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Low-grade serous ovarian cancer (LGSOC) is a rare form of epithelial ovarian cancer that generally exhibits a protracted course and is less sensitive to chemotherapy than high-grade serous ovarian cancer. Over the past decade, it has become clear that patients with LGSOC have a clinically distinct course and are molecularly and histologically unique from patients with high-grade serous ovarian cancer.Endocrine therapy is frequently used for the treatment of patients with recurrent LGSOC and is now also part of the standard upfront treatment of this disease, with an ongoing phase III clinical trial seeking to determine if chemotherapy can be eliminated altogether from the initial treatment of LGSOC. Tumors are frequently found to exhibit alterations affecting the mitogen-activated protein kinase (MAPK) pathway, recently leading to developments in the use of targeted treatments for those patients with recurrent disease. LGSOC is a clinically, histologically, and molecularly unique form of epithelial ovarian cancer. Recent advances in the understanding of endocrine and molecular drivers of this disease have led to changes in both the treatment of newly diagnosed and recurrent disease, with ongoing studies focused on refining upfront therapy and seeking novel targeted combinations for those patients with recurrent disease.

Supplementary Data from MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma

Purpose:To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC).Experimental Design:Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected.Results:Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation.Conclusions:This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.See related commentary by Veneziani and Oza, p. 4357

Progression-free survival and hazard ratios by histology

Table S1. Plasma pharmacokinetic sampling times Table S2. Identified Alterations, Listed by Patient Table S3. Adverse events reported in {greater than or equal to}10% of patients (safety cohort) Table S4. Grade 3 to 5 adverse events reported in >1 patient (safety cohort) Table S5. Evaluation of Best Overall Response in Patients with Initial Measurable Disease and Evaluable by CA-125 Figure S1. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 7, 8, and 15: semi-logarithmic scale (pharmacokinetic set [30 mg BID binimetinib continuous]) Figure S2. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 7, 8, and 15: semi-logarithmic scale (pharmacokinetic set [45 mg BID binimetinib continuous]) Figure S3. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 1, 8, and 15: semi-logarithmic scale (pharmacokinetic set [45 mg BID binimetinib intermittent]) Figure S4. Representative CT Resolution of Implant in a Complete Responder

Purpose:Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials.Experimental Design:We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center.Results:Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit.Conclusions:Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.

Additional clinical information for patients in MSKCC cohort

Supplementary Table and Figure Legends

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. MEK inhibition targets tumors harboring MAPK pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC.Patients and Methods: Patients received intravenous weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing.Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice-a-day continuous or 45-mg twice-a-day intermittent binimetinib dose was deemed the recommended phase II dose (RP2D) in combination with 80 mg/m2 i.v. weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%—one complete (CR) and four partial responses (PR)—among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg twice-a-day continuous cohort and lowest in the 45-mg twice-a-day intermittent cohort. All four evaluable patients with MAPK pathway–altered tumors experienced clinical benefit.Conclusions: The combination of binimetinib and intravenous weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg twice a day as a continuous or 45 mg twice a day as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway. Clin Cancer Res; 24(22); 5525–33. ©2018 AACR.

Purpose: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). Experimental Design: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. Results: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. Conclusions: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357

Pathogenic germline variants underlie up to 20% of ovarian cancer (OC) and are associated with varying degrees of risk for OC. For mutations in high-penetrance genes such as BRCA1/ 2, the role of risk-reducing bilateral salpingo-oophorectomy (RRSO) in cancer prevention is well-established and improves mortality. However, in moderate-penetrance genes where the degree of risk for OC is less precisely defined, the role of RRSO is more controversial. Although national guidelines have evolved to incorporate gene-specific recommendations, studies demonstrate significant variations in practice. Given this, our multidisciplinary group has reviewed the available literature on risk estimates for genes associated with OC, incorporated levels of evidence, and set thresholds for consideration of RRSO. We found that the benefit of RRSO is well-established for pathogenic variants in BRCA1/2 as well as BRIP1 and RAD51C/ D where the risk of OC is elevated beyond our threshold for RRSO. In PALB2, RRSO is particularly controversial as newer studies consistently demonstrate an increased risk of OC that is dependent on family history, making uniform recommendations challenging. Additionally, new guidelines for Lynch syndrome provide gene-specific risks, questioning the role of RRSO, and even hysterectomy, for MSH6 and PMS2 mutation carriers. Given these uncertainties, shared decision making should be used around RRSO with discussion of individual risk factors, family history, and adverse effects of surgery and premature menopause. Herein, we provide a clinical guide and counseling points.

