Faculty Bibliography

Objectives Minority U.S. populations are underrepresented in oncologic clinical trials. In an urban NCI-designated Comprehensive Cancer Center, we evaluated enrollment in gynecologic cancer trials by race/ethnicity pre and post the June 2020 NCI call-to-action for increased diversity in clinical trials. Methods Enrollment data in 22 therapeutic clinical trials from January 2018-May 2022 was analyzed. Chi-square/Fisher's exact analysis compared proportions of accrued patients by race/ethnicity pre and post the NCI call-to-action. Results Over the study period 205 patients were enrolled in gynecologic cancer trials: 129 (62.9%) ovarian, 52 (25.4%) endometrial, 24 (11.7%) cervical. Overall racial/ethnic distribution of patients in clinical trials was: 112 (54.6%) non-Hispanic White, 33 (16.1%) Hispanic, 32 (15.6%) Black, 28 (13.7%) Asian. Although not statistically significant, accrual of underrepresented populations increased from pre call-to-action (45/108, 41.7%) to post (48/97, 49.5%). Significantly more Black patients were accrued post NCI call-to-action (8/108, 7.4% vs 24/97, 24.7%, p=0.001). However, significantly fewer Asian patients were accrued post NCI call-to-action (21/ 108, 19.4% vs 7/97, 7.2%, p=0.01). Conclusions Overall accrual of Black patients in gynecologic cancer clinical trials increased following the NCI call-to-action, but accrual of Asian patients decreased. Further efforts are needed to ensure all racial/ethnic groups are represented in clinical trials

Objectives Patterns of recurrence on PARP inhibitor maintenance therapy are unclear and may affect treatment choices for subsequent therapy, including secondary cytoreductive surgery (SCS). This analysis of PRIMA/ENGOT-OV26/GOG-3012 evaluated patterns of recurrence on niraparib maintenance therapy. Methods This post hoc subgroup analysis included 314 patients treated with niraparib maintenance monotherapy following first-line chemotherapy and who had no lesions identified by CT/MRI (or by investigator assessment) at baseline. Number and site(s) of initial recurrent lesions at the time of investigator-assessed RECIST-defined progressive disease (PD) were evaluated. Results As of the primary data cut, May 17, 2019, with a median follow-up of 13.8 months (range <1-28), 141/ 314 (45%) patients developed investigator-assessed PD, with an average 1.9 (standard deviation 0.9) lesions at PD. At the time of recurrence, 62 patients (44%) had 1 lesion, 46 (33%) had 2 lesions, 24 (17%) had 3 lesions, and 9 (6%) had 4-5 lesions. The five most common sites with >=1 lesion at PD were the peritoneum (n=45), lymph nodes (n=36), liver (n=34), other (n=26), and pelvis (n=20). Conclusions For patients who received niraparib maintenance monotherapy after first-line chemotherapy and had no lesions at baseline, <50% had recurrent disease after a median 13.8 months of follow-up and >75% of patients with recurrence progressed in 1-2 sites. Prospective evaluation is required to determine whether patients with oligoprogressive disease have improved outcomes with local therapies, like SCS, in addition to systemic therapy

Objectives Perioperative management varies for patients with bleeding disorders. We sought to determine the association between bleeding disorders and perioperative transfusions for hysterectomy patients. Methods We included patients undergoing non-emergent hysterectomy between 2014-2019 from the NSQIP, a validated, risk-adjusted database from 700 hospitals. We compared 30- day perioperative transfusions between patients with and without bleeding disorders (chronic, persistent, active hematologic disorders). Transfusions <=1day were immediate, and after >=2days were delayed. Covariates were age, race/ethnicity, preoperative anemia (hematocrit <=30%) and thrombocytopenia (platelet <100,000/mL), fibroids, endometriosis, cancer, and surgical route. Results Of 290,642 patients, 10,705 (3.7%) received perioperative transfusions (8,679 ,2.9%, immediate; 2,026, 0.7%, delayed). Of 2,687 patients with bleeding disorders, 283 (10.5%) received transfusions, compared to 10,422/287,995 (3.6%) of those without (p<0.001). For gynecologic cancer patients, 17.1% (121/707) with bleeding disorders received transfusions compared to 8.4% (3,261/38,379) of those without (p<0.001). 999 (0.3%) underwent reoperation for bleeding, and this was more likely with bleeding disorders (27/2,687, 1.0% vs. 972/287,955, 0.3%, p<0.001). Anemia (OR 11.7, CI 11.1-12.4) and bleeding disorders (OR 2.0, CI 1.7-2.3) were associated with transfusions when adjusting for age, race/ethnicity, fibroids, endometriosis, cancer, and surgical approach. The effect of bleeding disorders on transfusions persisted in the laparoscopic group (OR 2.5, CI 1.9-3.3). Bleeding disorders were associated with immediate transfusions (OR 1.7, CI 1.5-2.0) and delayed transfusions (OR 2.1, CI 1.6- 2.7). Conclusions Patients with bleeding disorders are twice as likely to receive immediate and delayed transfusions for hysterectomies, even with a laparoscopic approach. Data are needed to optimize bleeding disorders to decrease transfusion risk

