Faculty Bibliography

Objective: We sought to prospectively evaluate the feasibility of obtaining genetic testing for at least 1 first- or second-degree family member of a proband known to have actionable germline mutation associated with endometrial and/or ovarian cancer through a coordinated referral system. We also identified barriers to genetic assessment in family members. Here we report initial probands screened and their reasons for declining cascade testing.
Method(s): Patients with a diagnosed pathogenic or suspected pathogenic mutation associated with ovarian and/or endometrial cancer were identified from the gynecologic oncology and genetics clinics. If patients did not consent to the study, their reasons for declining participation were documented. Patients who provided consent were asked to contact their first- and/or second-degree relatives to disclose their genetic testing results and advise them to contact our center for a referral to a genetic counselor. The number of relatives per proband who contacted us for a genetic counseling referral was recorded. In addition to providing the referral, we followed up with relatives to determine whether they attended their genetic counseling appointment, received genetic testing, or took any cancer risk-reducing measures based on their results.
Result(s): This study opened in March 2019. To date, we have screened 71 patients and enrolled 26 (37%). Among the 45 patients who were screened but not enrolled, 48.9% (n = 22) reported that their reason for declining participation in the study was that their family members had already received genetic testing. Other common reasons for declining participation were family members refusing testing (17.8%, n = 8) or no eligible family members (17.8%, n = 8) (Table 1).
Conclusion(s): The majority of probands declined participation in this facilitated cascade testing protocol. The most common reason for lack of participation was family members already having genetic testing or not having eligible family members. Patients who declined participation because family members refused testing could benefit from counseling on how to best to communicate with their relatives. Genetic testing for both patients and their relatives is critical to provision of appropriate cancer screening and prevention services. Knowledge of these barriers is important to further improve cascade testing among family members.
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Objectives: Interest in utilizing poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of recurrent disease beyond BRCA1 and BRCA2 carriers has been growing. We sought to characterize the prevalence of somatic and germline mutations in non-BRCA1 and BRCA2 homologous recombination deficiency (HRD) pathway genes among ovarian cancer patients.
Method(s): We reviewed Foundation Medicine (Cambridge, MA) comprehensive genomic profiling (CGP) of tumor tissue for all patients from a single institution between January 2014 and July 2019 as well as germline genetic testing results for newly diagnosed ovarian cancer patients participating in a prospective research study of germline genetic testing from October 2015 to October 2018. Alterations in non-BRCA1 and BRCA2 HRD genes, including ATM, BARD1, BRIP1, PALB2, RAD51C, and RAD51D, were included. Clinicopathologic and treatment data were extracted from the electronic medical record. Descriptive statistics were used to report patient and treatment characteristics.
Result(s): Among 79 ovarian cancer patients whose tumors underwent tumor CGP, 3 (4%) had somatic mutations in non-BRCA1 and BRCA2 HRD genes. Among 133 patients who underwent germline genetic testing, no non-BRCA1 and BRCA2 HRD mutations were noted. One patient each had an ATM, BRIP1, and RAD51C mutation on tumor CGP. All patients with mutations on tumor testing underwent panel germline genetic testing, and no pathogenic mutations were identified. All patients with non-BRCA1 and BRCA2 HRD mutations had stage III disease, with initial disease-free intervals of 18-23 months after primary therapy. See Table 1.
Conclusion(s): Among patients with ovarian cancer, somatic, or germline mutations in non-BRCA1 and BRCA2 HRD genes are rare, detected in less than 5% of tumors. Although PARPi may benefit this patient population, our data suggest they represent a small percentage of ovarian cancer patients. Further study confirming these data in a larger cohort of ovarian cancer patients as well as testing efficacy of PARPi in these patients is needed.
