Faculty Bibliography

OBJECTIVES/OBJECTIVE:Lynch syndrome (LS) accounts for the majority of inherited endometrial cancers (EC), and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. The diagnosis of EC can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates in an ethnically diverse group of high-risk women. METHODS:All women diagnosed with EC between 2011 and 2016 were identified. Risk factors for LS including age, family and personal histories of Lynch-related cancers and loss of tumor mismatch repair (MMR) protein expression were identified from laboratory and medical records. Standard two-sided statistical tests were used. RESULTS:Of 583 women diagnosed with EC, 184 (31.6%) were found to have at least one high-risk characteristic for LS. Among these high-risk women, 58% were given GCR and resulting in only 35% undergoing GT. Ten of the 65 high-risk women who had GT (15.4%) were diagnosed with Lynch syndrome, and all ten met high-risk criteria. Two women of Asian race had tumors exhibiting retained MMR protein expression despite germline testing demonstrating Lynch syndrome. CONCLUSIONS:Many high-risk women do not receive GCR despite a high rate of germline mutations among these women. Improving GCR among high-risk women will lead to more subsequent GT to identify more Lynch syndrome families and prevent additional cancers. Among our ethnically diverse cohort, two women diagnosed with LS had retained MMR protein expression. GCR should be offered to women who possess high-risk characteristics despite normal MMR protein expression.

PURPOSE/OBJECTIVE:To evaluate the outcomes of intraperitoneal chemotherapy (IP) compared with those of intravenous chemotherapy (IV) in patients with advanced ovarian cancer after neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS). METHODS:Patients with advanced epithelial ovarian carcinoma treated with PDS or NACT and IDS from 2006 to 2015 were identified. Comparative statistics were used to evaluate covariates, and survival rates were calculated using the Kaplan-Meier method and compared with log-rank tests. RESULTS:Sixty-six patients received NACT followed by IDS with residual disease of ≤ 1 cm; 42 of these patients (63.6%) received IP therapy; and 24 patients (36.3%) had IV therapy only after IDS. The median progression-free survival (PFS) was 16.0 months in the IP group and 13.5 months in the IV group (p = 0.13). The estimated median overall survival (OS) was 64.0 months with IP and 50.0 months with IV (p = 0.44). During the same study period, 149 patients underwent optimal PDS after which 93 patients (62.4%) received IP and 56 patients (37.6%) were given IV chemotherapy. Patients after IP demonstrated improved survival outcomes when compared to patients after IV therapy. The median PFS was 28.0 months after IP and 16.5 months after IV (p = 0.0006), and the median OS was not reached for IP and 50.0 months after IV (p < 0.0001). CONCLUSIONS:Although IP chemotherapy after PDS is associated with improved survival, IP therapy after NACT and IDS, despite high rates of completion, may not have the same degree of survival advantage over IV therapy.

Purpose: There is limited data regarding how many cycles of chemotherapy are optimal prior to debulking surgery in metastatic ovarian cancer. Furthermore, early identification of non-responders would prompt discontinuation of chemotherapy and earlier surgical management. The purpose of our study was to investigate the performance of FDG PET, dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR as early predictors of treatment response in ovarian cancer. Parametric images of molecular diffusion restriction (D), tissue perfusion (D[asterisk]), vascular volume fraction (F), blood->interstitium constant of transfer (Ktrans), interstitum->plasma constant of transfer (Kep), extravascular/extracellular volume % (Ve) and plasma volume % (Ve) were investigated along with routine measures of SUV and ADC. Materials & Methods: Five subjects with a new diagnosis of epithelial ovarian cancer enrolled in the study. All subjects underwent 3 cycles of standardized chemotherapy followed by cytoreduction (debulking surgery). FDG PET/MR including DCE and IVIM was performed at baseline (T1), after cycle 1 (T2) and after cycle 3 (T3) of chemotherapy. Final responses were categorized at T3 by RECIST 1.1. Olea 3.0 software was used to generate parametric images from the multi-B-value DWI and DCE-MR datasets at all three timepoints. Parametric DICOM images were then coregistered to anatomical datasets using MIMvista and fusion was manually adjusted to optimize co-registration of tumor lesions across the multiple datasets. VOIs were manually drawn on clearly visible solid tumor deposits on PET, DCE-MR and DWI MR images. The parametric images derived from IVIM and DCE-MR at T2 were analyzed as early predictors of final response. Results: Five subjects completed FDG PET and IVIM-MR, three of which underwent DCE-MR. All subjects were partial responders by RECIST at T3. SUV values were only available for 4/5 patients due to technical difficulties and DCE-MR was only available for 3/5. All 5 subjects had good IVIM data. At T2, the SUVmax decreased on average by -39% across all subjects (p<0.001) and the SUVmean decreased on average by -43% across all subjects (p<0.001). At T2, the ADCmean increased on average by +25% across all subjects (p<0.05). At T2, the molecular diffusion restriction (D) increased on average by +43% across all subjects, approaching statistical significance (p=0.058). Furthermore, D[asterisk], F, Kep, Ktrans, and Vp increased in some subjects and decreased in others, without any recognizable pattern. Ve decreased in 3/3 patients, however, not reaching statistical significance. Conclusions: In this current FDG PET/MR study of ovarian cancer, SUVmax and ADCmean values obtained after one cycle of chemotherapy were consistently associated with partial anatomical treatment responses at end of therapy. These findings are in agreement with pre-existing literature studying the value of SUV and ADC in early treatment response assessment. Only one of seven advanced perfusion/diffusion metrics (D; molecular diffusion restriction) was reliably associated with treatment response. This finding that D is associated with treatment response is not surprising given that it is based on ADC without the contribution of intravascular diffusion. Our current small dataset does not yet demonstrate the value of the remaining analyzed advanced DCE-MR and DWI parameters. Further study is required to determine the utility of DCE- and IVIM-derived parameters in early response assessment. Voxelwise correlative studies and other advanced data processing methods are underway to determine if these advanced quantitative parameters may provide further information in the early assessment of chemotherapy treatment response. (Table Presented)