Objectives GEN-1, an IL-12 DNA plasmid formulated with a synthetic carrier is being evaluated with neoadjuvant platinumtaxane chemotherapy (NACT) in patients with advanced epithelial ovarian cancer. OVATION 2 is a multi-center, randomized, open-label phase I/II study evaluating the safety, antitumor activity, and immunological response to GEN-1 at a dose of 100 mg/m2 intraperitoneal (IP) actively enrolling at 20 centers in USA and Canada. Methods Up to 130 patients will be randomized 1:1 to receive either NACT plus GEN-1 or NACT alone. The phase I portion will evaluate safety in at least 6 patients administered in 8 weekly infusions starting at cycle 1 week 2 in combination with three 21-day cycles of carboplatin AUC 6 with paclitaxel 175 mg/m2 (PC). Following interval cytoreductive surgery an additional 9 weekly GEN-1 IP infusions starting at cycle 4 week 1 with three 21-day cycles of PC. If no dose limiting toxicities are found, then the study will continue into the phase II portion. To evaluate biological activity a subgroup of patients will have tumor tissue at initial biopsy/laparoscopy collected and at interval cytoreductive surgery. Tissue will be analyzed for the density of CD8, FoxP3, IDO-1, PD-1, and PDL-1 cells. Blood, peritoneal fluid/wash will be collected before and after treatment in a subgroup of patients to quantify for levels of IFN-g. The primary endpoint is PFS. Results Trial in progress: there are no available results at the time of submission. Conclusions Trial in progress: there are no available conclusions at the time of submission

Objectives Prior studies suggest use of genetic testing (GT) varies by race. In gynecologic cancer patients, we assessed frequency of positive tumor next generation sequencing (NGS) results that met ESMO 2019 recommendations for germline GT and determined differences in referral to and completion of germline GT by race/ethnicity. Methods Patients with tumor NGS within a large healthcare system in New York City were retrospectively identified (Sept 2019-Feb 2022). Eligible patients with potentially actionable germline mutations on NGS were identified based on ESMO guidelines (Mandelker et al. 2019). Chi-square/Fisher's exact analysis assessed differences in outcomes by race/ethnicity. Results Of 357 gynecologic cancer patients undergoing tumor NGS, 79 (22.1%) had at least one positive tumor mutation meeting ESMO guidelines for germline GT. The racial/ethnic distribution of eligible patients was: 48 (60.7%) non-Hispanic White, 12 (15.2%) Asian, 8 (10.1%) Hispanic, 7 (8.9%) Black, 4 (5.1%) Other. Non-Hispanic White patients were more likely to be referred to GT than patients of Other race/ ethnicity (93.8% vs 71.0%, p=0.009) as well as more likely to complete GT (81.3% vs 54.8%, p=0.02). Conclusions There are racial disparities in referral to and completion of GT in gynecologic cancer patients whose tumor results met EMSO criteria for germline testing. As outcomes of gynecologic cancer are worse for racial minorities, actions need to be taken to avoid further exacerbating health disparities regarding GT. Development of reflex protocols based on positive somatic mutations identified on tumor NGS or, alternatively, population based germline GT may help reduce disparities related to germline GT in gynecologic cancer patients

