: Dr. Tewari, let’s move on to biomarkers. This first section is about biology, screening, and prevention. You’ve been an advocate of biomarkers, and you have an NIH [National Institutes of Health] grant for biomarkers in cervical cancer. For the practicing clinician, what are the biomarkers that are relevant in treating cervical cancer today?

For treatment, it’s a matter of looking at patients that need to be treated with immune checkpoint inhibitors. Patients with recurrent or metastatic cervical cancer, we calculate a CPS [combined positive score] for looking at their PD-L1 expression of not just the cancer cells, but also the lymphocytes, and the macrophages. We get a score and that can help guide selection of therapy, especially in the second line. As far as other panel testing, if you want to sequence the entire genome, you could get the tumor mutational burden and immunotherapy. PD-L1 expression is the predominant biomarker that’s used in practice today.

: We’re going to talk about a phase 3 trial that’s called KEYNOTE-826, where 89% of the patients were combined PD-L1 score greater than 1+. Of those 11% that are negative, many of those are adenocarcinomas, and at least some of them, are TMB high, tumor mutational burden-high, or MSI [microsatellite instability]-high. By the time you take the 89% that are PD-L1 positive, and then add 2-3% of TMB and MSI, Dr. Pothuri, is it worth testing at all? Or do you say there’s so few patients that are biomarker negative, give a checkpoint to everybody?

 I test because I’ve had some insurance difficulties without having the PD-L1 status to utilize pembrolizumab [Keytruda]. Going forward, given the data from KEYNOTE-826 and the cemiplimab [Libtayo] data, it appears to be efficacious regardless of PD-L1 status. In the future, we’re not going to need to test.

: Yes, that’s likely. Where we are today, it’s the labeled indication, it’s companion diagnostic, and maybe it will evolve. Dr. Huh or Dr. Thaker, looking at the TCGA [The Cancer Genome Atlas], there were EGF [epidermal growth factor] activating mutations and now there’s data saying that in the small proportion that have EGF-activating mutations, you can use a tyrosine kinase inhibitor and would require next-gen [next generation] sequencing. Do you do that or is it hard to get the medication paid for and it’s just a PD-L1-TMB-MSI world?

 In our recurrent patients for cervical cancer, we are doing commercially acceptable testing. We have next-gen sequencing, and a lot of immunohistochemistry, because to your point, there’s that rare patient that could use neratinib [Nerlynx]. It’s even smaller portions of the pie, but for that 1 patient that you’re seeing in front of you, you can make a huge difference.

Yes, we do the exact same thing. It’s become the standard of care, at least at our institutions, to do next-gen sequencing on essentially every cervical cancer patient, particularly in the recurrent setting. We’re looking for mutations that would put them on a clinical trial whether to taper or match. But I agree with Dr. Thaker, we take a similar approach to that. Is it hard? Yes. But is it worth fighting for? Absolutely. And we’ve seen successes that are notable.

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The panel reflects on the current, optimal use of biomarker testing to guide the management of cervical cancer.

What is the Current Role of Biomarker Testing in Cervical Cancer?

: Dr. Thaker, you’ve been a passioned advocate for all levels of special populations. This is a preventable disease. We live now in the pandemic and vaccination is important. What’s the role of vaccination in preventing what Dr. Pothuri said, a virally-induced cancer? Tell us about that.

 It’s critical to know that we’ve had an HPV [human papillomavirus] vaccine that’s been approved since 2006. I wish the United States was as great as other countries have been in vaccination, but we’re catching up slowly. There’s critical work done by the CDC [Centers for Disease Control and Prevention] and ASCO [American Society of Clinical Oncology], looking at our SEER [Surveillance, Epidemiology, and End Results] databases and our cancer databases trying to see the impact of vaccination, and we are seeing a decline especially in our women who have been vaccinated at the ages of 10 to 11. I do think we’re making progress. We’re making progress in the cancers that we can screen for, like cervical cancer, but we’re also seeing a rise of anal and rectal cancers. We need to get the word out about vaccination, but also being proactive with screening for other cancers, too.

: It’s a new indication for head and neck cancer, too. If we’ve learned anything from the pandemic, if you don’t get vaccinated, you might die.

: And if you don’t get vaccinated against HPV, you might die.