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With the introduction of PARP inhibitors into frontline chemotherapy, with or without bevacizumab, the hope exists that more women may be spared a recurrence of their ovarian cancer. Whether or not this proves to be true, the fact remains that many or most women with ovarian cancer will experience a recurrence requiring the use of additional active chemotherapy and targeted options. This manuscript summarizes the known data to date regarding the use of PARP inhibitors in the recurrent setting.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been rapidly integrated into clinical practice for women with ovarian cancer. Currently, PARP inhibitors are approved as frontline maintenance treatment for patients with and without BRCA-associated cancers, and they are listed by the National Comprehensive Cancer Network (NCCN) as a treatment option for all high-grade serous and endometrioid cancers with or without bevacizumab. PARP inhibitors are also approved as maintenance treatment following a response to platinum-based therapy in the recurrent setting, irrespective of biomarker status. Additionally, PARP inhibitors are approved as third-line treatment and beyond in lieu of chemotherapy for patients with BRCA-associated cancers, and as fourth-line treatment and beyond for patients with platinum-sensitive homologous recombination-deficient tumors. They are also listed by the NCCN in combination with bevacizumab for the treatment of patients who have platinum-sensitive recurrent disease. The first part of this 2-part review focuses on the changing paradigm of frontline therapy options resulting from the recent approvals of PARP inhibitors; the second part considers the role of PARP inhibition in recurrent ovarian cancer.

Background: The PRIMA/ENGOT-OV26/GOG-3012 (PRIMA) trial showed that niraparib significantly improves progression-free survival (PFS) in pts with newly diagnosed advanced OC that responded to first-line platinum-based chemotherapy (CT) (hazard ratio [HR] 0.62; 95% CI 0.50-0.76). Here we discuss the impact of age on efficacy and safety of niraparib.
Method(s): This double-blind, placebo (PBO)-controlled phase III trial evaluated niraparib in pts with newly diagnosed, advanced, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response to first-line platinum-based CT. Pts were randomized 2:1 to receive either a fixed starting dose (FSD) of 300 mg niraparib or PBO QD. A protocol amendment introduced an individualized starting dose (ISD): 200 mg QD in pts with bodyweight <77 kg or platelet count <150,000/muL or 300 mg QD for all others. Pts were dichotomized by age group <65 vs >=65 years old (yo) to analyze efficacy and safety of niraparib vs PBO in older patients. The primary endpoint was PFS assessed by blinded independent central review.
Result(s): Of 733 enrolled pts, 444 were <65 yo (297 niraparib, 147 PBO), and 289 were >=65 yo (190 niraparib, 99 PBO). Efficacy was comparable in pts <65 yo (HR 0.61; 95% CI 0.47-0.81) and >=65 yo (HR 0.53; 95% CI 0.39-0.74) who received niraparib compared with PBO. Any-grade and grade >=3 treatment emergent adverse events were similar across age groups (Table). Grade >=3 thrombocytopenia events in pts <65 yo were reported in 43% of pts receiving a FSD and 18% of pts receiving ISD. In pts >=65 yo, the values were 57% and 26%, respectively. Patient reported outcomes (PROs) and quality of life (QOL) were similar in both age groups as assessed by FOSI and EQ-5D-5L.
Conclusion(s): Niraparib efficacy, safety, and QOL were similar in compared age groups. Implementation of an ISD regimen improved rates of grade >=3 thrombocytopenia events in older pts. [Formula presented] Clinical trial identification: NCT02655016. Editorial acknowledgement: Writing and editorial support, funded by GlaxoSmithKline (Waltham, MA, USA) and coordinated by Ashujit Tagde, PhD of GlaxoSmithKline, was provided by Eric Scocchera, PhD and Anne Cooper, MA of Ashfield Healthcare Communications (Middletown, CT, USA). Legal entity responsible for the study: GlaxoSmithKline, Waltham, MA, USA.