PURPOSE Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAFV600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors. METHODS Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600E oncoprotein expression was assessed by immunohistochemistry on selected cases. RESULTS BRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAFV600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit. CONCLUSION Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

We investigated the feasibility, safety, and survival outcomes of intrathoracic cytoreduction during primary debulking surgery (PDS) for advanced ovarian cancer.We conducted a database review of patients with stage IIIB-IV ovarian (including fallopian tube and primary peritoneal) carcinoma who underwent PDS at our institution from 01/01/2006-9/30/2021. Patients who underwent intrathoracic cytoreduction as part of primary treatment were included. Patients who received neoadjuvant chemotherapy or surgery for reasons other than cytoreduction were excluded.Among 178 patients identified for inclusion, complete gross resection (CGR) in the abdomen and thorax was achieved in 131 (74%); 45 (25%) had optimal cytoreduction, and 2 (1%) had suboptimal cytoreduction. Thirty-one patients (17%) had at least one grade ≥ 3 complication; 8 were possibly related to intrathoracic cytoreduction. There were no deaths within 30 days following surgery. Median length of follow-up among survivors was 53.4 months. Among all patients, the median PFS was 33.6 months (95% CI: 24.7-61.9) and the 3-year PFS rate was 48.9% (95% CI: 41.2%-56.2%). Median OS was 81.3 months (95% CI: 68.9-103). When stratified by residual disease status, median PFS was 51.8 months when CGR was achieved versus 16.7 months with residual disease (HR: 2.17; P.001) and median OS was 97.6 months when CGR was achieved versus 65.9 months with residual disease (HR: 2.05; P = .003).Intrathoracic cytoreduction during PDS for advanced ovarian cancer is both safe and feasible. CGR can be achieved in patients with intrathoracic disease if properly selected, and could significantly improve both PFS and OS.

ObjectiveWe sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery.MethodsWe retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan–Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression.ResultsOf 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (pConclusionsIn patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

We assessed a conditional probability of survival (CPS) model to determine the probability of living 10 years after ovarian cancer diagnosis after having already survived 5 years.We identified patients newly diagnosed with high-grade epithelial ovarian cancer from 1/1/2001-12/31/2009 and treated at our institution. Patients with3 years follow-up were excluded. CPS was defined as the probability of surviving additional years (y) based on the condition a patient had already survived a given time (x): S(x + y)/S(x). Confidence intervals were estimated using a variation of Greenwood's formula.Of 916 patients meeting inclusion criteria, 473 (52%) were diagnosed from 2001 to 2005 and 443 (48%) from 2006 to 2009. Median age at diagnosis was 60 years (range, 25-95). The conventional 10-year OS rate for all patients was 29% (95% CI: 26%-32%)-75% (95% CI: 68%-82%) for stage I/II disease, 22% (95% CI: 19%-26%) for stage III, and 6.9% (95% CI: 3.9%-12%) for stage IV. For patients65 years, the 10-year CPS for 5-year survivors was 65% (95% CI: 59%-70%); for those ≥65 years, it was 48% (95% CI: 38%-57%). For patients65 years, the 10-year CPS for 5-year survivors by stage was: stage I/II, 89% (95% CI: 81%-94%); stage III, 58% (95% CI: 50%-66%); and stage IV, 26% (95% CI: 12%-42%). For patients ≥65 years, rates by stage were 78% (95% CI: 53%-91%), 42% (95% CI: 30%-53%), and 29% (95% CI: 7%-56%), respectively.For long-term survivors with high-grade epithelial ovarian cancer, CPS provides better prediction of survival than conventional methods.

