Search

Purpose: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. Experimental Design: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. Results: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status. Conclusions: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

Visceral adiposity has been established as a predictor of outcomes in various cancers. We aimed to determine the association of radiographic measurements of visceral fat with clinical outcomes in patients with endometrial cancer.A retrospective review of patients with stage III-IV endometrial cancer who underwent surgery between 2004 and 2014 was performed. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT;VAT+SAT) were assessed on preoperative computed tomography (CT) scans. Exploratory analysis was performed to establish the optimal cut-off values for VAT, SAT, and TAT to identify patients with poor prognostic body composition. Survival rates were analyzed using Kaplan-Meier analysis, log-rank tests, and cox-regression.Eighty-three patients were included. Forty-two (51%) patients had a low VAT/SAT ratio (0.45) and 41 (49.4%) had a high VAT/SAT ratio (0.45). There were no significant differences in demographics between the groups. The mean VAT, SAT, and TAT were 176.3 cmVisceral fat measurements are predictive of outcomes in patients with advanced stage endometrial cancer. Specifically, VAT to SAT ratios are predictive of overall survival. Future studies should be pursued to identify potential therapeutic targets and biological mechanisms that underlie obesity's relationship with endometrial cancer.

Patient characteristics of patient-derived ovarian cancer cells

RAD51 expression and platinum chemotherapy response in vitro and in patient tumors

Patient characteristics of patient-derived ovarian cancer organoids

Patient characteristics of FFPE discovery cohort

Summary of Antibodies

Purpose:To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples.Experimental Design:RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated.Results:RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status.Conclusions:RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

Patient characteristics of FFPE validation cohort

Supplementary Table S1. Comprehensive radiologic, surgical, and pathologic scoring system used to evaluate tumor response to neoadjuvant chemotherapy. Supplementary Table S2. Summary of antibodies used. Supplementary Table S3. Disease characteristics of ovarian cancer patients receiving neoadjuvant chemotherapy and undergoing interval cytoreductive surgery stratified by chemoresponse. Supplementary Table S4. Disease characteristics of ovarian cancer patients receiving neoadjuvant chemotherapy and undergoing interval cytoreductive surgery stratified by high and low serum GAS6 expression prior to neoadjuvant chemotherapy. Supplementary Figure S1. RAD51 foci formation in irradiated ovarian cancer cells. Supplementary Figure S2. GAS6 and AXL expression in four ovarian cancer cell lines. Supplementary Figure S3. Mean combination indexes and dose response curves for paclitaxel and AVB-500 in three ovarian cancer cell lines. Supplementary Figure S4. GAS6/AXL inhibitor AVB-500 improves response to carboplatin and decreases tumor burden in PDX mouse model of ovarian cancer. Supplementary Figure S5. GAS6/AXL inhibitor AVB-500 decreases GAS6 and pAKT expression in mouse tumors. Supplementary Figure S6. Cleaved Caspase 3 levels in OVCAR8 ovarian cancer cells at 24 and 48 hours of treatment. Supplementary Figure S7. Treatment with AVB-500 increases DNA damage. Supplementary Figure S8. Treatment with AVB-500 decreases activation of AKT and does not affect protein expression of 53BP1, AXL, or RAD51. Supplementary Figure S9. Treatment with carboplatin plus AVB-500 decreases pATM and increases pCHK1. Supplementary Figure S10. Treatment with AVB-500 decreases RPA binding and does not affect the cell cycle. Supplementary Figure S11. Treatment with AVB-500 in addition to olaparib increases DNA damage and decreases homologous recombination. Supplementary Figure S12. Proposed mechanism of AVB-500 and carboplatin increasing DNA damage through replication fork perturbation.

Supplementary Figure from GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis

Supplementary Table from GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis

Over 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC.Implications:GAS6/AXL is a novel target to sensitize ovarian cancers to carboplatin and olaparib. Additionally, GAS6 levels can be associated with response to carboplatin treatment.

Chemotherapy is often ineffective in advanced-stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared with tumors with a good response to chemotherapy. We showed that chemotherapy-resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared with paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling, which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong preclinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models.

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease.OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure.METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States.RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001).CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Background Standard treatment for placental site trophoblastic tumor is hysterectomy. This may be unacceptable to women desiring fertility. Cells aberrant in placental site trophoblastic tumor display an ability to invade normal tissue while evading the immune system. Case We present a case of a 23-year-old woman with stage I placental site trophoblastic tumor who declined hysterectomy. Tumor assay for program cell death-ligand 1 staining was performed and suggestive of an immune-responsive tumor. The patient initiated intravenous pembrolizumab 200 mg every 2 weeks, and by cycle 3 her β-hCG level fell to undetectable. She subsequently conceived and went on to have an uncomplicated term vaginal birth after cesarean. At 6 weeks postpartum, she remained without evidence of disease. Conclusion Immunotherapy can eliminate early program cell death-ligand 1-positive placental site trophoblastic tumor with subsequent normal pregnancy.

