Dr Modesitt on Shared Decision-Making When Choosing PARP Inhibitors in Ovarian Cancer

Susan C. Modesitt, MD, FACOG, FACS, professor, Department of Gynecology and Obstetrics, director, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, and a researcher with Winship Cancer Institute of Emory University, discusses the role of PARP inhibitors in the treatment of patients with ovarian cancer.

Interpretations of clinical data regarding the use of PARP inhibitors in ovarian cancer can yield varying opinions, influenced by both oncological perspectives and individual patient treatment goals, Modesitt says. However, the general consensus among oncologists is that patients who are diagnosed with ovarian cancer harboring either a somatic or genetic 

 mutation or homologous recombination deficient (HRD) status should receive frontline PARP inhibitors, Modesitt explains.

Debate arises regarding the treatment of patients with ovarian cancer that is not HRD or does not harbor 

 mutations, Modesitt notes. Determining the optimal sequencing of PARP inhibitor administration for these patients is nuanced, as questions remain regarding the potential benefits and limitations of using these agents upfront or delaying their use, the latter of which may decrease overall survival outcomes, Modesitt emphasizes. Findings from ongoing trials continue to contribute to the body of evidence with PARP inhibitors in ovarian cancer, with a focus on long-term safety outcomes, time to subsequent therapies, and responses to subsequent therapies, according to Modesitt. The gynecologic oncology field remains vigilant in monitoring these research developments, recognizing that the interpretation of available evidence can vary, Modesitt adds.

Furthermore, oncologists often tailor their treatment recommendations to individual patient needs and preferences, Modesitt says. Shared decision-making is pivotal, and presenting patients with data, along with the associated benefits and limitations, fosters an open dialogue regarding treatment decisions, Modesitt emphasizes. For instance, patients who may not benefit from PARP inhibitors may still be interested in trying this treatment approach, according to Modesitt. Conversely, patients who have a good chance of benefitting from these agents may decide they do not want to receive them, Modesitt notes. Although PARP inhibitors have influenced the ovarian cancer treatment paradigm and have been shown to prevent disease recurrence in many patients, oncologists should respect individual patient choices regarding their willingness to receive these agents, Modesitt concludes.

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Susan C. Modesitt, MD, FACOG, FACS, discusses the role of PARP inhibitors in the treatment of patients with ovarian cancer.

Director, High Risk Breast/ Ovarian Cancer Clinic

Richard N. and Louise R. Crockett Professor of Obstetrics and Gynecology

Epithelial ovarian cancer remains one of the deadliest cancers in the United States, with 22,440 cases and 14,080 deaths expected in 2017.

 This lethality largely occurs because the vast majority of women are diagnosed in advanced stages. In the past, a primary research focus to decrease ovarian cancer mortality has been to develop an effective ovarian cancer screening method.

 This goal was based on the fact that women with a stage I ovarian cancer have a 90% five-year survival rate compared with a 15% to 30% 5-year survival rate in stage III/IV.

 If screening were effective, it would decrease mortality.

Emerging data, however, have confirmed that ovarian cancer is a much more heterogeneous disease than previously recognized. Of note, about 65% of high-grade serous cancers classified as ovarian likely originate in the fallopian tube and most gynecologic oncologists lump ovarian, primary peritoneal, and fallopian tube cancer together as 1 disease entity.

 Because the majority of these “ovarian” cancers likely arise in the fallopian tube as small cancer cells that disseminate prior to reaching a point where they could be detected by current radiographic and serologic screening modalities, screening with current methods is likely doomed to failure. Since today’s ovarian cancer screening is not effective, and every major medical organization recommends 

 broad population ovarian cancer screening, the best current option is to focus on prevention rather than early detection to decrease ovarian cancer mortality.

In contrast to most other cancers, there is a much stronger hereditary component in ovarian cancer. As many as 25% of ovarian cancers are now known to be associated with an inherited cancer susceptibility syndrome, with the majority due to either 

 Thus, identifying women who are at vastly greater risk of developing ovarian cancer and implementing proven risk-reduction measures should be of paramount importance to every physician caring for women or patients with cancer.

Table 1. Genes Associated With Increased Ovarian Cancer Risk

How can women with high-risk disease be identified before they develop cancer? Due to the high risk associated with having a deleterious mutation, essentially every woman with epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer will qualify for insurance coverage for genetic testing. This testing should include, at the minimum, 

 and Lynch mutations but cancer panels can incorporate up to 50 cancer-related mutations for identical costs. Studies continue to show that we still fail to complete recommended genetic testing on the majority of women with ovarian cancer.

Diagnosis of deleterious germline mutations in patients with ovarian cancer serves 3 purposes: (1) to identify women with ovarian cancer who might benefit from the addition of targeted cancer therapies such as PARP inhibitors for women with a 

 mutation; (2) to allow for risk-stratification and surveillance for other cancers for which a patient may be at risk, such as breast for 

 carriers or colon for Lynch mutation carriers; and (3) to initiate “cascade” genetic testing in families where a deleterious mutation has been identified to enable prevention of cancers in women and men in the family who also carry a high-risk gene.

Physicians must have a high index of suspicion to be able to recognize families that might carry an inherited cancer predisposition syndrome that increases ovarian cancer risk in order to be able to refer them to high-risk cancer programs, such as the High Risk Breast & Ovarian Cancer Clinic at UVA Cancer Center. UVA’s program provides individualized assessment for risk stratification that could be followed by genetic counseling and testing as well as appropriate chemoprevention or surgical interventions. For women with other cancers, particularly breast, endometrial, or colon, there are hallmark signs that should also prompt potential genetic referral for inherited cancer syndromes (TABLE 2).

 Most cancer syndromes affect multiple generations and diagnoses will often occur at an earlier age (<50 years) compared with sporadic malignancies. Additionally, both male and triple-negative breast cancers can be signs of hereditary cancer. Lastly, having a relative affected by 2 primary malignancies (eg, breast and ovarian cancer, endometrial and colon cancer, or breast and pancreatic cancer) can also be a sign of a potential hereditary cancer.

Table 2. High-Risk Female Populations Who Could Benefit From Genetic Counseling

For now, our best strategy to decrease ovarian cancer lethality is to focus research efforts on:

Identifying high-risk women and families who carry an inherited cancer predisposition in order to implement known successful risk-reduction measures that improve survival, such as risk-reducing salpingo-oophorectomy

Elucidating the myriad pathways leading to ovarian cancer to identify potential novel screening modalities

Educating providers regarding proven ovarian cancer risk-reduction measures that are available for all women, not just high-risk women, such as birth control pills for chemoprevention and opportunistic salpingectomies

If possible, we must focus efforts on ultimately achieving universal ovarian cancer prevention rather than universal ovarian cancer screening.

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Emerging data have confirmed that ovarian cancer is a much more heterogeneous disease than previously recognized.

Susan C. Modesitt, MD, FACS, FACOG

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