Faculty Bibliography

BACKGROUND:mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS:In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS:Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS:Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Introduction/Background Niraparib improves progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer after 1st-line (1L) platinum-based chemotherapy (CT). We report the efficacy of niraparib in pts by biomarker status. Methodology This double-blind, placebo (PBO)-controlled, phase 3 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 1L platinum-based CT. Stratification factors were best response to the 1L CT (CR/PR), receipt of neoadjuvant CT (yes/no), and homologous recombination status (deficient/proficient/ not determined). Pts received niraparib or PBO once daily. The primary endpoint of PFS assessed by blinded independent central review was analyzed using a stratified Cox proportional hazards model and hierarchically tested in homologous recombination deficient pts, then the overall population. Results Of 733 randomized pts (niraparib, 487; PBO, 246), 373 (51%) were homologous recombination deficient (niraparib, 247; PBO, 126) and 249 (34%) were homologous recombination proficient (niraparib, 169; PBO, 80). Overall, 35% had stage IV disease, 67% received NACT, and 31% had a PR to 1L CT. Niraparib-treated pts in all the biomarkers groups had a statistically significant and clinically meaningful benefit in PFS (table 1). The most common grade >=3 adverse events were anemia (31%), thrombocytopenia (29%), and neutropenia (13%). Conclusion Niraparib improved PFS as evidenced by reduction in the risk of recurrence or death due to any cause in the overall population of advanced ovarian cancer. No new safety signals were identified

Background: Niraparib has shown progression-free survival (PFS) benefit in recurrent OC after platinum-based chemotherapy (CT) in all patients (pts) regardless of BRCA status. This study evaluated the efficacy of niraparib in pts with newly diagnosed advanced OC after completion of first-line (1L) CT regardless of BRCA status.
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 (CR or PR) to 1L platinum-based CT. Stratification factors were best response to the 1L CT regimen (CR/PR), receipt of neoadjuvant CT (NACT; yes/no), and homologous recombination deficiency (HRD) status (positive/negative/unknown) per the Myriad myChoice HRD test. Pts received niraparib or PBO once daily. PFS assessed by blinded independent central review was the primary end point, analyzed using a stratified Cox proportional hazards model and hierarchically tested in HRD-positive (HRDpos) pts and then the overall population.
Result(s): Of 733 randomized pts (niraparib, 487; PBO, 246), 373 (51%) were HRDpos (niraparib, 247; PBO, 126). Overall, 35% had stage IV disease, 67% received NACT, and 31% had a PR to 1L CT. Niraparib-treated pts in the HRDpos subgroup and overall population had a significant reduction in the risk of disease recurrence or death with a substantial improvement in PFS (Table). All subgroups showed a sustained and durable treatment effect. The most common grade >=3 adverse events were anemia (31%), thrombocytopenia (29%), and neutropenia (13%). No treatment-related deaths occurred.
Conclusion(s): Niraparib significantly improved PFS in pts with newly diagnosed advanced OC, including pts at high risk of progressive disease in the HRDpos subgroup and overall population. No new safety signals were identified. Niraparib should be considered as a treatment option for pts with advanced OC after completion of 1L CT. (Table Presented)

Objectives To describe the practice patterns and treatment of nonagenarians who initiated care with a gynecologic oncologist. Methods Retrospective chart review of women aged 90 or older who presented to a gynecologic oncologist between 10/09 and 12/18 at an urban academic medical center. Descriptive statistics utilized for variables of interest. Results We identified 34 nonagenarians (median age 92, range 90-98): 10 (29%) had benign disease, 8 (24%) pre-malignancy or suspected malignancy, and 16 (47%) malignancy. Of these, 79% had age and/or functional status discussed in the care plan. Of the 8 with suspected malignancy, 5 declined further workup. The cancer distribution revealed 5 (31%) vulvar, 5 (31%) uterine, 4 (25%) ovarian, 1 (6%) vaginal and 1 (6%) cervical cancers. Combined, 37% had stage I disease; 6% stage 3; 6% stage 4; 13% recurrent; and 25% unstaged. All received treatment plans: 7 (47%) with palliative intent and 8 (53%) with curative intent. In the curative group, 7 underwent surgery (1 adjuvant chemotherapy) and 1 chemotherapy/radiation. In the palliative group, 4 underwent radiation, 1 chemotherapy and 2 declined/unknown. Overall, 13 (87%) completed the proposed treatment. Treatment-related complications included 1 superficial skin infection and 1 thirty-day readmission. Conclusions Nonagenarians often presented with vulvar or endometrial cancer and 87% successfully completed treatment with minimal adverse effects or toxicity. Age and/or functional status were considered in the care plan for 79% of women, but it did not preclude treatments that had the potential to preserve meaningful quality of life and/or cure patients of their disease