OBJECTIVE. To determine the association between scores from a 25-item patient-reported Rockwood Accumulation of Deficits Frailty Index (DAFI) and survival outcomes in gynecologic cancer patients. METHODS. A frailty index was constructed from the SEER-MHOS database. The DAFI was applied to women age ≥ 65 diagnosed with all types of gynecologic cancers between 1998 and 2015. The impact of frailty status at cancer diagnosis on overall survival (OS) was analyzed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS. In this cohort (n = 1336) the median age at diagnosis was 74 (range 65–97). Nine hundred sixty-two (72%) women were Caucasian and 132 (10%) were African-American. Overall, 651(49%) of patients were considered frail. On multivariate analysis, frail patients had a 48% increased risk for death (aHR 1.48; 95% CI 1.29–1.69; P < 0.0001). Each 10% increase in frailty index was associated with a 16% increased risk of death (aHR, 1.16; 95% CI, 1.11 to 1.21; P < 0.0001). In subgroup analyses of the varying cancer types, the association of frailty status with prognosis was fairly consistent (aHR 1.15–2.24). The DAFI was more prognostic in endometrial (aHR 1.76; 95% CI 1.41–2.18, P < 0.0001) and vaginal/vulvar (aHR 1.94; 95% CI 1.34–2.81, P = 0.0005) cancers as well as patients with loco-regional disease (aHR 1.94; 95% CI 1.62–2.33, P < 0.0001). CONCLUSIONS. Frailty appears to be a significant predictor of mortality in gynecologic cancer patients regardless of chronological age. This measure of functional age may be of particular utility in women with loco-regional disease only who otherwise would have a favorable prognosis.

The use of Poly ADP ribose polymerase inhibitors (PARPi) has revolutionized the treatment of homologous recombination (HR) deficient ovarian cancer tumors. A subset of these tumors exhibit genetic and acquired resistance to PARPi treatment. We have previously shown histone deacetylase inhibitors (HDACi) resensitizes ovarian cancer cells to PARPi. The objective of this study is to examine the effectiveness of combination HDACi and PARPi treatment in two in vitro models of mouse ovarian cancer cells. To investigate these effects, we used the following three ID8 murine ovarian cancer epithelial cell lines: TP53− / − (HR deficient), TP53− / −/BRCA2− / − (HR proficient), and an olaparib resistant line TP53− / −/BRCA2− / −-OR (ID8_OR). We also created ovarian cancer organoids from these three lines. In short, 8-week old female C57BL/6 mice were injected with 7 million untreated cells in PBS. Following the formation of ascites, mice were sacrificed and organoids were derived from both ascites and tumors. For viability assays, cells were pretreated with entinostat (Ent, 0.25uM) for 24h, followed by 72h (2D cells) or 7 days (organoids) of Ent (0-2uM), olaparib (Ola, 0-40uM), or in combination. Cell proliferation and viability was assessed using MTS and ATP-based assays. For immunofluorescence and western blotting analysis, cells were treated with 0.5uM Ent, 10uM Ola or the combination.TP53 adherent cells and organoids treated with 0.5uM Ent + 10uM of Ola significantly reduced cell proliferation when compared to Ola alone (p= 0.0028, 0.0021 Two-Way ANOVA). When compared to Ola and Ent alone, TP53/BRCA2 adherent cells treated with 0.125uM of Ent + 2.5uM of Ola also reduced cell proliferation (p=0.0011 and p=0.0072, 0.0845). Lastly, ID8_OR adherent cells and organoids treated with 0.125uM of Ent + 2.5μM of Ola significantly reduced cell proliferation when compared to Ola alone (p=0.0018, 0.0264).Immunofluorescences analysis revealed, when treated with Ola and Ent combination, adherent TP53 (p= 0.002, n.s), TP53/BRCA2 (p=0.0033, 0.0315), and ID8_OR (n.s) cells displayed increased expression of DNA damage marker gH2AX when compared to Control and Ola alone. We also observed decreased expression of RAD51 in cells treated with combination when compared to control and Ola alone, TP53 (p= Citation Format: Bisiayo E. Fashemi, Lilian N. van Biljon1, Tyler Woodard, Vijayalaxmi Gupta, Mary M. Mullen, Benjamin Bitler, Dineo Khabele. Entinostat restores sensitivity to olaparib in two in vitro models of PARPi resistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB164.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in women with gynecologic malignancies. This practice statement provides clinical data and overall quality of evidence regarding the use of direct oral anticoagulants (DOACs) in this patient population. Specifically, it reviews patient selection, safety measures, and nuances of perioperative use of these medications. The scope of this document is limited to DOAC use in gynecologic oncology rather than a broad discussion of VTE prophylaxis and management in general. The following recommendations and examination of extant data are based on DOAC trials conducted primarily in mixed populations with different cancer subtypes. Many of these trials include few, or no, women with gynecologic cancer. However, because there is very limited data in gynecologic cancer-specific populations, the results of these studies represent the best available evidence to support treatment recommendations in our patients. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee believe that the results of these studies may be extrapolated, with caution, to VTE treatment and prophylaxis for patients with gynecologic cancer.

