Faculty Bibliography

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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Objective: Surplus postoperative opiate pills can lead to misuse and dependence for patients and household contacts. We aimed to omit or reduce opiate prescriptions after gynecologic surgery with a prospective quality improvement initiative.
Method(s): Patients undergoing scheduled surgery by a gynecologic oncologist at an academic hospital were included. Procedures performed vaginally were excluded. Patients received preoperative counseling, including setting expectations and pain management strategies. Preoperative gabapentin and acetaminophen and postoperative acetaminophen, ibuprofen, and gabapentin were prescribed. Ambulatory patients were not prescribed opiates, and minimally invasive (MIS) 23-hour observation patients were prescribed only 4 pills of oxycodone if they used >5 opiate doses prior to discharge. Laparotomy patients were provided oxycodone opiate prescriptions according to their usage 24 hours prior to discharge: no opiate prescriptions if 0-1 dose used, 4 pills if 2-5 doses used, and 12 pills if >5 doses used. Baseline characteristics, postoperative opiate prescriptions, opiate refills, and pain scores were collected 60 days pre- and post-intervention. Pre- and post-intervention variables were compared using t tests, Wilcoxon rank sum tests, Pearson X², and Fischer exact tests.
Result(s): A total of 193 procedures (103 pre- and 90 post-intervention) were analyzed. The mean number of opiate pills prescribed decreased from 5.63 to 1.96 (P < 0.001); mean oral morphine equivalent decreased from 29 to 12 (P < 0.001), and the percentage of patients sent home with an opiate prescription was reduced from 69% to 23% (P < 0.001). MIS hysterectomy patients who received an opiate prescription decreased from 81% to 18% (P < 0.001), and laparotomy patients who received an opiate prescription decreased from 64% to 50% (P = 0.400). There was no significant change in postoperative opiate prescription refills (6% vs 11%, P = 0.184) or postoperative pain calls (9% to 14%, P = 0.137). Ninety-five percent of patients agreed to the statement "my pain was well controlled after surgery" at their postoperative visit. See Table 1.
Conclusion(s): Opiate prescriptions were significantly reduced or omitted with excellent patient satisfaction and without increasing refills. More than 80% of MIS hysterectomy and 50% of laparotomy patients were discharged without an opiate prescription. Curtailing or omitting opiate prescriptions is a very important step in reducing the opioid epidemic by surgeons.
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Objective: We aimed to explore the disparities associated with the delay of initiating chemoradiation therapy (CRT) and brachytherapy (BT) beyond the recommended 8 weeks for patients with cervical cancer and the effect on outcomes.
Method(s): Patients with FIGO stage IB2-IVA cervical cancer treated at an academic medical center and an urban public hospital by the same team of gynecologic and radiation oncologists with definitive CRT and BT from July 2009 to September 2017 were included. Patients received CRT followed by BT (7 Gy x 4 fractions) delivered via 2 insertions 1 week apart with image-guided CT/MR delineation. Patients who initiated CRT within 8 weeks from diagnosis as recommended (rCRT) were compared across demographic and cancer outcomes to patients who received delayed CRT after 8 weeks (dCRT). Disease-free survival (DFS) and overall survival (OS) were analyzed using adjusted Cox regression analysis (P < 0.05).
Result(s): In our cohort of 97 patients, 72 (75.0%) had rCRT and 24 (25.0%) had dCRT. At a median follow-up of 31.5 months, overall local control was achieved in 94.8% of patients. Patients with dCRT were more likely to be African-American (37.5% vs 17.8%, P = 0.046) and be uninsured or on Medicaid (87.5% vs 61.6%, P = 0.023). There were no differences in stage and grade. Patients with dCRT were more likely to recur or progress (OR = 2.65, 95% CI 1.02-6.86). Of those who recurred, 35.0% of rCRT patients had locoregional recurrence versus 66.7% of dCRT patients (P = 0.144). When controlling for age, race, insurance, referring hospital, and stage, patients with dCRT had lower DFS than patients with rCRT (50.6 vs 63.2 months, aHR = 6.11, 95% CI 2.00-18.62). However, there were no differences in OS.
Conclusion(s): Patients receiving delayed CRT tended to have worse recurrence and DFS than those initiating CRT by 8 weeks from diagnosis. African-American and uninsured patients were more likely to experience a delay in care. Navigator and social work services may help improve access to treatments for these patients.
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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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OBJECTIVE:Elevated inflammatory markers are predictive of COVID-19 infection severity and mortality. It is unclear if these markers are associated with severe infection in patients with cancer due to underlying tumor related inflammation. We sought to further understand the inflammatory response related to COVID-19 infection in patients with gynecologic cancer. METHODS:Patients with a history of gynecologic cancer hospitalized for COVID-19 infection with available laboratory data were identified. Admission laboratory values and clinical outcomes were abstracted from electronic medical records. Severe infection was defined as infection requiring ICU admission, mechanical ventilation, or resulting in death. RESULTS:86 patients with gynecologic cancer were hospitalized with COVID-19 infection with a median age of 68.5 years (interquartile range (IQR), 59.0-74.8). Of the 86 patients, 29 (33.7%) patients required ICU admission and 25 (29.1%) patients died of COVID-19 complications. Fifty (58.1%) patients had active cancer and 36 (41.9%) were in remission. Patients with severe infection had significantly higher ferritin (median 1163.0 vs 624.0 ng/mL, p < 0.01), procalcitonin (median 0.8 vs 0.2 ng/mL, p < 0.01), and C-reactive protein (median 142.0 vs 62.3 mg/L, p = 0.02) levels compared to those with moderate infection. White blood cell count, lactate, and creatinine were also associated with severe infection. D-dimer levels were not significantly associated with severe infection (p = 0.20). CONCLUSIONS:The inflammatory markers ferritin, procalcitonin, and CRP were associated with COVID-19 severity in gynecologic cancer patients and may be used as prognostic markers at the time of admission.

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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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.

PARP inhibitors (PARPi) have shown have activity in the treatment of ovarian cancer. Previous studies documented activity in patients with germline (gBRCA) and tumor (tBRCA) BRCA mutations (BRCAm) for treatment in lieu of chemotherapy as well as in recurrent ovarian cancer as maintenance therapy. The recent data from four randomized phase 3 trials have established an important role for frontline PARPi maintenance therapy in ovarian cancer. While SOLO-1 only included BRCAm patients, PRIMA, VELIA, and PAOLA-1 enrolled broader patient populations. The magnitude of benefit of PARPi in these studies was consistently greatest in the BRCAm patients (germline or tumor). PARPi treatment also improved PFS in the HRD cohort but to a lesser degree than in patients with BRCAm. In secondary analyses, the overall impact of PARPi treatment in HR proficient patients, which comprise about 50% of ovarian cancers, was more limited than in the other subgroups. Data for overall survival, also a secondary endpoint, is currently immature for these four trials. Fatigue, hematologic, and GI toxicities are the most commonly noted adverse events with PARPi therapy. The recent FDA approvals of PARPi in the maintenance setting will enable clinicians to incorporate these into frontline armamentarium of ovarian cancer treatment.