Rebecca A. Previs, MD, discusses the role of biomarkers in uterine and endometrial cancers, the standard of care for patients with different biomarkers in uterine cancer, how PARP inhibitors have affected the treatment of ovarian cancer, and the key clinical trials in gynecologic cancers.
Rebecca A. Previs, MD
The 4 known molecular subtypes of uterine cancer include POLE hypermutated, microsatellite instability high (MSI-H), copy-number high, and copy-number low. Biomarker testing to classify patients into these subtypes is vital to identify the appropriate therapies for patients, according to Rebecca A. Previs, MD.
“Biomarkers are how we individualize therapy, and there is much to learn. It’s an exciting, ever-changing area. I really encourage my colleagues to think about how they can incorporate biomarker-directed care. I always recommend a clinical trial if I don’t have a curative standard therapy. For uterine cancer, [it is important to think] about molecular classifications and how that prognosticates response, and then how to incorporate therapies based on patient’s individual biomarkers,” Previs said in an interview with OncLive® following an Institutional Perspectives in Cancer webinar on women’s health.
In the interview, Previs, who chaired the meeting, discussed the role of biomarkers in uterine and endometrial cancers, the standard of care for patients with different biomarkers in uterine cancer, how PARP inhibitors have affected the treatment of ovarian cancer, and the key clinical trials in gynecologic cancers. Previs is a gynecologic oncologist and assistant professor of obstetrics and gynecology at Duke Cancer Institute.
Previs: This was an exciting opportunity and a timely event because there have been many changes for patients with gynecologic and breast cancers. I’m very pleased with the presentations and my colleagues that presented.
My presentation touched on how we think about molecularly classifying uterine cancers and the biomarkers that we think about to direct [our choice of] targeted therapies. We know there are 4 molecular subtypes of uterine cancer: POLE hypermutated, MSI-H, copy-number high, and copy-number low. We know from next-generation sequencing projects that these molecular subgroups portend survival. It is not a perfect classification but one that helps us think about prognosis for our patients with uterine cancer.
We talked a lot about the different biomarkers that we incorporate in the advanced and recurrent cancer setting for patients with uterine cancer within these molecular subgroups. As of right now, we don’t have any definitive prospective data that suggests that a patient with a POLE-hypermutated cancer doesn’t need therapy. That said, we know these patients do well, even though under the microscope, sometimes their cancers look aggressive.
The phase 2 KEYNOTE-158 study [NCT02628067] examined the incorporation of pembrolizumab into the treatment of patients with a variety of tumors, one of which was uterine cancer.
When considering patients that are MSI-H, we know that those patients have an option for pembrolizumab [Keytruda], based on the FDA approval. We recommend testing for all our patients for that [indication].
Patients that are copy-number low tend to do well, although a small percentage can recur. In the recurrent setting, testing again for MSI-H or microsatellite-stable [MSS] disease is important to help guide therapy in this setting.
Patients with copy-number low tumors often express estrogen and progesterone receptors. I incorporate these biomarkers when thinking about using tamoxifen, alternating with megestrol acetate or everolimus [Afinitor] in combination with letrozole.
In copy-number high tumors, we know these patients have a high risk of recurrence given the histologies, [which include] underlying TP53 mutations. I try to get these patients on a clinical trial whenever I can. There’s data from a phase 2 trial [NCT01367002] to support the incorporation of trastuzumab [Herceptin] for patients that have HER2 amplification. The phase 2 study with trastuzumab coauthored by Amanda Nickles Fader, MD, of Johns Hopkins Hospital, with Alessandro D. Santin, MD, of Yale Cancer Center, as the senior author showed that there was an overall survival benefit in patients receiving trastuzumab, especially in the advanced setting.For my advanced stage copy-number high patients [who are newly diagnosed], I test for HER2, as well as [those] in the recurrent setting.