Cancers with deficiencies in homologous recombination-mediated DNA repair (HRR) demonstrate improved clinical outcomes and increased survival. Approximately 50% of high-grade serous ovarian cancers (HGSOC) exhibit homologous recombination deficiency (HRD). HRD can be caused by germline or somatic mutations of genes involved in the HR pathway. Given platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPis) are used in HGSOC, double-strand breaks (DSBs) are common. Unrepaired DSBs are toxic to cells as genomic instability ensues and cells eventually die. Thus, tumor cells with DSBs utilize the high-fidelity HRR as one of the central pathways for repair. In tumors that have HRD, an alternate pathway such as non-homologous end-joining (NHEJ) is used and leads to error-prone repair. To date, methods for clinical detection of homologous recombination deficiency (HRD) are limited to genomic changes of HRR genes and genomic mutation patterns resulting from HRD genes involved in HR-mediated DNA repair. However, these tests detect genomic scars that might not always correlate well with PARP inhibitor or platinum sensitivity in the current state. Therefore, a functional HRD assay should be able to more accurately predict tumor response in real-time. RAD51 foci formation has been used as a functional assay to define HRD and closely correlates with chemotherapy and PARPi sensitivity. The inability to form RAD51 foci is a common feature of HRD. DNA damage can also cause transient slowing or stalling of replication forks defined as replication stress. Replication fork stalling can lead to fork degradation and decreased cell viability if forks do not resume DNA synthesis. Fork degradation has been found to lead to chemosensitivity in BRCA-deficient tumors. To determine this fork degradation phenotype, replication fork/DNA fiber assays are utilized. This review will highlight functional assays for HRD in the context of translating these to real-time clinical assays.

Objectives There are limited methods to identify which obese patients will experience wound complications after undergoing gynecologic surgery. We sought to determine the association between frailty and postoperative wound complications and to develop a prediction model for wound complications in this patient population. Methods We reviewed prospectively collected data of obese patients undergoing laparotomy though midline vertical incisions from 7/2013-3/2016. Modified frailty index (mFI) was calculated using 11 comorbidities previously validated. The primary outcome was the composite rate of postoperative wound complication. Data was analyzed using Fisher exact test or Chi-square and t-tests or Kruskal-Wallis tests. Poisson regression models were used to generate relative risks. Prediction models were created with receiver-operator characteristic curve analysis. Results Of 163 patients included, 56 (34%) were considered frail. Wound complications occurred in 52 patients (31.9%): 28 (50%) frail and 24 (22.4%) non-frail patients (RR 2.23, 95%CI 1.29-3.85). Frail patients had significantly greater frequencies of wound breakdown (37.5% vs 15%, RR 2.51, 95%CI 1.31-4.81). After controlling for BMI, tobacco use, and maximum postoperative glucose, frailty remained an independent predictor of wound complication (aRR 1.88, 95%CI 1.04-3.40). The area under the curve for the predictive model incorporating frailty was 0.73 for wound complications. Conclusion Frailty is associated with wound complications in obese patients undergoing gynecologic surgery via a midline vertical incision and is a useful tool in identifying the most high risk patients. Further prospective research is necessary to incorporate mFI into preoperative planning and counseling.

Simple Summary Uterine serous cancer (USC) is an aggressive form of endometrial cancer. USC constitutes less than 10% of endometrial cancer cases but is responsible for up to 40% of endometrial cancer deaths. Response to standard platinum and taxane therapy is modest, particularly in the recurrent setting. Thus, novel therapeutic strategies are needed to overcome this drug resistance. We hope that our findings provide strong preclinical support for the combination of an AXL inhibitor with bevacizumab in USC clinical trials in the recurrent setting. Abstract Endometrial cancer remains the most prevalent gynecologic cancer with continued rising incidence. A less common form of this cancer is uterine serous cancer, which represents 10% of endometrial cancer cases. However, this is the most aggressive cancer. The objective was to assess whether inhibiting the receptor tyrosine kinase AXL with AVB-500 in combination with bevacizumab would improve response in uterine serous cancer. To prove this, we conducted multiple angiogenesis assays including tube formation assays and angiogenesis invasion assays. In addition, we utilized mouse models with multiple cells lines and subsequently analyzed harvested tissue through immunohistochemistry CD31 staining to assess microvessel density. The combination treatment arms demonstrated decreased angiogenic potential in each assay. In addition, intraperitoneal mouse models demonstrated a significant decrease in tumor burden in two cell lines. The combination of AVB-500 and bevacizumab reduced tumor burden in vivo and reduced morphogenesis and migration in vitro which are vital to the process of angiogenesis.