Selective glucocorticoid receptor (GR) modulators (SGRMs) represent a clinically validated mechanism of enhancing chemosensitivity and ameliorating the sequelae of hypercortisolism. While GRs reportedly control the expression of up to 20% of the human genome, specific targets of systemic GR antagonism in humans have yet to be identified. To address this question, we established a robust NanoString assay to measure candidate GR target genes in human blood and assessed them before and after therapy with the oral SGRM relacorilant, which selectively antagonizes the GR. In a randomized, controlled phase 2 study in patients with recurrent, platinum-resistant ovarian cancer (NCT03776812), gene changes were assessed in 139 patients after treatment with relacorilant + nab-paclitaxel (NP) or NP alone. Using cross-validated random forest methods, a gene panel that accurately identified patients who had received relacorilant was established (ROC AUC 0.945 +/- 0.038). In 13 patients who crossed over from NP alone to relacorilant + NP, the genes in the panel were modified only after crossover (paired t-test P=0.0003), validating the gene panel’s ability to detect GR activity. The 4 most induced (LILRB4, FPR3, CLEC10A, CCR2) and 4 most suppressed (CDKN1C, TNFRSF17, BRIP1, PDK1) genes by relacorilant + NP vs. NP alone were selected and shown to be reliable indicators of GR activity across clinical studies in patients with pancreatic, prostate, and other solid tumors (NCT04329949, NCT03674814, NCT02762981), independent of concomitant medications or other confounders. CLEC10A (C-type lectin domain containing 10A) was identified as a particularly sensitive marker of GR activity as its expression was strongly suppressed by the GR agonist prednisone in healthy volunteers (paired t-test P Citation Format: Nicoletta Colombo, Toon Van Gorp, Ursula A. Matulonis, Ana Oaknin, Rachel N. Grisham, Diane Provencher, Gini F. Fleming, Alexander B. Olawaiye, Erkut H. Borazanci, Russell Z. Szmulewitz, Subhagya A. Wadekar, Grace Mann, Hazel J. Hunt, Andrew E. Greenstein, Domenica Lorusso. Selective glucocorticoid receptor modulation reveals a new role for CLEC10A in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3434.

PURPOSE Homologous DNA repair–deficient (HRD) ovarian cancers (OCs), including those with BRCA1/2 mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair–proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between BRCA1/2 mutations, HRD, and other genomic parameters and response to ICIs and survival in OC. METHODS This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. BRCA1/2 mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of BRCA1/2 status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models. RESULTS Of the 143 women treated with ICIs, 134 had known BRCA1/2 mutation status. Deleterious germline or somatic BRCA1/2 mutations were present in 31 women (24%). There was no association between presence of BRCA1/2 mutations and response ( P = .796) or survival. Genomic analysis in 73 women found no association between TMB ( P = .344) or HRD ( P = .222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS ( P = .014) and OS ( P = .01). CONCLUSION TMB, BRCA1/2 mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC.

Objective We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. Methods Treatment included: (Cycles 1–6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2–8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7–22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. Results Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47–73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). Conclusions The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.

Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

Objectives We sought to determine the safety and efficacy of the oral androgen receptor antagonist enzalutamide in patients with previously treated, recurrent, AR-positive (AR+) ovarian cancer. Methods This was a single-institution phase II study of patients with AR+ ovarian cancer with measurable disease with 1–3 prior lines of chemotherapy; patients were screened for enrollment from 11/2013–7/2018. Following consent, archival tissue was evaluated for AR+. Enrolled patients received daily enzalutamide 160 mg until progression of disease or treatment discontinuation. Adverse events were graded by CTCAE v4.0. Co-primary endpoints were 6-month progression-free survival (PFS6) and overall response rate (ORR) by RECIST 1.1 criteria. Results During the study period, 160 patients were screened and 59 (45 high-grade serous [HGS] and 14 low-grade serous [LGS]) consented to treatment on study. There was 1 confirmed and 1 unconfirmed partial response. The ORR was 1.7% (90% CI: 0.2–100%). The overall PFS6 rate (as binary) was 22% (90% CI: 15.1–100%). The 6-month PFS rate (as time to event) was 19.8% for HGS patients (90% CI: 12.7–100%) and 38.5% (90% CI: 21.7%–100%) for LGS patients. Grade 3 toxicities occurred in 6 patients (one toxicity (Grade 3 rash) was considered a dose-limiting toxicity). One patient died of cardiac arrest after 42 days on treatment of a cardiac arrest not attributed to study drug. Conclusions The study met its primary endpoint, with a PFS6 rate of 22% (n = 13); however, the overall response rate was low. Enzalutamide was well tolerated and may be a potential treatment option in select patients.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, intratumoral heterogeneity and intraperitoneal spread. We investigated determinants of immune recognition and evasion in HGSOC to elucidate co- evolutionary processes underlying malignant progression and tumor immunity. Mutational processes and anatomic sites of tumor foci were key determinants of tumor microenvironment cellular phenotypes, inferred from whole genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive HGSOC patients. Homologous recombination-deficient (HRD)-Dup (BRCA1 mutant-like) and HRD- Del (BRCA2 mutant-like) tumors harbored increased neoantigen burden, inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly- differentiated dysfunctional CD8+ T cells. Foldback inversion (FBI, non-HRD) tumors exhibited elevated TGFβ signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Our findings implicate distinct immune resistance mechanisms across HGSOC subtypes which can inform future immunotherapeutic strategies.HIGHLIGHTSMulti-region, multi-modal profiling of malignant and immune cell phenotypes in ovarian cancerAnatomic site specificity is a determinant of cancer cell and intratumoral immune phenotypesTumor mutational processes impact mechanisms of immune control and immune evasionSpatial topology of HR-deficient tumors is defined by immune interactions absent from immune inert HR-proficient subtypes