Aims Niraparib (ZEJULATM) is a selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor. The ENGOT-OV16/NOVA trial demonstrated the clinical efficacy of niraparib in patients with recurrent ovarian cancer (OC) who are in complete or partial response (CR or PR) to platinum-based chemotherapy, regardless of their germline BRCA mutation (gBRCAmut) or homologous recombination deficiency (HRD) status. The primary objective of this trial is to measure the efficacy of niraparib maintenance in patients with advanced OC with a CR or PR to front-line platinum-based chemotherapy. Method This multicenter international trial is enrolling =330 patients with ovarian, fallopian tube, or peritoneal cancer. Eligibility criteria includes all patients with stage IV disease, and patients with stage III disease who were treated with neoadjuvant chemotherapy followed by interval debulking surgery, or who have either inoperable disease or visible residual disease after primary debulking surgery. Patients must have had a PR or CR to front-line platinum-based chemotherapy. Stratification factors include neoadjuvant chemotherapy (yes/no), best response to platinum therapy (CR or PR), and HRD status (HRD positive, including the known deleterious BRCA mutations gBRCAmut or somatic BRCAmut, or HRD negative). Patients are randomized 2:1 to receive either oral niraparib (300 mg) or matched placebo once daily in 28-day cycles. Tumors are assessed every 12 weeks per RECIST v1.1. The primary endpoint is progression-free survival, assessed by RECIST criteria and clinical criteria using blinded central review. Secondary endpoints include overall survival, patient-reported outcomes, safety and tolerability, and time to progression on next therapy. Results In progress Conclusion In progress

Aims It's recommended that all women with OC undergo genetic counseling (GC) and consider testing (GT). Universal referral was endorsed by SGO in 2014. However, rates of referral to GC are 15-30%. Since 10/2015, women newly diagnosed at our institution have been offered GC through a facilitated referral pathway (FRP). Our objective is to examine differences in GC and GT since implementation of FRP. Method Patients with new diagnosis of OC were retrospectively evaluated from 2012-9/2015 and prospectively since. Through FRP, patients are contacted by a genetics-navigator to schedule GC and communication between patient, physician and genetic counselor are facilitated. Chi-square and Mann-Whitney tests were used. Results There were 216 women diagnosed with OC who hadn't undergone previous GT identified between 2/2012-10/2016, of which 61 (28%) were in FRP and 154 (72%) weren't. Patients in the FRP were significantly more likely to obtain GC than non-FRP patients, and similarly, GT was obtained more often in the FRP group. There were 10 (21%) patients in the FRP and 21 (23%) in the non-FRP group found to have at least one deleterious mutation (p=0.98). Conclusion Implementation of FRP has resulted in a significant increase in GT, with a rate >80% among women with newly diagnosed OC with similar mutation rates in both groups. Although historically uptake of GT has been low, this study highlights the effectiveness of FRP. The implications of increased GT are profound; targeted therapies are now FDA-approved for BRCA1/2 mutation carriers. GT can result in increased screening/risk-reducing measures and allows for cascade testing

Background: Niraparib (ZEJULATM) is a selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor. In preclinical studies, niraparib concentrated in the tumor vs plasma, delivering >=90% durable PARP 1/2 inhibition and a persistent antitumor effect. In the ENGOT-OV16/NOVA trial, niraparib demonstrated clinical efficacy in patients with recurrent ovarian cancer (OC) following complete response (CR) or partial response (PR) to platinum-based chemotherapy (PBC) regardless of BRCA mutation or homologous recombination deficiency (HRD) status. Trial design: The primary objective of the ongoing ENGOT-OV26/PRIMA trial is efficacy (measured as progression-free survival) of niraparib vs placebo in advanced OC patients with CR or PR following frontline PBC. Secondary objectives include overall survival, patient-reported outcomes (PROs), time to first subsequent therapy, time to progression on the next anticancer therapy, and safety and tolerability of niraparib. Target enrollment is =330 patients with stage III or IV OC with PR or CR after PBC. Eligibility criteria include all patients with stage IV disease and patients with stage III disease who were treated with neoadjuvant chemotherapy followed by interval debulking surgery or who have either inoperable disease or visible residual disease after primary debulking surgery. Patients are stratified based on HRD status (HRD positive, including the known deleterious BRCA mutations gBRCAmut or sBRCAmut/HRD negative), neoadjuvant chemotherapy (yes/no), and best response to PBC (CR/PR). Patients are randomized 2:1 to oral niraparib 300 mg or matched placebo once daily in 28-day cycles. PRO data will be collected

OBJECTIVE: To assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers. METHODS: The Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE). Three subject areas were discussed: care delivery models for genetic testing, barriers to genetic testing, and educational opportunities for providers of genetic testing. RESULTS: The group endorsed current SGO, National Comprehensive Cancer Network (NCCN), and NSGC genetic testing guidelines for women affected with ovarian, tubal, peritoneal cancers, or DNA mismatch repair deficient endometrial cancer. Three main areas of unmet need were identified: timely and universal genetic testing for women with ovarian, fallopian tube, and peritoneal cancers; education regarding minimum standards for genetic counseling and testing; and barriers to implementation of testing of both affected individuals as well as cascade testing of family members. Consensus building among all stakeholders resulted in an action plan to address gaps in education of gynecologic oncology providers and delivery of cancer genetics care.