Highlights • The COVID-19 pandemic has significantly impacted gynecologic cancer care. • Referrals to gynecologic oncology decreased in the early months of the pandemic. • Referral time to gynecologic oncology evaluation was not impacted by the pandemic. • Time to cancer treatment initiation decreased significantly during the pandemic. • Disparities in time to cancer treatment initiation improving during the pandemic., Objective To evaluate the impact of the COVID-19 pandemic on referral to and delivery of gynecologic oncology care at a National Cancer Institute-designated Comprehensive Cancer Center. Methods We conducted a retrospective cohort study of patients referred for evaluation by a gynecologic oncologist at Washington University in St. Louis from October 2019 – February 2020 (pre-COVID-19), and April - August 2020 (COVID-19). The primary outcome, time from referral to evaluation by a gynecologic oncologist, was compared between the two time periods. Secondary outcomes included time from initial evaluation to treatment and delays/interruptions in care due to the pandemic. Sub-group analyses were performed on patients with a cancer diagnosis to evaluate the impact of COVID-19 on treatment decision making. Results 884 patients were referred during the study period. Total referrals fell by 32% (526 to 358 patients, p

To assess the rate of wound complications and evaluate the effectiveness of antibiotic prophylaxis in vulvar wide local excision procedures.We performed a single-institution, retrospective cohort study of women undergoing vulvar surgery for premalignant lesions between January 2007 and January 2017. The primary outcome was a composite wound complication rate that included breakdown or infection within 8 weeks postoperatively. Data were analyzed using Fisher exact or χ test, Student t-test, and Poisson regression.Wound complications occurred in 154 (28.7%) of the 537 patients. Mean age was 52 years; most patients were white (83.1%), cigarette smokers (65.2%), had no prior vulvar treatment (54.4%), and had a preoperative diagnosis of high-grade squamous intraepithelial lesion (vulvar HSIL) (70.0%). The presence of other predisposing factors was similar between groups. In multivariate analysis, smoking (odds ratio [OR] 1.64, 95% CI 1.14-2.38) and primary rather than repeat vulvar surgery (OR 1.99, 95% CI 1.31-3.01) were associated with increased risk for wound complications. There was no significant difference in wound complications between women who received preoperative antibiotics and those who did not (30.4% vs 27.4%, P=.45), although the mean length of wound separation in the antibiotic group was shorter (1 vs 2 cm, P=.03).Wound complications are common among women undergoing surgery for vulvar HSIL, and interventional trials are warranted to evaluate the role of smoking cessation and prophylactic antibiotics to reduce postoperative morbidity.

Highlights • Surveillance for women with medically inoperable, stage I endometrial cancer (EC) depends on the management strategy. • Uterine sampling may be omitted for asymptomatic women with medically inoperative Stage I EC treated with radiation. • Endometrial sampling effectively detects recurrence among medically inoperable EC patients treated with progestin therapy. • Patient adherence to follow-up should be considered when recommending treatment for clinical stage I EC., It is unclear if surveillance for postmenopausal women with medically inoperable stage 1 endometrial cancer (EC) should differ depending on their management strategy. Thus, we investigated the utility of surveillance endometrial sampling among 53 postmenopausal women with medically inoperable, clinical stage I, grade 1 endometrioid EC who received either progestin therapy or radiation between 2009 and 2018, at a single academic institution. Frequency and results of endometrial sampling, as well as recurrence and survival rates were studied. Of 53 patients, 18 (34.0%) received progestin therapy and 35 (66.0%) radiation. Medically managed patients were treated with megestrol acetate (27.7%), a levonorgestrel intrauterine device (27.7%), or both (44.4%). Radiated patients were mostly treated with high-dose rate brachytherapy only (77.1%). Surveillance endometrial sampling (median procedures = 4, range 1–10) was strictly adhered to among all patients who received progestin therapy, but infrequently (6/35, 17.1%) performed among radiated patients, yielding no positive results. Three recurrences occurred over the median follow-up of 38 months. Two (11%) women in the progestin therapy group recurred locally and were diagnosed by endometrial sampling. One (3%) patient in the radiation group recurred distally in the lung 25.3 months after completing brachytherapy. We conclude that appropriate surveillance for women with medically inoperable, clinical stage I, grade 1 EC depends on the management strategy. For those treated with progestins, surveillance with endometrial sampling every 3–6 months can reveal local recurrence. However, given the excellent local control after radiation, endometrial sampling may not be warranted for women treated with definitive radiation.