In my presentation, I briefly touch on the role of PD-L1 testing for patients, which is defined by their combined positive score [CPS]. For patients that have a greater than or equal to CPS of 1, it’s recommended in the advanced and recurrent setting to add pembrolizumab in combination with platinum-based chemotherapy, with or without bevacizumab [Avastin].
Dr Davidson presented on patients that present with advanced stage ovarian cancer and how we think about incorporating PARP inhibitor maintenance. We have several phase 3 randomized, prospective trials in this space that help us understand the incorporation of biomarkers. These trials include the phase 3 SOLO-1 [NCT01844986], PRIMA [NCT02655016], and PAOLA-1 [NCT02477644] trials.
These trials all enrolled slightly different patient populations but evaluated several PARP inhibitors, [such as] olaparib [Lynparza] and niraparib [Zejula]. The PAOLA-1 trial evaluated the combination of olaparib and bevacizumab. The key takeaway that I had from Dr Davidson’s presentation is the value of biomarker testing, specifically the standard of care being germline testing for all patients with epithelial ovarian cancer to help patients decide whether PARP inhibitor maintenance therapy is right for them.
Dr Davidson is an expert at shared-decision making and asking: If a patient doesn’t have an underlying germline BRCA mutation, how can we incorporate homologous recombination deficiency testing or genomic instability as a biomarker? The most challenging patient population for me is those patients who do not have an underlying germline mutation. They have a tumor that’s homologous recombination proficient. This is an area where we need to continue active investigation. [Although] the benefit of PARP inhibitors is present [in that population], it is not as much as we see for patients with other biomarkers.
[After hearing about the pivotal trials,] we discussed the FDA approvals of both olaparib and niraparib in the primary setting following adjuvant chemotherapy. We discussed the differences and nuances between FDA approvals, the different toxicity profiles of these agents, and the monitoring that’s required so we can ensure our patients understand that it’s not a simple as taking [the PARP inhibitor] and walking away. It does require careful follow-up, but there is an absolute benefit in patients [receiving PARP inhibitors] who have biomarker-driven cancers.
Dr Moss did a fantastic job reviewing this area. This patient population is very challenging to treat. This area was one of the first where we started the incorporation of PARP inhibitors, with [olaparib] in the phase 2 Study 19 trial [NCT00753545] and other earlier PARP trials.
Since the approvals of olaparib, rucaparib [Rubraca], and niraparib, [these PARP inhibitors] have been in standard practice. Thinking about Dr Davidson’s presentation of frontline [treatment], one of the things that I grapple with as a clinician is whether we should retreat patients with a PARP inhibitor. Dr Moss highlighted the phase 3 OReO study [NCT03106987], which did show some benefit with retreatment with olaparib for certain groups of patients.
We were grateful for Dr Sammons’ presentation. She is a real expert in this space and is very progressive and forward thinking. She highlighted the various trials that have reported out and are ongoing in this space. One trial that was brought to the forefront of the talk was the phase 3 OlympiA trial [NCT02032823], [which examined patients] very similar to those with high-grade serous ovarian cancer.
Dr Sammons discussed the real value of biomarker testing, specifically with germline testing. [OlympiA] did show a survival benefit for patients that had an underlying BRCA mutation. There’s more to come in this area, and it is an active area of rapid investigation.
[It is important] to impart hope. Hope is a bit of a biomarker in a way that we don’t necessarily test for. With all of this rapid change and evolution in our clinical trials and knowledge about tumor biology, breaking down this complex data can be overwhelming for patients.
This is an exciting area, and as providers, we owe our patients the hope for improvement in survival prognosis, as well as toxicity. I’m hopeful that our audience also took that away.
Anytime that we can get together, either virtually or in person, to discuss clinical trial data, the current guidelines, and current expert opinion is valuable. It’s important for health care providers that are in academic settings, hybrid practices, and community practices to come together. We know that the real-world population is not as neat as the clinical trial population. That is when we rely on real-world experience. We can talk from the trenches about what it’s like to care for our patients.