 We need to get the word out to vaccinate not only our females, but our males. When we first came out, the stigma was only females, and now it’s all-encompassing and we’ve extended the age of vaccination, not that we’re advising people in their 40s, but we have the indication. We’re trying to get people vaccinated before they’ve been exposed to HPV, which is the key. We need to get the word out.

 Dr. Monk on that topic, countries like Australia that have some of the highest vaccination rates in the world, are making statements that cervical cancer will largely be eradicated in 15 to 20 years. They’ll accomplish it. It’s not a pipe dream. It’s an attainable goal.

 How many cases were in Australia to begin with, 5?

: Enough to be prevented, Dr. Tewari to your point. What’s the problem, Dr. Pothuri? Why aren’t we doing better with vaccination?

 There’s a stigma associated with the HPV vaccine, and it’s unfortunate. People think that it’s sexual in nature and you’re promoting that by saying you can get the vaccine and be safe. It begs to better education of parents because it’s the children that need to be vaccinated. We have to pivot away from that. This is a vaccine that can prevent cancer, probably the most important discovery that we’ve had in GYN oncology, and we need to push that home. We can prevent cancer with this.

: Dr. Warner, you’ve done remarkable things in creating guidelines. Screening is still here, because as they said we’re not vaccinating enough. What are the screening recommendations, whatever you prefer, the U.S. Preventive Services Task Force, the American Cancer Society? What are the guidelines for screening?

 As you know, Dr. Monk, there are slight differences between the Task Force and the American Cancer Society and now even ACOG [American College of Obstetricians and Gynecologists]. There are 3 things for the listeners that are important. One is when do we start screening, and it’s clear that we are raising the age of screening. Not long ago, we started screening at 18 or within 3 years of sexual activity. We increased it to 21, and now the American Cancer Society is espousing starting at the age of 25. Cervical cancer is exceedingly rare and uncommon and arguably unscreenable under the age of 25.

At 25, we have the Pap, but most experts in the U.S. and worldwide want people to use HPV testing, either by itself or in conjunction with Pap. There’s not a single negative phase 3 randomized trial that has demonstrated that HPV is worse or performs equal or less to Pap. If you screen women with HPV, that constitutes about a 70% lifetime risk reduction of getting cervical cancer. At 20 to 30, either getting an HPV test by itself or with a Pap, also known as co-testing, and you screen every 5 years. If you get a Pap, it’s every 3 years. The third thing is to have an end screening, and this is where I profoundly disagree with the recommendations. We recommend cessation of screening at 65, but we’ve published data that demonstrates about 20% of all cervical cancer cases, at least in the U.S., occur in women after 65 years of age. The problem is the majority of those people are on Medicare, and Medicare won’t cover screenings. It’s a major gap in how we screen people. The bottom line, use HPV screening, that’s the best. HPV screening is a better paradigm for screening the general population.

: Yes, test for the virus from the cervix, and women need to keep themselves safe.

A comprehensive review of the current paradigm for HPV vaccination and screening to prevent cervical cancer.

Role of HPV Vaccination and Screening to Prevent Cervical Cancer

 Peer Exchange entitled “Recent Advances in Cervical Cancer Treatment.” We’re sharing a negative phase 3 trial, 2 positive practice-changing phase 3 trials, and a recent approval of the first antibody-drug conjugate in a gynecologic malignancy; this will be a robust discussion. My name is Brad Monk, I’m a gynecologic oncologist from Phoenix, Arizona, and a professor at the University of Arizona and Creighton University, both in Phoenix. I am joined by 4 experts from across the country, and I want to introduce to you Warner Huh.

 Thanks, Dr. Monk. Warner Huh, I’m the chair of ob-gyn at the University of Alabama at Birmingham, practicing gynecologic oncologist, and I am excited to be here.

: My pleasure. I’m glad you could join us. Warner was a former president of the Society of Gynecologic Oncology. He has held every meaningful position, and now he’s chair of ob-gyn and likely leading gynecologic oncologist in cervical cancer screening and a thought leader in treatment. Bhavana Pothuri, greetings, please introduce yourself.

 Hi, I am Bhavana Pothuri. I am a GYN [gynecologic] oncologist at NYU Langone Health and Perlmutter Cancer Center [New York, New York]. I’m a professor there and I’m also the director of GYN oncology clinical trials. I am active with GOG [Gynecologic Oncology Group] Partners and serve as an associate clinical trial advisor for ovarian and endometrial cancers, and have an interest in cervical cancer. Thank you.

