there's also crossover panel testing for multiple cancer sites. That's important to understand. If we can't look at a whole panel, we can at least target the genes that we're interested in, in particular BRCA1/2. The same is true of tumor testing; multiple companies offer tumor testing profiles. The issue with that is we don't really know how reliable that information is. These type of somatic test results are a little less reproducible than germline testing because they’re more specific. One of the things to consider when you’re ordering genetic testing is whether it's a reliable company that has been tested amongst others. Very few companies actually do that. At Moffitt Cancer Center, we have our own next-generation sequencing panels specifically looking at tumor profiles. We hope to compare our tumor testing panel to others at some point and see how well they rate.
When should you do germline testing versus somatic testing? What’s the best timing to run these tests?
A lot of times when I see a patient, it’s because I’m getting them ready for surgery. I'll often send for somatic tumor testing at that time because I'm hoping I can get the results in a timely fashion. It can be difficult to get genetic testing done because of limited resources. This way, I can at least try to see if there's something actionable for my patient. Because germline testing is the standard, I will send for germline testing at some point along the course of the patient's treatment and get appropriate counseling as needed. There are also times I see patients with recurrent cancer who may not have had any genetic testing. Those patients should also get genetic testing. At that point, I may save the somatic test to see if I can identify an acquired mutation that may be actionable.
What is your take-home message to your colleagues?
The big take-home message is that getting genetic testing is quite important, not only for the patient because it could provide information that would affect their cancer treatment but also for the family members. If patients have a germline mutation, they could have cascade testing for their family. That could also impact their lives. If it's caught early enough, they can also consider implementing risk reducing strategies since the whole goal of testing is to prevent the next cancer.
You also gave a presentation on recurrent ovarian cancer. What does the treatment landscape look like in this setting?
It depends where we are. We know that with each recurrence, the median PFS shortens. On average, the time to progression for the first recurrence is about 18 months, and then it goes down to 10 months, 6 months, and so forth. We have to look at the role of treatment, whether that's chemotherapy, surgery, and other new drugs. Bevacizumab is not necessarily a new drug, but it has an impact on how patients do in the recurrent setting.
Could you discuss key trials in the platinum-sensitive setting?
The initial trials compared single-agent chemotherapy with doublet regimens. There are 2 major trials that looked at this; the first trial was ICON4 and the second was the international intergroup AGO study. ICON4 compared single-agent carboplatin with carboplatin and paclitaxel. This was the one study that showed an improvement in PFS and OS with the doublet.
The AGO study compared carboplatin alone with carboplatin and gemcitabine. They found an improvement in PFS, but the OS was similar [between arms]. The take-home message is that it’s better to use 2 chemotherapies in the platinum-sensitive setting instead of 1 in order to gain a survival benefit. In the platinum-sensitive recurrent setting, patients have already seen carboplatin and paclitaxel. The problem with that is there is significant toxicity, particularly peripheral neuropathy. Patients can also become neutropenic and develop alopecia.
Other drugs had to be explored and one of them was doxorubicin which is known to have good activity in the platinum sensitive population and is also well tolerated. Additionally, the CALYPSO study was a noninferiority trial that compared carboplatin and doxorubicin with carboplatin and paclitaxel. The primary endpoint of the trial was PFS. The study showed that carboplatin and doxorubicin was not inferior to the combination of carboplatin and paclitaxel and also showed an improvement in PFS. This is a good regimen to use as one of the first lines of treatment in the platinum-sensitive recurrent setting.
What questions remain in the platinum-sensitive setting?
We know the way to treat patients with platinum-sensitive disease is to give them more platinum because they should respond to that better. There are not a lot of studies in the platinum-sensitive setting. The studies that are available now are looking at mutations such as BRCA and seeing whether adding another drug such as a PARP inhibitor to the platinum- sensitive combination will impact PFS. That's what we have right now.
What is the role of surgery in the recurrent setting?
One of the big questions is whether there is a role for surgery in patients who recur for the first or second time. A few studies have looked at this. Most notably the DESKTOP trials. DESKTOP I incorporated an exploratory analysis to determine whether or not this is feasible. The analysis showed that patients with a really good performance status, early-stage disease at diagnosis, achieved a complete cytoreductive surgery, and minimal ascites could have a complete cytoreduction. Then DESKTOP II was designed to validate this kind of scoring method. If patients met those criteria, they were more likely to achieve a complete cytoreduction. In the DESKTOP II trial, that rate was 76%. Ultimately these data supported the DESKTOP III trial which randomized patients to surgery, or no surgery followed by platinum-based chemotherapy. They showed that patients who had a complete cytoreductive surgery had an improved PFS. Patients who didn't have a complete cytoreduction didn't fare as well with secondary debulking; they did just as if they didn't have surgery.
A group out of Japan looked at other prognostic factors. In addition to good performance status, they included a long disease-free interval, or a platinum-free interval ≥ 12 months. Distant metastasis was not a good indicator. If patients had a solitary [lesion], these factors were found to contribute to improved survival in the setting of secondary debulking surgery.
Conversely, one of the objectives of GOG-213 was to look at platinum-sensitive patients. Investigators looked at chemotherapy, but they also looked at chemotherapy with the addition of bevacizumab. The second objective was randomization to surgery versus not. Investigators found that patients who had surgery didn't have improved PFS or OS. It is possible, and it can be done safely, but the definition of whether or not these patients should undergo the second surgery is still up in the air and is not necessarily considered standard of care.
Are there specific patients you would recommend for secondary debulking?
I do follow the criteria of having a long platinum-free interval. The longer that interval is, the better outcome patients will have. I also think it makes sense to resect a localized or central solitary lesion. If there are multiple lesions or distant metastatic disease, the data from the initial DESKTOP studies suggest that patients won't do better [with secondary debulking]. Another component is whether patients can tolerate surgery. A good performance status is very important in terms of whether or not a patient can undergo such a big surgery.
What is the role of bevacizumab in the recurrent setting?
We've talked about bevacizumab in the upfront setting and in the maintenance setting. The question is what is its role in the recurrent setting? Three trials have looked at this. The OCEANS trial looked at bevacizumab in the platinum-sensitive setting. Patients were given chemotherapy and then randomized to bevacizumab or no bevacizumab. Patients who got bevacizumab had an improvement in PFS. The GOG-213 was also done in the platinum-sensitive population. These patients were randomized to surgery first or no surgery. All patients were then randomized to chemotherapy plus or minus bevacizumab. Patients who received bevacizumab had a better PFS and OS [than those who received chemotherapy alone].
The AURELIA trial was done in the platinum-resistant population. It was one of the first times bevacizumab was added to a single-agent regimen. The addition of bevacizumab, similar to in other studies, resulted in an improvement in PFS. In the recurrent setting, it's kind of standard to give bevacizumab unless there are risk factors [indicating otherwise]. Most regimens include bevacizumab unless patients progress through it or didn't tolerate it.
Moffitt Cancer Center has a team of GYN cancer specialists at the forefront of cancer research, who are regularly developing new therapies and screening methods to effectively detect and treat GYN cancers.
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