Objective/Background: Chemotherapy is often ineffective in advanced stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis in endometrial cancer. Our objective was to identify whether inhibition of AXL through a novel, selective targeted agent, AVB-500, would improve sensitivity to paclitaxel. Additionally, we sought to determine whether the mechanism for this improved sensitivity was through metabolic regulation. Methods: Immunohistochemistry (IHC) was performed on a tissue microarray containing specimens from patients with primary and metastatic uterine serous carcinoma. Blind scoring was performed by two reviewers. Kaplan-Meier methods were used to generate time-to-event curves. Cell viability was performed with high-grade endometrial, chemo-resistant cell lines, ARK1 and PUC198. Cells were treated with paclitaxel and with AVB-500+paclitaxel. Intraperitoneal (IP) ARK1 or PUC198 tumors were treated with vehicle, AVB-500, paclitaxel, or AVB-500+paclitaxel. A Seahorse Analyzer was used for glycolytic rate assays. Isotope tracing was used for in vivo metabolite abundance quantification. Results: We found that both GAS6 and AXL expression were higher by IHC in tumors with a poor response to chemotherapy compared to tumors with a good response to chemotherapy (GAS6: 40.9% vs. 30.4%, P=0.012; AXL: 60.7% vs. 42.7%, P=0.013). Median PFS and OS were longer in patients with low GAS6 expressing tumors compared to high GAS6 expressing tumors (PFS: 33.6 mo vs. 10.6 mo, P=0.003; OS: 39.5 mo vs. 27.7 mo, P=0.003). We showed that chemotherapy resistant endometrial cancer cell lines, ARK1 and PUC198 had improved sensitivity and synergy with paclitaxel when treated in combination with AVB-500. ARK1 and PUC198 in vivo IP models had significantly fewer tumors (ARK1: P=0.007; PUC198: P=0.029) and decreased tumor weight (ARK1: P Conclusions: Our study provides strong pre-clinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models. Additionally, continued identification of viable biomarkers is critical to the success of targeted therapies such as AVB-500. Given AXL’s role in glucose homeostasis, one or more glycolytic intermediates may prove to be a useful biomarker to help predict sensitivity in patients, thus tailoring who would benefit from this treatment combination. Citation Format: Shaina F. Bruce, Kevin Cho, Hollie Noia, Elena Lomonosova, Elizabeth Stock, Alyssa Oplt, Barbara Blachut, Mary M. Mullen, Lindsay M. Kuroki, Andrea R. Hagemann, Carolyn K. McCourt, Premal H. Thaker, Dineo Khabele, Matthew A. Powell, David G. Mutch, Leah P. Shriver, Gary J. Patti, Katherine C. Fuh. GAS6-AXL inhibition by AVB-500 overcomes resistance to paclitaxel in endometrial cancer by decreasing tumor cell glycolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB081.

Objectives: We determined whether inhibition of GAS6/AXL with AVB-500 in combination with olaparib could improve response in homologous recombination proficient (HRP) uterine serous cancer (USC). Methods: ARK1 & ARK4, uterine serous cancer cell lines, were radiated with 10Gy to identify homologous recombination repair status, and RAD51 foci were identified by immunofluorescence (IF). These were treated with AVB-500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were conducted with either AVB-500 alone, olaparib alone or combination treatment (olaparib + AVB-500). Colonies were stained and absorbance was obtained to calculate relative cell survival using Graph Pad Prism. In vivo studies were performed with treatment every 3 days for 14-days. Treatment groups were vehicle control, AVB-500 alone, olaparib alone and olaparib with AVB-500. Results: ARK1 and ARK4 cells were found to have an increase in gamma-H2AX and RAD51 foci after radiation that was consistent with HRP. In clonogenic assays, colonies were stained and absorbance was obtained for each experimental arm. Olaparib + AVB-500 had significantly less cell colonies survive as seen by a decrease in absorbance than the olaparib only group for ARK1s (0.417nm vs 0.756nm, p=0.001) as well as in ARK4s (0.186nm vs 0.641nm, p=0.003). In an intraperitoneal model with ARK1 tumors, the olaparib + AVB-500 treated group had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p=0.002) and AVB-500 alone (0.008g vs 0.145g, p=0.0006) after 14 days of treatment. Conclusions: AVB-500 in combination with olaparib demonstrates an improved response than olaparib alone with a greater decrease in tumor burden in HRP USC models. Additional therapeutic and mechanistic experiments are ongoing.

Highlights • Choroid metastases are extremely rare in endometrial cancer. • Choroid metastases can present as many different eye complaints. • Comprehensive eye exams are important in patients with visual complaints.