Women with endometrial cancer (EC) frequently receive adjuvant paclitaxel and carboplatin (PC) chemotherapy. There is no standard first line chemotherapy at disease recurrence. Data extrapolated from ovarian cancer has suggested that patients with recurrent EC may benefit from further platinum-based chemotherapy. We performed a retrospective analysis of patients who were retreated with PC chemotherapy for recurrent EC at Memorial Sloan Kettering Cancer Center between January 2000 and December 2014. The median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Twenty patients were included in the analysis. Patients were re-treated with PC a median of 25 (8–79) months from their original PC. There were no complete responses, 10 (50%) patients had partial response (PR), 3 (15%) had stable disease, 2 (10%) had progression at best response and 5 (20%) were not evaluable by RECIST. A median of 6 cycles of PC were administered (2–9). Four patients (20%) transitioned to paclitaxel only due to carboplatin allergy. At the data cut off, one patient continued PC, and another was off therapy with PR. The remainder (N = 18, 90%) received a median of 2.5 (1–6) further lines of treatments. Median PFS and OS from re-treatment were 10 and 27 months respectively. Median OS from original diagnosis was 74 months. In this small retrospective study, selected patients with recurrent EC who are >6 months from completion of PC derive benefit from retreatment with PC with a response rate of 50%., Highlights • Re-exposure to paclitaxel and carboplatin chemotherapy resulted in tumor shrinkage in 50% of women with endometrial cancer. • 15% of patients with recurrent endometrial cancer had stable disease upon re-exposure. • Re-using paclitaxel and carboplatin >6 months after adjuvant therapy is effective for disease control.

LBA5503 Background: Cortisol contributes to chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents utilize. Preclinical and clinical data indicate that glucocorticoid receptor (GR) modulation with relacorilant (RELA) reverses the anti-apoptotic effects of cortisol and restores the efficacy of cytotoxic agents. We report overall survival (OS) results from a randomized, controlled phase 2 study of RELA + nab-paclitaxel (NP) compared to NP only in patients with ovarian cancer (NCT03776812). The primary analysis showed improved progression-free survival (PFS) and a favorable safety profile with intermittent RELA + NP vs NP only, despite overrepresentation of primary platinum-refractory patients in the intermittent RELA + NP (n = 7) vs the NP-only arm (n = 1). Methods: A phase 2, open-label, randomized, 3-arm study of 2 RELA dosing schedules + NP compared with NP only was performed. 178 women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma with ≤4 prior chemotherapeutic regimens were enrolled. Patients were randomized 1:1:1 to: a) NP (80 mg/m2) + intermittent RELA (150 mg QD the day before, of, and after NP) (n = 60); b) NP (80 mg/m2) + continuous RELA (100 mg QD) (n = 58); or c) NP only (100 mg/m2) (n = 60). NP was administered on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was PFS; OS was a secondary endpoint. OS data for the intermittent and continuous arms were compared to NP only using a 2-sided log-rank test, stratified by presence of ascites and relapse within 6 months on previous taxane, at a 0.05 level of significance without multiplicity adjustment. Results: At the pre-defined OS analysis (128 OS events), hazard ratios (HRs) were 0.67 (95% CI [0.43, 1.03], P= 0.066) and 0.85 (95% CI [0.56, 1.29], P= 0.447) for intermittent and continuous RELA + NP vs NP only. Median OS was 13.9 (95% CI [11.1, 18.4]), 11.3 (95% CI [7.5, 16.4]), and 12.2 (95% CI [7.7, 15.3]) months in the intermittent RELA + NP, continuous RELA + NP, and NP-only arms. In the subgroup of patients without primary platinum-refractory disease, a statistically significant improvement in OS was observed with HR 0.63 (95% CI [0.39, 0.99], P= 0.045) and median OS of 13.9 (95% CI [11.1, 18.4]) vs 12.2 (95% CI [7.7, 15.3]) months for intermittent RELA + NP vs NP only. Conclusions: In addition to the improved PFS and DOR observed at the primary analysis, the OS analysis confirmed the survival benefit of intermittent RELA + NP compared to NP only, particularly in patients who were not primary platinum refractory. A phase 3 trial evaluating intermittent RELA + NP vs investigator’s choice of chemotherapy in patients without primary platinum-refractory disease is ongoing (NCT05257408). Clinical trial information: NCT03776812.