Objectives Focusing on gynecologic cancer, we aimed to describe the frequency of positive tumor NGS results that met ESMO 2019 recommendations for germline genetic testing (GT), receipt of germline GT and positive GT results in a large cancer cohort. Methods Patients with tumor NGS within a large, urban healthcare system were retrospectively identified (Sept 2019- Feb 2022). ESMO guidelines were used to identify eligible patients with potentially actionable germline mutations on NGS (Mandelker et al. 2019). Chi-square analysis compared rates in gynecologic and all cancer patients. Results In 3796 patients undergoing tumor NGS, 357 (9.4%) had gynecologic cancers: ovarian, 177 (49.6%); endometrial, 149 (41.7%); cervical/vulvar/vaginal, 31 (8.7%). There were 454/3796 (12.0%) total cancer patients and 79/357 (22.1%) gynecologic cancer patients with at least one positive tumor result meeting ESMO guidelines for germline GT (table 1). Of eligible patients, more gynecologic cancer patients received germline GT than total cancer patients (70.9% vs 35.7%, p<0.05). Among 56 gynecologic cancer patients receiving germline GT, 40 (71.4%) had positive results: BRCA1, 12; BRCA2, 11; MUTYH, 5; BRIP1, 5; RAD51C, 2; and one each CHEK2, SDHA, MLH1, MSH2, MSH6, NF1, PMS2. Conclusions Germline GT rates in gynecologic cancer may be higher than in all cancer patients due to guidelines recommending all ovarian cancer patients get GT and all endometrial cancer patients be screened for Lynch syndrome. Nonetheless, education and reflex protocols to further improve germline GT rates are warranted as almost 30% of gynecologic cancer patients with eligible tumor results based on ESMO criteria still did not receive GT

Objectives With the National Cancer Institute (NCI) call-toaction to increase racial/ethnic diversity in clinical trial enrollment, we sought to evaluate minority patient enrollment in gynecologic cancer clinical trials as compared with disease prevalence estimates by race/ethnicity. Methods Enrollment data from endometrial and ovarian therapeutic clinical trials from January 2018-May 2022 at a NCI-designated Comprehensive Cancer Center in New York City was analyzed. Minority enrollment in ovarian and endometrial cancer trials was compared to SEER estimates of disease prevalence using chi-square analysis. Population estimates of NYC demographics were obtained from the U. S. Census. Results Over the study period, 129 patients were enrolled in ovarian cancer trials and 52 patients in endometrial cancer trials. Regarding total enrollment, the proportion of clinical trial participants identifying as racial/ethnic minorities (34.1%) was significantly higher than the SEER disease estimate of ovarian cancer in minority patients (25.7%, p<0.05). Likewise, total enrollment of minority patients in endometrial cancer trials (61.5%) exceeded their disease prevalence estimate of 28.5% (p<0.05). However, enrollment of Asian patients in endometrial cancer trials (1.9%) remained under disease prevalence estimates (7.7%) despite the NCI call-to-action (table 2). Conclusions In a diverse city population, enrollment of minority patients exceeded disease prevalence estimates for most underrepresented racial/ethnic groups in gynecologic cancer, with the exception of Asian patients in endometrial cancer. Further efforts are needed to increase enrollment of Asian patients in endometrial cancer clinical trials so that novel therapies can be tested in all patients

Objectives We evaluated the feasibility of a facilitated referral pathway for cascade genetic testing (GT) for patients with mutations associated with gynecologic cancers. Methods This is a prospective cohort study of patients with BRCA1, BRCA2, BRIP1, MSH2, MLH1, MSH6, PMS2, EPCAM, RAD51C, and RAD51D mutations from March 2019-March 2022. Eligible patients were offered a facilitated referral pathway for GT for first and second-degree relatives (figure 1). Decision Regret Scale and Impact of Events Scale assessed psychological impact at 3-months. The primary outcome was the proportion of patients with a relative who successfully completed GT. Results Of 583 eligible patients, 73 (13%) enrolled in our study. Reasons for declining participation were: no eligible relatives or previously tested (235, 40%), lost to follow-up (105, 18%), does not want to discuss GT with family (55, 9%), relatives not interested (50, 9%), language (38, 7%), and other (27, 5%). Of 73 enrolled patients, 45 (62%) contacted at least one relative to discuss GT within two months of enrollment. Twelve patients had at least one relative who participated in our facilitated referral pathway, but only 2 (3%) relatives completed GT through our pathway. Two additional relatives underwent GT separately. Of 20 patients who completed 3-month psychological impact questionnaires, 13 (65%) had no regret, and 19 (95%) had none to subclinical range stress. Conclusions Although over 50% of patients contacted family members regarding GT, only 3% had a relative undergo GT via our facilitated referral pathway. Comprehensive novel efforts to simplify access to GT for relatives are desperately needed. (Figure Presented)

