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Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.

Objective The primary aim of this study was to pilot the use of an objective measurement technique to prospectively evaluate the incidence of lower extremity lymphedema (LEL) after minimally invasive staging surgery for endometrial cancer. Secondary objectives included observation of changes in lower extremity function and quality of life in this patient population. Methods A prospective evaluation of LEL was performed in 97 women who underwent minimally invasive staging surgery for endometrial cancer using comparative circumferential volume measurements. Postoperative changes in lower extremity function and global quality of life were also assessed using patient-reported outcome measures. Results Ninety-seven patients were included for lymphedema analysis. The rate of LEL was 25% at 4–6 weeks, 19% at 6–9 months, and 27% at 12–18 months postoperatively. The presence of LEL was associated with a significant worsening from baseline Lower Extremity Functional Scale (LEFS) scores at 4–6 weeks (−27.0% vs −3.7%, p = 0.02) and 6–9 months (−13.0% vs 0%, p = 0.01). LEL was not associated with a change in patient-reported global quality of life. Conclusions Up to one in four women experience lymphedema following surgical staging for endometrial cancer, and its presence is associated with diminished lower extremity function. Larger, prospective trials using the objective methodology piloted in this study should better clarify risk factors and long-term outcomes of this morbidity.

To determine rates and factors associated with regression of cervical intraepithelial neoplasia (CIN) 2 + between colposcopic biopsy and therapeutic excisional procedure in standard practice. A retrospective chart review was performed for women undergoing a cervical excisional procedure for CIN 2 + at clinics at three academic institutions over a 3-year period. Cytology, histology, patient age and time-to-excision were analyzed to determine factors influencing rates of regression. Of 356 women undergoing excision for CIN 2 + on colposcopic biopsy, 91 (25.3%) of final pathology diagnoses displayed clinically significant regression. Age and time-to-excision were not associated with regression, but referral cytology and severity of initial biopsy histology were, with ASC-H (aOR 0.1, CI 0.03, 0.8) and CIN 3/AIS (aOR 0.4, CI 0.2, 0.7) being less likely to regress than less severe lesions. Disease severity by referral cytology or diagnostic biopsy, as opposed to age or length of time-to-excision, is likely the most relevant factor in determination of regression for cervical intraepithelial neoplasia in women undergoing excisional treatment for biopsy-confirmed CIN2 +.

Practice changing standardization of lower extremity lymphedema quantitative measurements with integrated patient reported outcomes will likely refine and redefine the optimal risk-reduction strategies to diminish the devastating limb-related dysfunction and morbidity associated with treatment of gynecologic cancers. The National Cancer Institute (NCI), Division of Cancer Prevention brought together a diverse group of cancer treatment, therapy and patient reported outcomes experts to discuss the current state-of-the-science in lymphedema evaluation with the potential goal of incorporating new strategies for optimal evaluation of lymphedema in future developing gynecologic clinical trials.

Highlights • There is no consensus on optimal treatment for GTN and brain metastases. • Brain metastasis treated with craniotomy and intravenous, EMA-CO chemotherapy • Intravenous high-dose methotrexate may be adequate to treat brain metastases.

Predictive models are increasingly being used in clinical practice. The aim of the study was to develop a predictive model to identify patients with platinum-resistant ovarian cancer with a prognosis of less than 6 to 12 months who may benefit from immediate referral to hospice care.A retrospective chart review identified patients with platinum-resistant epithelial ovarian cancer who were treated at our institution between 2000 and 2011. A predictive model for survival was constructed based on the time from development of platinum resistance to death. Multivariate logistic regression modeling was used to identify significant survival predictors and to develop a predictive model. The following variables were included: time from diagnosis to platinum resistance, initial stage, debulking status, number of relapses, comorbidity score, albumin, hemoglobin, CA-125 levels, liver/lung metastasis, and the presence of a significant clinical event (SCE). An SCE was defined as a malignant bowel obstruction, pleural effusion, or ascites occurring on or before the diagnosis of platinum resistance.One hundred sixty-four patients met inclusion criteria. In the regression analysis, only an SCE and the presence of liver or lung metastasis were associated with poorer short-term survival (P0.001). Nine percent of patients with an SCE or liver or lung metastasis survived 6 months or greater and 0% survived 12 months or greater, compared with 85% and 67% of patients without an SCE or liver or lung metastasis, respectively.Patients with platinum-resistant ovarian cancer who have experienced an SCE or liver or lung metastasis have a high risk of death within 6 months and should be considered for immediate referral to hospice care.