5521 Background: ONA-XR is a type I full progesterone antagonist that inhibits progesterone-mediated PR activation and stabilizes PR association with corepressors. GCT (98% of cases PR+), LGSOC (58% of cases PR+) and EEC (67% of cases PR+) are hormonally driven cancers that generally have poor responses to chemotherapy. Methods: This is an open-label, single-institution basket study of ONA-XR in patients with PR+ recurrent GCT (cohort 1), LGSOC (cohort 2), or EEC (cohort 3) (NCT03909152). Eligible patients required receipt of >1 prior line of chemotherapy, measurable disease by RECIST 1.1, and tumor tissue collected ≤3 years prior to enrollment with PR ≥ 1% by IHC. Patients received ONA-XR 50 mg PO BID until progression or intolerable toxicity. The study was designed as 3 parallel Simon 2-Stage studies. The primary objective was to evaluate efficacy, determined by RECIST 1.1, with at least 1/14 (cohort 1), 2/16 (cohort 2) or 4/19 (cohort 3) responses needed during stage 1 for advancement to stage 2. Secondary objectives included safety and tolerability, clinical benefit rate (CBR; stable disease lasting ≥ 16 weeks), and progression-free survival (PFS) as estimated by Kaplan Meier method. Results: The study enrolled patients to cohorts 1-3 from 5/2019 to 5/2020. Cohort 2 (LGSOC) enrolled 5 patients and cohort 3 (EEC) enrolled 1, both closed early due to slow accrual. Cohort 1 (GCT) enrolled 14 patients and completed Stage 1 accrual. There were no responses by RECIST 1.1 criteria observed in cohorts 1-3. In cohort 2 (LGSOC), 4/5 enrolled patients were evaluable, the median PFS was 4.4 months (1.8-NE) and CBR was 50% (6.8-93.2%). All 14 patients enrolled to cohort 1 (GCT) were evaluable with a median PFS of 3.5 months (1.6-8.8%), 6-month PFS rate of 30.1 % (8.4-56%), and 12-month PFS rate of 20.1% (3.5-46.4%). The CBR was 35.7% (12.8-64.9%). Two patients with GCT remain on active treatment for > 18 months. Grade 3 adverse events occurred in 5 patients: abdominal pain (2), small bowel obstruction (1), syncope (1), thromboembolism (1), urinary tract infection (1), and febrile neutropenia (1). Grade 3 laboratory toxicity occurred in 5 patients: anemia (2), neutropenia (1) and lymphopenia (2). Conclusions: ONA-XR was well tolerated and exhibited a 12-month PFS rate of 20.1% and a CBR of 35.7% in patients with GCT. No objective responses were observed. Cohorts 1-3 have closed to accrual, with 2 patients continuing active treatment for >18 months. Cohort 4, which combines ONA-XR with anastrozole, is currently enrolling patients with GCT. Clinical trial information: NCT03909152. [Table: see text]