The tumor-specific immune response in endometrial cancer is variable within molecular subtypes. Thus, the tumor immune response offers a novel biomarker, separate from molecular subtypes, to predict which patients might respond to immunotherapy. See related article by Talhouk et al., p. 2537

Objectives: More than 80% of women with high grade serous ovarian carcinoma (HGSOC) ultimately develop platinum resistance. There are no FDA approved agents to improve sensitivity to carboplatin. On candidate target is growth arrest-specific 6 (GAS6) which has been associated with prognosis in HGSOC. We hypothesized that GAS6 inhibition with AVB-500 (AVB) sensitizes platinum-resistant cells to platinum chemotherapy by stalling replication forks and increasing replication stress. We also hypothesized that GAS6 expression would predict response to neoadjuvant chemotherapy. Methods: AVB was supplied by Aravive Biologics. Both homologous recombination (HR)-proficient (OVCAR3-TPMES, CAOV3, COV362) and HR-deficient (OVCAR8) cells were used for all experiments. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carbo±AVB. The effect of carbo + AVB on intraperitoneal tumor burden was evaluated in mouse models. For DNA fiber assays, cells were labeled with the thymidine analog IdU for 20 minutes followed by CldU for 60 minutes and treatment with carbo, cisplatin (cis), or AVB. Immunofluorescent (IF) assays targeting γH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for HR and 53BP1 for non-homologous end joining (NHEJ) were performed. Human HGSOC samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Results: Carbo + AVB decreased survival of platinum-resistant cells as measured by clonogenic colonies than carbo alone (p 80%) (n=7) or serum GAS6 concentrations (>25ng/mL) (n=13) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P=0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus median not reached, P=0.009). Conclusions: Inhibition of the GAS6 pathway with AVB improves sensitivity of platinum-resistant cells to platinum chemotherapy by increasing replication stress and DNA damage and decreasing HR. GAS6 is a potential biomarker predictive of poor response to platinum-based neoadjuvant chemotherapy and might identify patients who would benefit from treatment with AVB.

Objectives: Visceral adiposity has been established as a predictor of outcomes in various cancers; however, its role in predicting outcomes in advanced stage endometrial cancer patients is unknown. We aimed to determine the association of radiographic measurements of visceral fat with clinical outcomes in patients with endometrial cancer. Methods: A retrospective review of stage III-IV endometrial cancer patients who underwent surgery after preoperative computed tomography (CT) scans between 2005 and 2014 was performed. Follow-up was continued until 10/2020. Visceral fat area (VFA) and subcutaneous fat area (SFA) were assessed in CT scans by a board certified radiologist. Total fat area (TFA) is the sum of VFA and SFA. Exploratory analysis was performed to establish the optimal cut-off values for VFA to SFA ratios to identify patients with poor prognostic body composition. Survival rates were analyzed using Kaplan-Meier analysis and log-rank tests. Results: Ninety-two patients were included. Forty-two (51%) patients had a low VFA/SFA ratio ( 0.45). There were no significant differences in demographics or clinical characteristics including grade and stage and adjuvant therapy between the groups. The mean age was 62.7 years and the mean BMI was 33 kg/m2. The majority of patients had endometrioid histology (57, 68.7%) and grade 1 (25, 30.1%) and grade 3 (19, 22.9%) disease. Twenty four (28.9%) patients had mixed history and two (2.4%) had high grade serous histology. The mean VFA, SFA, and TFA were 176.3 cm2, 379.3 cm2, and 555.3 cm2 respectively. Compared to patients with low VFA/SFA ratios, patients with high VFA/SFA ratios had a shorter recurrence-free survival (median 29.6 vs 32.3 months, P=0.01) and shorter overall survival (median 56 vs 93.7 months, P=0.03). Conclusions: Visceral fat measurements are predictive of outcomes in patients with endometrial cancer. Specifically, VFA:SFA ratios are predictive of overall survival in this cohort. Future studies should be pursued to validate this tool prospectively in order to determine the independent prognostic significance.

Objectives To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment. Methods After retrospective analysis of a database of molecularly-profiled gynecologic cancer patients, 149 vulvar cancer patients were included and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (C/FISH). A Fisher's exact test was used when indicated with a p -value≤0.05 indicating significance. Results Median age was 65. 85% had squamous cell carcinoma (SCC) and 15% adenocarcinoma (ADC) histologies. 46% had metastatic (Stage IV) disease. Targeted hot-spot sequencing identified variants in the following genes: TP53 (33%), PIK3CA/BRCA2 (8%, 10%, respectively), HRAS/FBXW7 (5%, 4%, respectively) and ERBB4/GNAS (3%, 3% respectively). Mutations in AKT1 , ATM , FGFR2 , KRAS , NRAS (n=1, respectively) and BRAF (n=2) also occurred. Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancers (e.g. PIK3CA : exon 9 [E545K], RAS : G13D, Q61L, BRCA2 : S1667X, BRAF : R443T, FBXW7 : E471fs, etc.). Drug targets identified by IHC and ISH methodologies include cMET (32% IHC, 2% ISH), PDL1 (18%), PTEN loss (56%), HER2 (4% IHC, 2% ISH) and hormone receptors (AR, 4%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2 and GNAS with an increased presence in ADC ( p -values all Conclusions Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.