Objectives To identify referral patterns and uptake of risk reducing surgery (RRS) in patients with non-BRCA genes associated with an increased risk of epithelial ovarian cancer. Methods A chart review of patients with mutations in MLH1, MSH2, EPCAM, MSH6, PMS2, RAD51C/D, BRIP1 was conducted from 2015-2018. Patients with BRCA1/2 and variants of uncertain significance were excluded; MSH6 and PMS2 were included (though recent change to insufficient evidence). Primary outcomes of interest were referral to a gynecologic oncologist and the uptake of RRS. Results Of 78 patients, 18 had undergone surgical management for treatment of cancer prior to genetic testing and were excluded. The majority of the patients (41 of 60, 68%) with non-BRCA actionable mutations were associated with Lynch Syndrome (LS). Of these patients, 23 of 60 (56%) were seen by gynecologic oncologists. Twenty of 41 (49%) underwent RRS. Excluding the MSH6 and PMS2 patients, 9 of 21 (43%) of patients with LS underwent RRS. Among patients with the non-BRCA and non-LS associated genes (RAD51C, RAD51D, BRIP1) the most common reason for testing was family history of cancer (10 of 19). Fifteen of 19 were referred to a gynecologic oncologist; all patients with BRIP1 mutation were referred, while 70% of those with RAD51/D were referred. Among this subset of patients, 9/19 (47%) patients underwent RRS; the remaining patients were screened with surveillance ultrasounds and/or CA-125. Conclusions Two-thirds of patients with non-BRCA genes associated with increased risk of ovarian cancer were referred to gynecologic oncologists, with a 48% of uptake or RRS

Objectives Platinum and taxane-based therapy is considered standard for patients with newly diagnosed advanced/recurrent EC. We sought to compare post-platinum treatment outcomes between published and real-world sources. Methods We searched PubMed (10 years) and Embase conference proceedings (3 years) for median OS (mOS), PFS (mPFS), ORR, and grade 3/4 adverse events (AEs) in advanced/recurrent EC, and compared to IBM Market-Scan real-world US claims data (1/2014-11/2018). For MarketScan, post-platinum therapy initiation (Index) represents the date of first EC drug claim after the end of platinum. Results Data were extracted from 28 studies, including 4 controlled studies (3 randomized). Across studies, mOS was 9.6 mo (range 5.5-14.5 mo) and mPFS 2.8 mo (1.4-7.4 mo). Among the 5 studies with highest ORR, mPFS was 3.4 mo (3.0-7.4 mo). Most commonly reported grade 3/4 AEs were diarrhea (in 9/28 studies=32%), fatigue (8/28=29%), and anemia (7/28=25%). 1,576 patients met the real-world inclusion criteria. Median follow-up was 9.3 mo post-Index, and median 29.6 mo pre-Index coverage. 76% of patients received initial platinum-taxane therapy, most commonly carboplatin-paclitaxel (63%). Post-Index, 48% of patients received monotherapy: 19% hormonal therapy, 9% liposomal doxorubicin, 5% bevacizumab, 3% taxane; 2% any other monotherapy. Besides carboplatin-paclitaxel (13%), 4% received any other combination regimen. Median duration of post-platinum treatment was 3.5 mo across regimens. Conclusions Although chemotherapy and hormonal therapy are used for EC post-platinum, efficacy is lacking among reported studies and real-world data, and no uniform standard of care exists. More effective and tolerable therapies are needed for advanced/recurrent EC

OBJECTIVES/OBJECTIVE:Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a treatment strategy for ovarian cancer patients with unresectable disease or poor performance status (PS). This strategy has been used in the treatment of advanced endometrial cancer and a survival benefit has been shown in patients who are subsequently able to undergo interval cytoreduction. This study sought to review our single institution experience with NACT for advanced endometrial cancer. METHODS:We conducted a retrospective review of all patients who received NACT for advanced endometrial cancer at two institutions in New York City between 2002 and 2016. RESULTS:We identified 39 patients (median age 61, range 35-89). The histologic subtype distribution was: serous (44%), endometrioid (28%), carcinosarcoma (10%), clear cell (8%), mixed (8%), neuroendocrine (3%). Contraindications to primary surgery included: unresectable disease (72%), poor PS (15%), unresectable disease and poor PS (13%). Twenty-three patients (59%) did not undergo IDS due to: progression of disease (70%), medical ineligibility (4%), unresectable disease (17%), lost to follow-up (4%), death (4%). Sixteen patients (41%) underwent IDS, 81% had an optimal cytoreduction. Disease status at NACT completion was: partial response (56%), stable disease (3%) and progression of disease (41%). There were no complete responses. Patients who responded to NACT had a significantly longer overall survival than those who did not (15 vs. 5 months. P = 0.015). IDS was also associated with an improvement in overall survival versus no surgery (16 vs. 6 months, P = 0.04). CONCLUSIONS:Unlike ovarian cancer, less than half of the patients undergoing NACT for endometrial cancer underwent IDS, none had a complete response, and 41% had disease progression during NACT. However, endometrial cancer patients who underwent IDS had a high rate of optimal cytoreduction. Both response to NACT and IDS were associated with improved survival.