5589 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) allows tumor escape through kynurenine production, which induces regulatory T cells and suppresses effector T-cell proliferation. NIVO, an anti-PD-1 inhibitor can upregulate IDO1, supporting the rationale for combining NIVO with IDO. We report results of NIVO as monotherapy and in combination with IDO inhibitor BMS-986205 in the treatment of pts with recurrent EC. Methods: In this single-institution, randomized phase 2 study, eligible pts must have received 1-4 prior lines of chemotherapy and have measurable disease by RECIST v 1.1. All EC histologies, including carcinosarcoma, were allowed. Pts with microsatellite insufficient (MSI-H) or mismatch repair (MMR)-deficient tumors were excluded. Pts were randomized to NIVO 480mg IV every 4 weeks (wks) with or without IDO 100mg orally daily. Primary endpoints were Overall Response Rate [ORR = Complete Response (CR) + Partial Response (PR)] by RECIST v 1.1. Secondary objectives were duration of response (DOR), median progression free survival (mPFS), PFS rate at 24 wks (PFS24wks) and safety. Overall survival (OS) was also evaluated. Results: Between 10/2019 and 11/2021, pts were randomized to receive either NIVO (n = 12) or NIVO + IDO (n = 12). Median age was 67 years (range 48-82) and median number of prior lines of therapy was 2 (range 1-3). Histologies included serous (n = 5, 21%), endometrioid (n = 10, 42%), clear cell (n = 1, 4.2%), carcinosarcoma (n = 6, 25%), undifferentiated (n = 1, 4.2%), and mucinous (n = 1, 4.2%). In the NIVO + IDO arm, 1 pt achieved partial response (8.3%, CI: 0.9-100%) with DOR of 17.6 months. In the NIVO arm, no responses were observed. Efficacy outcomes are summarized in the table. Treatment-related adverse events (TRAEs) grade ≥ 3 in the NIVO arm included acute kidney injury (n = 1, 8.3%), hypokalemia (n = 1, 8.3%), and thromboembolic event (n = 1, 8.3%). In the NIVO + IDO arm, TRAEs grade ≥ 3 included fatigue (n = 1, 8.3%), and elevated liver function (n = 1, 8.3%). No TRAEs led to study-drug interruption or dose reductions. Conclusions: NIVO monotherapy and in combination with IDO showed acceptable safety in pts with recurrent EC. NIVO in combination with IDO showed ORR of 8.3%. No responses were observed with NIVO monotherapy. The trial closed to accrual due to lack of observed clinical efficacy. Clinical trial information: NCT04106414. [Table: see text]

5583 Background: EC and a subset of OVCA are associated with high rates of dMMR and are responsive to PD-1 blockade. It is unknown what additional biomarkers beyond dMMR may enrich for benefit in these patients (pts). Methods: This was an investigator-initiated, single-arm, phase II study. Eligible pts had recurrent EC or OVCA that met one of the following criteria: 1) dMMR, as determined by immunohistochemical loss of expression of 1+ MMR genes; 2) MSI-H, as determined by next generation sequencing (MSK-IMPACT); or 3) hypermutated, defined as 20+ non-synonymous somatic mutations. Pts received nivo 240mg IV every 2 weeks or 480mg IV every 4 weeks until toxicity or progression. The co-primary endpoints were 1) the progression-free survival (PFS) rate at 24 weeks (PFS24) and 2) the objective response rate (ORR) by RECIST v1.1. The study was designed using Simon’s two-stage design, with a sample size of 40 pts based on a promising ORR of 25% with a type I error rate of 0.025 and a type II error rate of 0.05. Overall survival (OS), PFS and duration of response (DOR) were calculated using the method of Kaplan-Meier. Adverse events (AEs) were graded per CTCAE and tabulated. Biomarker analyses on the available archival tissue were performed using multiplex immunofluorescence (mIF) labeling for CD8, PD-1, TOX, PD-1, PD-L1, and FoxP3. Quantification of immune phenotypes and interaction studies between CD8+ T cells and PD-L1+ cells was performed in HALO. Results: Between 9/2017 and 5/2021, 35 pts were enrolled; the study closed early due to slow accrual. The median duration of follow-up was 33.2 months. The median age was 64 years (range 36-87); 82% of pts were white, 54% had high grade EC, and 65% had confirmed MLH1 hypermethylation. The ORR was 57.1% (97.5% CI 39.4-100%) [37% PR, 20% CR]. The PFS24 was 62.9% and median PFS was 26.7 months (95% CI 4.9-NE). Neither median DOR nor OS was reached. OS at 1 year was 76.4% (95% CI 58.2-87.4%). The ORR in patients with MLH1 hypermethylation was 52%; 4 of 5 patients with confirmed germline MMR alterations had a response by RECIST. AEs were consistent with the reported literature. Notable treatment related AEs included Grade 4 myocarditis with associated grade 4 AV block, grade 2 extraocular paresis, grade 3 Type 1 diabetes mellitus, and grade 3 elevations in AST/ALT. On mIF analysis, PD-L1 expression did not distinguish responders from non-responders, though interaction between CD8+ T cells and PD-L1+ cells was associated with CR/PR. Increase in relative fraction of dysfunctional CD8+ T cells (characterized by CD8+TOX+PD-1+ phenotype) was also associated with CR/PR. Conclusions: Nivo is an effective and tolerable treatment option for patients with MMR-D/MSI-H or hypermutated EC or OVCA. Presence of dysfunctional CD8+ T cells in the tumors was associated with response, while expression of PD-L1 was not predictive. Clinical trial information: NCT03241745.