Highlights • DICER1 mutations play a significant role in gynecologic malignancy. • DICER1 may be involved in the sarcomagenesis of endometrial adenosarcoma. • The knowledge of a genetic mutation can help clarify a patient's medical history.

The integration of palliative care and hospice into standard gynecologic oncology care is associated with cost-savings, longer survival, lower symptom burden, and better quality of life for patients and caregivers. Consequently, this comprehensive approach is formally recognized and endorsed by the Society of Gynecologic Oncology, the National Comprehensive Cancer Network, and the American Society of Clinical Oncology. This article reviews the background, benefits, barriers, and most practical delivery models of palliative care. It also discusses management of common symptoms experienced by gynecologic oncology patients.

TPS5605 Background: The AXL receptor and its activating ligand, GAS6, are important drivers of metastasis and therapeutic resistance in human cancers. This signaling axis represents an attractive target for therapeutic intervention, but the strong picomolar binding affinity between endogenous GAS6 and AXL and the promiscuity of small molecule AXL inhibitors have presented a barrier to specific and potent inhibition of AXL. AVB-S6-500 is a highly sensitive and specific inhibitor of AXL, with ̃200-fold higher affinity than wild-type (WT) AXL. AVB-S6-500 binds GAS6, the sole ligand of AXL, inhibiting its interaction with AXL thereby dramatically reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic disease in nonclinical models of aggressive human cancers. A Phase 1b study in platinum resistant ovarian cancer showed no dose limiting toxicities and established a recommended Phase 2 dose of 15mg/kg administered every 2 weeks. Longer progression free survival (PFS) and overall survival (OS) times were observed in patients who had not been previously treated with bevacizumab. Furthermore, retrospective analyses demonstrated that serum soluble AXL to GAS6 ratio may identify patients more likely to respond to this therapy. Methods: Patients with high grade serous, platinum resistant ovarian cancer, who have received no more than 4 prior therapy regimens will be randomized 1:1 to AVB-500 + PAC or PAC + placebo. Patients will be stratified by recurrence after last platinum regimen (90% statistical power for PFS under the following assumptions of PFS medians. Study recruitment began in Q1. Clinical trial information: NCT04729608.

Objectives: We determined whether inhibition of GAS6/AXL with AVB-500 in combination with olaparib could improve response in HR-proficient (HRP) uterine serous cancer (USC). Methods: Two USC cell lines (ARK1 & ARK4) were radiated with 10Gy, and RAD51 foci were identified by immunofluorescence (IF). These were treated with AVB-500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB-500 alone, olaparib alone or combination treatment (olaparib + AVB-500). Colonies were stained and absorbance was obtained to calculate relative cell survival using Graph Pad Prism. In vivo studies were performed using NOD-SCID mice injected with 1 × 107 ARK1 cells intraperitoneally followed by treatment q3 days for 14-day treatment period. Treatment groups were vehicle control, AVB-500 alone, olaparib alone and olaparib with AVB-500. Results: ARK1 and ARK4 cells were found to have an increase in gamma-H2AX and RAD51 foci after radiation that was consistent with HRP. In clonogenic assays, colonies were stained and absorbance was obtained for each experimental arm. Olaparib + AVB-500 had significantly less absorbance than the olaparib only group for ARK1s (0.417nm vs 0.756nm, p=0.001) as well as in ARK4s (0.186nm vs 0.641nm, p=0.003). In an intraperitoneal model with ARK1 tumors, the olaparib + AVB-500 treated group had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p=0.002) and AVB-500 alone (0.008g vs 0.145g, p=0.0006) after a 14-day treatment period. Conclusions: AVB-500 in combination with olaparib demonstrates an improved response than olaparib alone with a greater decrease in tumor burden. This was demonstrated in two HRP cell lines. Additional therapeutic and mechanistic experiments are ongoing. Citation Format: Michael D. Toboni, Mary Mullen, Jo'an Tankou, Hollie Noia, Alyssa Oplt, Daniel Wilke, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO047.