Funding(s): GlaxoSmithKline, Waltham, MA, USA. Disclosure: G. Valabrega: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: GSK-Tesaro; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: PharmaMar; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Clovis. B. Pothuri: Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Tesaro; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Clovis Oncology. A. Oaknin: Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Tesaro; Honoraria (institution), Advisory/Consultancy: Clovis; Honoraria (institution), Advisory/Consultancy: PharmaMar; Honoraria (institution), Advisory/Consultancy: Roche. W. Graybill: Advisory/Consultancy: Tesaro. A.B. Sanchez: Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: Tesaro; Speaker Bureau/Expert testimony: GSK; Speaker Bureau/Expert testimony: PharmaMar; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: MSD. P. Hoskins: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: GSK; Advisory/Consultancy: Roche. H. Denys: Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: PharmaMar; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: Tesaro; Travel/Accommodation/Expenses: Teva. R.E. O'Cearbhaill: Advisory/Consultancy: Tesaro; Advisory/Consultancy: GlaxoSmithKline; Research grant/Funding (institution): NIH/NCI Cancer Center. R.G. Moore: Advisory/Consultancy: Fujirebio Diagnostics Inc.; Research grant/Funding (institution): Angle Plc; Advisory/Consultancy: Abcodia Inc.; Advisory/Consultancy: Humphries Pharmaceutical. T. de La Motte Rouge: Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy, Non-remunerated activity/ies: MSD; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Tesaro GSK; Advisory/Consultancy, Non-remunerated activity/ies: Roche; Advisory/Consultancy, Non-remunerated activity/ies: Pfizer. F. Heitz: Non-remunerated activity/ies: NewOncology; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Clovis; Advisory/Consultancy: Tesaro; Advisory/Consultancy: PharmaMar. Y. Li, D. Gupta: Full/Part-time employment: GlaxoSmithKline. B.J. Monk: Advisory/Consultancy, Research grant/Funding (institution): Tesaro. A. Gonzalez Martin: Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Tesaro; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Roche Holding AG; Advisory/Consultancy: Merck & Co., Inc.; Advisory/Consultancy: Genmab; Advisory/Consultancy: Immunogen; Advisory/Consultancy: Pharma Mar, S.A; Advisory/Consultancy: Oncoinvent AS. All other authors have declared no conflicts of interest.
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Background: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that is approved for use in heavily pretreated pts and as maintenance treatment of pts with newly diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy (CT). Here we report PROs in pts receiving niraparib and placebo (PBO) in the PRIMA/ENGOT-OV26/GOG-3012 trial.
Method(s): This double-blind, PBO-controlled, phase III study randomized 733 pts with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response (CR or PR) to first-line (1L) platinum-based CT. Pts received niraparib or PBO once daily for 36 months or until disease progression. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. PROs, a secondary endpoint, were collected every 8 weeks for 56 weeks, then every 12 weeks thereafter while treatment was ongoing. Once a pt discontinued treatment, PRO evaluations were performed at the time of treatment discontinuation and then at 4, 8, 12, and 24 weeks (+/-1 week for each time point) after the end of treatment, regardless of the status of subsequent treatment. The validated PRO instruments utilized were FOSI, EQ-5D-5L, EORTC-QLQ-C30, and EORTC-QLQ-OV28.
Result(s): Compliance rates were high for all of the PRO instruments used in the study. PRO analysis of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 did not indicate a difference in health-related quality of life scores of pts treated with niraparib vs placebo. Mean scores between niraparib and placebo arms were similar at each time point. Overall, the health utility index showed a slight improvement trend in pts who received niraparib vs placebo.
Conclusion(s): Consistent with PRO results in the NOVA study, pts receiving niraparib in the PRIMA trial did not experience a decrease in quality of life compared with those receiving placebo. Clinical trial identification: NCT02655016. Editorial acknowledgement: Writing and editorial support, funded by GlaxoSmithKline (Waltham, MA, USA) and coordinated by Ashujit Tagde, PhD of GlaxoSmithKline, was provided by Eric Scocchera, PhD and Anne Cooper, MA of Ashfield Healthcare Communications (Middletown, CT, USA). Legal entity responsible for the study: GlaxoSmithKline, Waltham, MA, USA.