TPS5615 Background: Low-grade serous ovarian cancer (LGSOC) constitutes up to 10% of all ovarian cancer and has clinical and molecular characteristics distinct from high-grade serous ovarian cancer. Approximately a third of patients (pts) with recurrent LGSOC harbor KRAS mutations (mt) and pts with KRAS wild-type (wt) LGSOC may have mutations in NRAS, BRAF, or other RAS pathway-associated genes. Prior clinical studies with single agent MEK inhibitors have shown response rates of 16-26% in recurrent LGSOC. VS-6766 is a unique small molecule RAF/MEK clamp that inhibits both RAF and MEK activities by trapping them in inactive complexes. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Focal adhesion kinase (FAK) activation is a putative resistance mechanism to RAF and MEK inhibition, and defactinib, a small molecule inhibitor of FAK, has shown synergistic anti-tumor activity with VS-6766 in preclinical models, including organoids from LGSOC pts. Furthermore, FAK inhibition combined with VS-6766 induces tumor regression in a KRAS mt ovarian cancer xenograft model. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof-of-concept study, durable objective responses (ORR = 46%; 11/24) have been reported in recurrent LGSOC pts, including pts who have had a prior MEK inhibitor (Banerjee ESMO 2021) and the combination of VS-6766 + defactinib has received FDA Breakthrough Therapy Designation for recurrent LGSOC. These initial preclinical and clinical results support the ongoing phase 2 ENGOT-ov60/GOG-3052 in recurrent LGSOC. Methods: This is an international phase 2, adaptive, multicenter, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 vs VS-6766 in combination with defactinib currently open to enrollment (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS mt and KRAS wt LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS mt and KRAS wt LGSOC. The minimum expected enrollment is 104 pts, 52 pts with KRAS mt and 52 KRAS wt (64 pts in Part A and 40 pts in Part B). Pts will be randomized to receive VS-6766 (4.0 mg orally (PO), twice weekly 3 wks on, 1 wk off) or VS-6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 wks on, 1 wk off) till progression. Key inclusion criteria include histologically confirmed LGSOC, known KRAS mutation status, prior systemic therapy including platinum for metastatic disease and up to 1 prior line of MEK inhibitor therapy permitted. Part A of this study has completed enrollment and Part B is currently enrolling pts. Clinical trial information: NCT04625270.

PURPOSE The purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery. MATERIALS AND METHODS Patients were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m2 for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics. RESULTS Of 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard ( P = .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37; P = .05). There was no significant difference in median overall survival (52.5 v 59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67; P = .31). These analyses were exploratory. CONCLUSION HIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.