Background: Over 80% of patients with advanced ovarian cancer will develop chemoresistance and die within 5 years. Biomarkers to predict chemoresponse and novel therapies to target chemoresistance would be practice changing. We aim to establish serum and tissue GAS6 as predictive biomarkers of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Further, we desired to understand the affect AVB has on DNA damage response (DDR). Methods: AVB was supplied by Aravive Biologics. High-grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor cells (OVCAR8, OVCAR5, COV62, and POV71-hTERT) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent (IF) assays targeting γH2AX were used to evaluate DNA damage and additional assays targeting 53BP1, RAD51, BRCA1, and BRCA2 were used to evaluate DNA damage response in cells treated with AVB, carboplatin, and/or AVB+carboplatin. Flow cytometry was used to evaluate RPA binding and cell cycle. Results: Patients with high pretreatment tumor GAS6 expression (>85%, n=7) or serum GAS6 concentrations (>25ng/mL, n=13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression ( Conclusions: High GAS6 is associated with poor neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability and tumor growth. AVB imparts a homologous recombination deficiency through downregulation of homology-directed DNA repair with an associated upregulation of nonhomologous end joining. Citation Format: Mary Margaret Mullen, Elena Lomonosova, Hollie Noia, Daniel Wilke, Alyssa Oplt, Lei Guo, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. Therapeutic AXL inhibition with AVB-S6-500 improves response to chemotherapy and induces a homologous recombination deficiency in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A13.

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.

e18108 Background: Evidence suggests DNA repair is a therapeutic target in endometrial cancer (EC). Given this, we determined whether combination therapy with AVB500, an AXL inhibitor, could improve response in a uterine serous cancer (USC) model. Methods: Two USC cell lines (ARK1 & ARK4) were treated with AVB500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB500 alone, olaparib alone or combination treatment (olaparib + AVB500); colonies were stained and absorbance was obtained to calculate relative cell viability using Graph Pad Prism. Baseline homologous recombination (HR) status was determined after radiating cells with 10Gy and identifying RAD51 foci by immunofluorescence (IF). Cell lines were considered to be HR proficient if over 30% of the cells expressed RAD51 ( > 5 foci per cell). IF was conducted using a Leica confocal microscope and foci were quantified using FociCounter. In vivo studies were performed using NOD-SCID mice injected with 1 x 107 ARK1 cells intraperitoneally followed by treatment q3 days for a 14 and 21 day treatment period. Treatment groups were vehicle control, AVB500 alone, olaparib alone and olaparib with AVB500. Results: The absorbance for olaparib + AVB500 was significantly less than the olaparib only group in two assays involving ARK1s (0.417nm vs 0.756nm, p = 0.001; 0.320nm vs 0.620nm, p = 0.008) as well as in ARK4s (0.186nm vs 0.641nm, p = 0.003). The HR assay indicated both cell lines were HR proficient. After baseline HR proficiency was established, the cell lines were pretreated with AVB500 prior to radiation. When compared to cells without treatment with AVB500, IF showed a decrease in RAD51 foci per cell in ARK1 (2.7 vs 7.3, p = 0.0003) and ARK4 (6.3 vs 13.0, p = 0.0054). The proportion of ARK1 cells expressing RAD51 decreased to 21%, indicating HR deficiency. Lastly, NOD-SCID mice receiving olaparib + AVB500 had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p = 0.002) and AVB500 alone (0.008g vs 0.145g, p = 0.0006) in a 14 day and a 21 day treatment period (0.212g vs 0.586g, p = 0.027 and 0.212 vs 0.494g, p = 0.005, respectively). Conclusions: HR proficient USC cell lines treated in vitro and in vivo with the combination of AVB500 and olaparib demonstrate an improved response to olaparib or AVB500 alone with a greater decrease in tumor burden. AVB500 appears to induce HR deficiency. Additional therapeutic and mechanistic experiments are ongoing.

Epithelial ovarian cancer (EOC) is the leading cause of death due to gynecologic malignancy. The majority of advanced stage EOC patients, even those who respond well to frontline therapy, will ultimately recur and succumb to their disease. In platinum-sensitive EOC patients, or those who recur ≥6 months from initial diagnosis, treatment of recurrent disease has traditionally consisted of repeat platinum-based chemotherapy. Secondary cytoreduction remains controversial. Due to recent advances in molecularly targeted treatment options, outcomes for advanced stage EOC patients are significantly improving and hold great promise. This review discusses pivotal trials establishing platinum-based combination chemotherapy as the standard of care and addresses the utility of increasing a patient's platinum-free interval. It then discusses the role of anti-angiogenesis therapeutics, specifically bevacizumab, cediranib, and trebananib and their side effects. Lastly, it reviews key trials for the three poly-adenosine diphosphate [ADP]-ribose polymerases (PARP) inhibitors that have been FDA-approved for maintenance therapy in platinum-sensitive recurrent EOC: olaparib, rucaparib, and niraparib. This review concludes with a discussion regarding ongoing and future clinical trials.