Funding(s): GlaxoSmithKline, Waltham, MA, USA. Disclosure: B. Pothuri: Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Tesaro; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Clovis Oncology. D. Chase: Speaker Bureau/Expert testimony: Tesaro. F. Heitz: Non-remunerated activity/ies: NewOncology; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Clovis; Advisory/Consultancy: Tesaro; Advisory/Consultancy: PharmaMar. R. Burger: Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Tesaro; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Genentech; Advisory/Consultancy: Gradalis; Advisory/Consultancy: Janssen Research & Development; Advisory/Consultancy: Merck; Advisory/Consultancy: VBL Therapeutics. E. Guerra: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy, Travel/Accommodation/Expenses: GlaxoSmithKline; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Baxter. J. Maenpaa: Honoraria (institution): Tesaro; Honoraria (institution): AstraZeneca; Honoraria (institution): Clovis; Honoraria (institution): Roche; Honoraria (institution): MSD; Honoraria (institution): OrionPharma. E. Bacque: Full/Part-time employment: GlaxoSmithKline. Y. Li: Full/Part-time employment: GlaxoSmithKline. A. Gonzalez Martin: Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Tesaro; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Roche Holding AG; Advisory/Consultancy: Merck & Co. Inc.; Advisory/Consultancy: Genmab; Advisory/Consultancy: Immunogen; Advisory/Consultancy: PharmaMar, S.A; Advisory/Consultancy: Oncoinvent AS. B.J. Monk: Advisory/Consultancy, Research grant/Funding (institution): Tesaro. All other authors have declared no conflicts of interest.
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The COVID-19 pandemic has challenged our ability to provide timely surgical care for our patients. In response, the U.S. Surgeon General, the American College of Srugeons, and other surgical professional societies recommended postponing elective surgical procedures and proceeding cautiously with cancer procedures that may require significant hospital resources and expose vulnerable patients to the virus. These challenges have particularly distressing for women with a gynecologic cancer diagnosis and their providers. Currently, circumstances vary greatly by region and by hospital, depending on COVID-19 prevalence, case mix, hospital type, and available resources. Therefore, COVID-19-related modifications to surgical practice guidelines must be individualized. Special consideration is necessary to evaluate the appropriateness of procedural interventions, recognizing the significant resources and personnel they require. Additionally, the pandemic may occur in waves, with patient demand for surgery ebbing and flowing accordingly. Hospitals, cancer centers and providers must prepare themselves to meet this demand. The purpose of this white paper is to highlight all phases of gynecologic cancer surgical care during the COVID-19 pandemic and to illustrate when it is best to operate, to hestitate, and reintegrate surgery. Triage and prioritization of surgical cases, preoperative COVID-19 testing, peri-operative safety principles, and preparations for the post-COVID-19 peak and surgical reintegration are reviewed.

OBJECTIVES/OBJECTIVE:The COVID-19 pandemic has consumed considerable resources and has impacted the delivery of cancer care. Patients with cancer may have factors which place them at high risk for COVID 19 morbidity or mortality. Highly immunosuppressive chemotherapy regimens and possible exposure to COVID-19 during treatment may put patients at additional risk. The Society of Gynecologic Oncology convened an expert panel to address recommendations for best practices during this crisis to minimize risk to patients from deviations in cancer care and from COVID-19 morbidity. METHODS:An expert panel convened to develop initial consensus guidelines regarding anti-neoplastic therapy during the COVID-19 pandemic with respect to gynecologic cancer care and clinical trials. RESULTS:COVID-19 poses special risks to patients who are older, have medical co-morbidities, and cancer. In addition, this pandemic will likely strain resources, making delivery of cancer care or conduct of clinical trials unpredictable. Recommendations are to limit visits and contact with health care facilities by using telemedicine when appropriate, and choosing regimens which require less frequent visits and which are less immunosuppressive. Deviations will occur in clinical trials as a result of limited resources, and it is important to understand regulatory obligations to trial sponsors as well as to the IRB to ensure that clinical trial and patient safety oversight are maintained. CONCLUSIONS:The ongoing crisis will strain resources needed to deliver cancer care. When alterations to the delivery of care are mandated, efforts should be taken to minimize risks and maximize safety while approximating standard practice.

Gynecologic oncologists have the unique opportunity of caring for patients in a broad range of surgical and medical settings. With increasing awareness of the opioid epidemic and the various factors that contribute to chronic opioid use, gynecologic oncologists must also better understand how to best address acute postoperative pain without unknowingly placing patients at risk for opioid misuse. This article examines the use of opioids in the acute surgical setting and provides clinical guidelines and various strategies to reduce opioid misuse.