: We appreciate your leadership in the GOG Partners program. You’re changing the world, and many of these trials that we’re going to discuss are GOG Partners trials. Krish Tewari, greetings, how are you?

 Great, thank you. My name is Krish Tewari. I’m a practicing GYN oncologist at the University of California Irvine [Orange, California].

: We’re going to discuss more than one New England Journal paper that Dr. Tewari has coauthored, so we’re interested to hear your perspectives. Last, but not least, Premal Thaker.

 Hi, thank you for this opportunity. I’m Premal Thaker. I’m a professor of GYN oncology at Washington University School of Medicine and Siteman Cancer Center in St. Louis, and I am the director of our gynecologic oncology clinical research.

: Washington University St. Louis is one of our top enrolling sites. It’s one thing to talk, and we’re going to talk today, but when it comes to getting things done, Dr. Thaker and her colleagues in St. Louis always do. I’d like to discuss biology and screening. Most people acknowledge that this is a preventable disease. Bhavana, can you talk about the histology’s and the staging for cervical cancer.

 Yes, cervical cancer is important to discuss. It’s the fourth leading cause of cancer death in women worldwide, and over 99% are caused by HPV [human papillomavirus]. It is the causative agent. This is a cancer that affects younger women, most are diagnosed between the ages of 35 and 44. It’s important that we’re having this discussion and focusing on these patients. The majority are classified as squamous cell cancers, about 80%, and the remainder are largely adenocarcinomas.

: There’s a staging system. Dr. Tewari, tell us about the FIGO [International Federation of Gynecology and Obstetrics] staging system. It’s different than what people are used to, the TNM [tumor nodes metastases] staging system.

 We’ve been using FIGO for years to stage cervical cancer, and for a long time it was a clinically assigned staging. If the cancer is involving the cervix, it’s a stage I; if it spreads into the upper vagina or the perimetrial tissues surrounding the cervix, it’s a stage II; if it goes up the pelvic side wall, it’s a stage III; if it’s involving the bladder or rectum, it’s a IVA; and if it’s metastasized, it’s a IVB. Recently, in 2018, FIGO updated their staging to allow for radiographic and/or pathologic evaluation specifically of lymph nodes. We have guidance and can designate a patient with stage III disease by virtue of their lymph nodes, whether they’re positive on pathologic examination or by radiographic imaging. You should denote that with a subscript.

: I like it because it’s the same as endometrial or uterine cancer, right? IIIC1 means it’s in the pelvic lymph nodes, and IIIC2 means it’s in the aortic lymph nodes. There’s not much to remember there.

Experts provide a brief overview of cervical cancer, focusing on the driving biology and FIGO staging system.

Understanding the Biology and Staging of Cervical Cancer

Bhavana Pothuri, MD, a professor in the Department of Obstetrics and Gynecology at NYU School of Medicine, and director of gynecologic oncology clinical trials at NYU Langone Health’s Perlmutter Cancer Center, discusses treatment considerations for PARP inhibitors in patients with ovarian cancer.

From an efficacy standpoint, all the PARP inhibitors that have been FDA approved for the treatment of this patient population are similar, according to Pothuri. However, some differences exist with regard to dosing schedule. For example, olaparib (Lynparza) and rucaparib (Rubraca) are given twice daily, and niraparib (Zejula) is given once daily. The dosing schedule is something to consider if patient compliance is an issue, Pothuri says.

Additionally, certain agents will impact the SIP metabolism, so it is important to understand drug–drug interactions when choosing a treatment regimen, Pothuri notes. Moreover, in patients with significant myelosuppression, niraparib has been shown to result in significant thrombocytopenia, especially in studies that did not utilize the individualized dosing where a 200-mL dose is given to those who are less than 77 kg, or have a platelet count of less than 150,000 per mL, Pothuri adds.

It is important to keep these factors in mind when utilizing PARP inhibitors, Pothuri says. Additionally, letting the bone marrow recover after completing frontline chemotherapy is needed to improve the tolerability of these agents, Pothuri concludes. 

Bhavana Pothuri, MD, discusses treatment considerations for PARP inhibitors in patients with ovarian cancer.