Objective: To determine the rate and performance of sentinel lymph node (SLN) mapping among women with high-risk endometrial cancers. Methods: Patients diagnosed between 2012 and 2015 with uterine cancer of grade 3 endometrioid, clear cell, serous or carcinosarcoma histology and who underwent SLN mapping prior to full pelvic lymph node dissection were included. Subjects underwent methylene blue or ICG injection for laparoscopic (N = 16) or robotic-assisted laparoscopic (N = 20) staging. Outcomes included SLN mapping rates, SLN and non-SLN positive rates, false negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. Fisher's exact test was used to compare mapping and node positivity rates. Results: 9/36 (25%) patients with high-risk uterine cancer had at least one metastatic lymph node identified. Successful mapping occurred in 30/36 (83%) patients. SLN mapped to pelvic nodes bilaterally in 20 (56%), unilaterally in 9 (25%), and aortic nodes only in 1 (3%). Malignancy was identified in 14/95 (15%) of all sentinel nodes and 12/775 (1.5%) of all non-sentinel nodes (p

Purpose: The advent of multigene panels has increased genetic testing options for women with epithelial ovarian cancer (EOC). We designed a decision model to compare costs and probabilities of identifying a deleterious mutation or variant of uncertain significance (VUS) using different genetic testing strategies. Methods: A decision model was developed to compare costs and outcomes of two testing strategies for women with EOC: multigene testing (MGT) versus single-gene testing for BRCA1/2. Outcomes were mean cost and number of deleterious mutations and VUSs identified. Model inputs were obtained from published genetic testing data in EOC. One-way sensitivity analyses and Monte Carlo probabilistic sensitivity analyses were performed. Results: No family history model: MGT cost $1,160 more on average than BRCA1/2 testing and identified an additional 3.8 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $30,812 and identified 5.4 additional VUSs. Family history model: MGT cost $654 more on average and identified an additional 7.0 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $9,909 and identified 2.6 additional VUSs. Conclusion: MGT was associated with a higher additional cost per deleterious mutation identified and a higher ratio of VUS burden to actionable information in women with no family history as compared with women with a family history. Family history should be considered when determining an initial genetic testing platform in women with EOC.

To determine if early palliative care intervention in patients with recurrent, platinum-resistant ovarian cancer is potentially cost saving or cost-effective.A decision model with a 6 month time horizon evaluated routine care versus routine care plus early referral to a palliative medicine specialist (EPC) for recurrent platinum-resistant ovarian cancer. Model parameters included rates of inpatient admissions, emergency department (ED) visits, chemotherapy administration, and quality of life (QOL). From published ovarian cancer data, we assumed baseline rates over the final 6 months: hospitalization 70%, chemotherapy 60%, and ED visit 30%. Published data from a randomized trial evaluating EPC in metastatic lung cancer were used to model odds ratios (ORs) for potential reductions in hospitalization (OR 0.69), chemotherapy (OR 0.77), and emergency department care (OR 0.74) and improvement in QOL (OR 1.07). The costs of hospitalization, ED visit, chemotherapy, and EPC were based on published data. Ranges were used for sensitivity analysis. Effectiveness was quantified in quality adjusted life years (QALYs); survival was assumed equivalent between strategies.EPC was associated with a cost savings of $1285 per patient over routine care. In sensitivity analysis incorporating QOL, EPC was either dominant or cost-effective, with an incremental cost-effectiveness ratio (ICER)$50,000/QALY, unless the cost of outpatient EPC exceeded $2400. Assuming no clinical benefit other than QOL (no change in chemotherapy administration, hospitalizations or ED visits), EPC remained highly cost-effective with ICER $37,440/QALY.Early palliative care intervention has the potential to reduce costs associated with end of life care in patients with ovarian cancer.