Purpose To determine the incidence of venous thromboembolism (VTE) and define clinical risk factors associated with the development of new-onset VTE in patients receiving neoadjuvant chemotherapy (NACT) for ovarian cancer (OC). Methods An institutional ovarian cancer database was used to identify all OC patients receiving NACT from 04/2015–09/2018. VTE events were recorded and included clinically diagnosed deep venous thrombosis (DVT) and/or pulmonary embolism (PE). The incidence of VTE events was categorized according to treatment phases (P): P0) First visit/prior to induction of NACT; P1) during NACT before interval debulking surgery (IDS); P2) intraoperative through day 28 post-IDS; P3) during adjuvant chemotherapy. Results A total of 290 patients were identified during the study period. Seventy-five (25.9%) developed a VTE at some point from time of presentation through the peri-operative period. Forty (13.8%) presented with VTE prior to initiation of NACT. An additional 27 (11.6%) developed a VTE during NACT (P1); 6 (3.9%) during the intraoperative and 28-day post-operative period (P2); and 2 (1.3%) during the adjuvant period (P3). The overall VTE rate was 25.9% (n = 75). FIGO stage IV disease was the only factor associated with increased risk for a new-onset VTE [Odds Ratio (OR): 3.9 (95% Confidence Interval [CI] = 1.2–13.6; p = 0.03]. Conclusions Patients receiving NACT for advanced OC are at extremely high risk for developing thromboembolic events, either at initial presentation or during induction of NACT, a treatment phase that is traditionally without use of prophylactic anticoagulation. Since Khorana scoring is not predictive in this population, clinicians might need to consider increased screening or use of prophylactic anticoagulation in patients receiving NACT for OC, particularly in advanced metastatic disease.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Highlights • Low-grade serous carcinoma is relatively resistant to chemotherapy. • MEK inhibitors have promising activity in recurrent low-grade serous carcinoma. • The first case of successful re-challenge with a MEK inhibitor is presented., Low-grade serous carcinoma of the ovary/peritoneum is a rare epithelial cancer subtype characterized by younger age at diagnosis, relative chemoresistance, and prolonged overall survival compared with high-grade serous carcinoma. In addition, alterations in the mitogen activated protein kinase pathway are frequent and play a major role in the pathogenesis of this tumor. MEK inhibitors have demonstrated promising activity in the treatment of recurrent low-grade serous carcinoma. Although prevailing wisdom in cancer therapy is that the re-treatment with a drug after emergence of resistance is futile, we report the initial case of a patient with recurrent low-grade serous carcinoma who experienced a partial response when re-challenged with a MEK inhibitor after previously having prolonged stable disease followed by disease progression on a MEK inhibitor.

OBJECTIVE: To describe oncologic outcomes after using acute normovolemic hemodilution (ANH) to reduce requirement for allogenic red blood cell transfusions (ABT) in patients undergoing primary debulking surgery (PDS) for advanced ovarian cancer. METHODS: We performed a post-hoc analysis of a recent prospective trial investigating the safety and feasibility of ANH during PDS for advanced ovarian cancer. We report long-term survival outcomes. We compared demographics, clinicopathological characteristics, survival outcomes in this cohort of Stage IIIB-IVB high-grade serous ovarian cancer patients undergoing ANH (ANH group), with a retrospective cohort of all other patients (standard group) undergoing PDS during the same time period (01/2012–04/2017). Standard statistical tests were used. RESULTS: There were no demographic or clinicopathological differences between ANH (n=33) and standard groups (n=360), except for higher median age at diagnosis (57 vs. 62 years, respectively; p=0.044) and shorter operative time (357 vs. 446 min, respectively; p1cm, 9.1 vs. 9.2% (p=0.78). RD after PDS was the only independent factor associated with worse progression-free survival (PFS) on multivariable analysis (p

PURPOSE Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician’s choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

Purpose Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population. Patients and methods This phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m2 or 60 mg plus CP at AUC 5 and 175 mg/m2 or 80 mg/m2, respectively) for 6–10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks. Results Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers. Conclusions Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.

PURPOSE: Early detection and management of symptoms in patients with cancer improves outcomes. However, the optimal approach to symptom monitoring and management is unknown. InSight Care is a mobile health intervention that captures symptom data and facilitates patient-provider communication to mitigate symptom escalation. PATIENTS AND METHODS: Patients initiating antineoplastic treatment at a Memorial Sloan Kettering regional location were eligible. Technology supporting the program included the following: a predictive model that identified patient risk for a potentially preventable acute care visit; a secure patient portal enabling communication, televisits, and daily delivery of patient symptom assessments; alerts for concerning symptoms; and a symptom-trending application. The main outcomes of the pilot were feasibility and acceptability evaluated through enrollment and response rates and symptom alerts, and perceived value evaluated on the basis of qualitative patient and provider interviews. RESULTS: The pilot program enrolled 100 high-risk patients with solid tumors and lymphoma (29% of new treatment starts v goal of 25%). Over 6 months of follow-up, the daily symptom assessment response rate was 56% (the goal was 50%), and 93% of patients generated a severe symptom alert. Patients and providers perceived value in the program, and archetypes were developed for program improvement. Enrolled patients were less likely to use acute care than were other high-risk patients. CONCLUSION: InSight Care was feasible and holds the potential to improve patient care and decrease facility-based care. Future work should focus on optimizing the cadence of patient assessments, the workforce supporting remote symptom management, and the return of symptom data to patients and clinical teams.