Dr. Pothuri on Treatment Considerations for PARP Inhibitors in Ovarian Cancer

Bhavana Pothuri, MD, professor, Department of Obstetrics and Gynecology, NYU School of Medicine, director of gynecologic oncology clinical trials, NYU Langone Health’s Perlmutter Cancer Center, discusses the role of maintenance therapy in 

Currently, maintenance therapy should be considered for all patients with ovarian cancer irrespective of 

 mutational status, says Pothuri. The type of maintenance therapy administered is dependent on whether the patient received bevacizumab (Avastin) in the frontline setting, Pothuri explains. 

As such, patients who received frontline bevacizumab should continue bevacizumab in the maintenance setting with added olaparib (Lynparza), Pothuri says. Typically, up-front bevacizumab is given to patients with bulky or stage IV disease, adds Pothuri. Patients who did not receive frontline bevacizumab will receive olaparib alone as maintenance therapy, Pothuri says.

 mutations or have homologous recombination deficient disease appear to derive additional benefit from maintenance therapy, Pothuri explains. As such, shared­–decision making, as well as genetic testing, is critical to optimize maintenance therapy in this patient population, concludes Pothuri. 

Bhavana Pothuri, MD, discusses the role of maintenance therapy in BRCA-positive ovarian cancer.   



Dr. Pothuri on the Role of Maintenance Therapy in BRCA+ Ovarian Cancer 

Bhavana Pothuri, MD, professor, Department of Obstetrics and Gynecology, NYU School of Medicine, director of gynecologic oncology clinical trials, NYU Langone Health’s Perlmutter Cancer Center, discusses patient-reported outcomes (PROs) with niraparib (Zejula) in advanced ovarian cancer.

, findings from an analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial revealed that patients with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer who derived a complete or partial response to first-line platinum-based chemotherapy and who received niraparib had similar quality of life (QOL) compared with patients who received placebo.

FOSI [Validation of the Functional Assessment of Cancer Therapy-Ovarian Symptom Index] scores were similar in patients who received niraparib versus placebo, Pothuri reports. Moreover, the number of patients who reported lethargy, nausea, vomiting, and abdominal cramps were similar between arms.

As determined by the EORTC-QLQ-C30 questionnaire, QOL was similar between arms, Pothuri says. Additionally, abdominal and gastrointestinal symptoms, as well as other chemotherapy-related adverse effects were similar as determined by the EORTC-QLQ-OV28 instrument.

Finally, the overall QOL of patients was shown to be similar based on the EQ-5D-5L index, concludes Pothuri. 

Bhavana Pothuri, MD, discusses patient-reported outcomes with niraparib in advanced ovarian cancer.  



Dr. Pothuri on Patient-Reported Outcomes With Niraparib in Advanced Ovarian Cancer 

Bhavana Pothuri, MD, professor, Department of Obstetrics and Gynecology, NYU School of Medicine, director of gynecologic oncology clinical trials, NYU Langone Health’s Perlmutter Cancer Center, discusses the importance of obtaining patient-reported outcomes (PROs) in ovarian cancer.

At part of the 2020 SGO Annual Meeting virtual platform, a PROs analysis from the phase III PRIMA trial (ENGOT-OV26/GOG-3012) revealed that health-related quality-of-life (QOL) scores were similar for patients who received niraparib (Zejula) as frontline maintenance therapy compared with placebo.

PROs are critically important in understanding the impact of an investigational treatment on patients’ QOL, says Pothuri. Additionally, PROs can influence FDA regulations and guide treatment decisions in the clinic.

From a patient perspective, PROs also allow individuals to share their experience with a novel regimen, concludes Pothuri.

Bhavana Pothuri, MD, discusses the importance of obtaining patient-reported outcomes in ovarian cancer.



Dr. Pothuri on the Importance of Obtaining Patient-Reported Outcomes in Ovarian Cancer

Bhavana Pothuri, MD, an associate professor in the Department of Obstetrics and Gynecology at NYU Langone's Perlmutter Cancer Center, discusses PARP inhibitors for the treatment of patients with ovarian cancer.

There is a need for new agents, says Pothuri, and PARP inhibitors are a new class of agents that are now approved. The first PARP inhibitor that was approved was olaparib (Lynparza) in December 2014. Olaparib is approved in patients with recurrent ovarian cancer who have had 3 or more prior lines of therapy, and are 

It is a very exciting time for PARP inhibitors, states Pothuri. PARP inhibitors are showing promise utilized in ovarian cancer accounts for only about 20% of gynecologic malignancies, but it accounts for over 50% of gynecologic cancer deaths.

Bhavana Pothuri, MD

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