Objectives Universal mismatch repair (MMR) immunohistochemistry (IHC) in endometrial cancer began at our institution in July 2015. In April 2017, genetic counselors (GC) obtained IHC data and contacted physicians to approve genetic counseling for Lynch Syndrome (LS) in eligible patients. We assessed if this protocol increased frequency of genetic counseling referrals (GCRs) and genetic testing (GT) in patients with abnormal MMR IHC. Methods We retrospectively (7/2015-6/2021) identified patients with abnormal MMR IHC at a large urban hospital. GCR and GT rates were compared between cases from 7/2015-4/ 2017 (pre-protocol) and 5/2017-6/2021 (post-protocol) with Fisher's exact test. Results Of 717 patients with IHC testing, 156 (21.8%) had abnormal MMR results: MLH1/PMS2, 123; MSH2/MSH6, 10; MSH2/PMS2, 1; MSH6, 13; MLH1, 2; PMS2, 7. MLH1 hypermethylation was identified in 114 (73.1%) patients; 42 (26.9%) patients met criteria for LS screening with GT based on IHC results. Of 42 patients, 16 (38.1%) were identified before and 26 (61.9%) after protocol initiation. GCRs significantly increased from 11/16 (68.8%) to 25/26 (96.2%) in the pre-protocol versus post-protocol groups, p=0.02. There was no statistically significant difference in GT frequency between groups (10/16, 62.5% vs 23/26, 88.5%, p=0.06). Of 33 patients undergoing GT, 16 (48.5%) had LS: MSH6, 9; MSH2, 4; PMS2, 2; MLH1, 1. Conclusions Increased frequency of GCRs was observed following the protocol change, which is important as LS screening has clinical implications for patients and their families. Reflex protocols can maximize identification of patients for germline GT; alternatively universal GT can be considered in endometrial cancer (Levine et al. 2021)

Objectives Progression-free survival (PFS) is a rational surrogate primary endpoint in ovarian cancer (OC) trials. However, PFS is subject to biases, with validity dependent upon proper methodologic assessment. Therefore, blinded independent centralized radiologic review (BICR) is often recommended. We evaluated BICR and investigator-assessed evaluation of progressive disease (PD) in the PRIMA/ ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy in intent-to-treat (ITT) and homologous recombination deficient (HRd) populations. Methods In the randomized, double-blind, placebo-controlled phase 3 PRIMA/ENGOT-ov26/GOG-3012 trial, patients with newly diagnosed stage III/IV OC were assigned to receive either niraparib or placebo. The primary endpoint was PFS (per RECIST v.1.1) by BICR. Discordance between BICR and investigator assessments of PD ([#BICR reviews with unconfirmed PD assessment]/[total# investigator-triggered reviews]) was monitored throughout the study. A training intervention was developed for BICR reviewers based on PD determination in OC. Results In an initial patient subset (n=80), a 39% discordance rate was identified between BICR and investigator-assessed PD by the sponsor, most commonly due to peritoneal carcinomatosis or fluid collections arising from new non-target lesions. After reviewer intervention, final discordance rate between BICR and investigator improved to 12% and 13% for ITT (N=733) and HRd (n=373) populations, respectively (figure 1). Across the entire study population, median PFS and hazard ratios for the ITT and HRd populations were comparable between BICR and investigator (table 1). Conclusions PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize BICR and investigator concordance using early, specialized OC-specific training to maximize trial validity. (Figure Presented)