Objective: To explore the feasibility of molecular tumor characterization in metastatic endometrial cancers (EC) to direct therapy using clinically actionable targets.
Method(s): In December 2017, our program prospectively instituted the Molecular Driven Endometrial Cancer Therapy (MODEL) paradigm to treat metastatic EC patients with selection of therapy based on molecular tumor characterization (in-house immunohistochemistry, IHC, or next-generation sequencing, NGS, FoundationOne) at the discretion of the treating physician. Therapies and reported predictive IHC and genomic alterations (GA) biomarkers included bevacizumab (B-catenin, CTNNB1), trastuzumab (ERBB2), temsirolimus (TSC), immunotherapy (MSI, dMMR, and Tumor Mutation Burden, TMB), and hormone therapy (estrogen, ER) and progesterone receptor (PR) for advanced disease (MODEL1). PI3K/AKT/mTOR pathway and ERBB3GA were also included for recurrent disease (MODEL2). A retrospective review of Foundation Medicine (FMD) and our institutional Endometrial Cancer Databases (IECD) was performed.
Result(s): Of 3,702 advanced EC in FMD (922 endometroid, 826 serous, 156 clear cell, and 40 mixed, 1,758 EC-NOS), 1,497 (40.4%) had at least one MODEL1 qualifying GA: ERBB2 (370, 10.0%); CTNNB1 mutation (660, 17.8%); TSC2 mutation (43, 1.2%); MSI-H (534, 14.4%), or MSS/TMB >20 (93, 2.5%). A total of 2,994 (80.9%) EC had MODEL2 qualifying GA: 2,836 (76.6%) had PI3K/AKT/mTOR and 115 (3.1%) ERBB3 GA. For MODEL1, 247 (6.7%) and for MODEL2 1,340 (36.2%) EC had alterations qualifying for more than 1 therapy arm (Table 1). Institutional results were similar with 33.8% (22/65) and 78.5% (51/65) having least one clinically actionable targets for MODEL1 and MODEL2, respectively. Twenty-two of twenty-three IECD patients were eligible and had tumor testing; 63.6% had at least one clinically actionable target; 40.9% (9/22) had ER/PR+ tumors (median ER 80%, range 20%-100%; median PR 40%, 10%-96%). The most common GA were in the PI3K/AKT/mTOR pathways (6/10, 60%). Seventeen percent have received biomarker-directed therapy. Tumor response and survival outcomes are being evaluated.
Conclusion(s): Treatment with clinically actionable genomically targeted drugs is feasible in metastatic endometrial cancer. Overlapping genomic alterations are common, and therapeutic prioritization is needed. [Figure presented]
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Objective: Lynch syndrome (LS) accounts for 3%-5% of endometrial cancers. Screening high-risk (HR) patients with endometrial cancer (EC) for LS can result in prevention of other cancers and cascade testing for family members. We implemented universal mismatch repair (MMR) immunohistochemistry (IHC) in patients undergoing hysterectomy for EC in July 2015. In April 2017, we implemented the practice of genetic counselors (GC) accessing IHC data from pathology reports and contacting physicians to approve genetic counseling for patients with a loss of MMR protein expression. By involving genetic counselors, we sought to increase rates of genetic counseling referrals (GCRs) and genetic testing (GT) in EC patients with abnormal MMR IHC.
Method(s): All women diagnosed with EC who underwent hysterectomy between July 2015 and July 2018 at a single institution were retrospectively identified. Demographic data, IHC results, rates of GCR, and GT rates were abstracted before and after implementation of GC involvement in MMR IHC review and GCR.
Result(s): Of 356 patients with EC who underwent hysterectomy, 321 (90%) had MMR IHC testing. Abnormal MMR IHC was found in 86 (27%) patients with the following distribution: MLH1 and PMS2, 68; MLH1, 2; PMS2, 3; MSH6, 8; and MSH2 and MSH6, 5. In 63 (73%) of the 86 patients, MLH1 promoter methylation was identified as the cause of the abnormal MMR IHC. Of the remaining 23 patients with abnormal MMR IHC, 18 (78%) received GCR, and 16 (70%) had GT. Comparing the time frame from July 2015 to April 2017 (prior to GC involvement) to April 2017 to July 2018 (after GC involvement), there was an increase in GCR from 10/15 (67.7%) to 8/8 (100%). GT rates for the MMR abnormal cohort were 8/15 (53%) compared to 8/8 (100%), respectively. Of the 16 patients with an abnormal MMR IHC result who underwent GT for LS, 9 (56%) were identified to have LS, 7 with MSH6 mutations and 2 with MSH2 mutations. See Table 1.
Conclusion(s): GC access to abnormal MMR IHC results in EC patients' improved rates of GCRs and GT to capture all patients with LS. GC involvement in the review of IHC results and GCR is a feasible and effective strategy to ensure both GCR and GT. Proper follow-up and GT of at-risk patients is critical to increase screening and prevention of other LS-related cancers in the proband, as well as for cascade testing of family members. [Figure presented]
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