Objectives (1) To describe the prevalence, timing and setting of documented end-of-life (EOL) discussions in patients with advanced ovarian cancer; and (2) to assess the impact of timing and setting of documented end-of-life discussions on EOL quality care measures. Methods A retrospective study of women who died of ovarian cancer diagnosed between 1999 and 2008 was conducted. The following are the EOL quality measures assessed: chemotherapy in the last 14days of life, >1 hospitalization in the last 30days, >1 ER visit in the last 30days, intensive care unit (ICU) admission in the last 30days, dying in an acute care setting, admitted to hospice ≤3days. Results One hundred seventy-seven (80%) patients had documented end-of-life discussions. Median interval from EOL discussion until death was 29days. Seventy-eight patients (44%) had EOL discussions as outpatient and 99 (56%) as inpatient. Sixty-four out of 220 (29%) patients' care did not conform to at least one EOL quality measure. An EOL discussion at least 30days before death was associated with a lower incidence of: chemotherapy in the last 14days of life ( p =0.003), >1 hospitalization in the last 30days ( p p =0.005), dying in acute care setting ( p =0.01), admitted to hospice ≤3days ( p =0.02). EOL discussion as outpatient was associated with fewer patients hospitalized >1 in the last 30days of life ( p Conclusions End-of-life care discussions are occurring too late in the disease process. Conformance with EOL quality measures can be achieved with earlier end-of-life care discussions.

Background: Therapies that activate the immune system to fight cancer have shown robust responses in solid tumors. However, most patients, including those with ovarian cancer, do not respond to these therapies alone. Drugs that inhibit epigenetic modifiers increase immune signaling from cancer cells. Epigenetic modifiers DNA methyltransferase inhibitors (DNMTi) and selective histone deacetylase inhibitors (HDACi),in particular selective HDAC6i, modulate immune-related pathways involved in anti-tumor immune responses. HDAC6i downregulate immunosuppressive ligands PD-L1 and PD-L2 via dephosphorylating pSTAT3 and upregulate tumor associated antigens (TAA) and antigen presentation machinery. Similarly, DNMTi activate anti-viral signaling via expression of Endogenous Retroviruses (ERVs) to trigger the type I interferon response, upregulate tumor antigen processing and presentation, and stimulate pro-inflammatory cytokines. The aim of our study is to test if the combination of epigenetic modulators Nexturastat A (Next A), a selective HDAC6i, and 5-azacytidine (AZA), a DNMTi, can be safely used to increase an immune response in ovarian cancer. We hypothesize that these drugs will enhance tumor immunity alone and when combined with immune checkpoint blockades targeting PD-1. Results: HDAC enzymes are differentially expressed in A2780, HEY, OVCAR3, SKOV3, and TYKNu human ovarian cancer cell lines. HDAC1 and HDAC2 proteins were similarly expressed in HEY and SKOV3 whereas HDAC6 was expressed at lower levels in HEY and TYKNu but at higher levels in SKOV3, OVCAR3, and A2780. As previously reported we believe this may be due to the presence of the chromatin modifier ARID1A mutation in the SKOV3 and A2780 cell lines. The upregulation of HDAC6 also correlated with a higher IC50 for NextA treatment in those particular cell lines. Further immunoblots showed that PD-L1, a marker of poor prognosis in ovarian cancer, decreased after treatment with NextA and even more in combination with AZA. Additionally, DNMT1, the known target of AZA, was decreased after treatment with AZA and NextA, both independently and in combination, a finding that has not been previously reported. Conclusions: As shown previously, HDAC6 enzyme levels are higher in cell lines with ARID1A mutations. DNMT1 was decreased after treatment with AZA, as expected, but surprisingly also after treatment with NextA. PD-L1 decreased after treatment with NextA and even more so when combined with AZA. We thus believe that combining these two epigenetic modifiers will lead to an additive effect on immune signaling through stimulation of antiviral signaling (DNMTi), which can upregulate the immunosuppressive ligand PD-L1, which is then reduced by HDAC6 inhibition. We are currently testing the combination of both epigenetic modifiers with anti-PD-1 in an immunocompetent mouse model of ovarian cancer. Citation Format: Aneil P. Srivastava, Sara M. Moufarrij, Melissa Hadley, Sarah Chisholm, Micael Lopez-Acevedo, Alejandro Villagra, Katherine B. Chiappinelli. HDAC6 and DNMT inhibition affect immunogenicity of ovarian cancer cells: A rationale for combining epigenetic and immune therapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1395.

Background To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway. Methods SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated. Results Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p

Despite the increasing availability of palliative care, oncology providers often misunderstand and underutilize these resources. The goals of palliative care are relief of suffering and provision of the best possible quality of life for both the patient and her family, regardless of where she is in the natural history of her disease. Lack of understanding and awareness of the services provided by palliative care physicians underlie barriers to referral. Oncologic providers spend a significant amount of time palliating the symptoms of cancer and its treatment; involvement of specialty palliative care providers can assist in managing the complex patient. Patients with gynecologic malignancies remain an ideal population for palliative care intervention. This review of the literature explores the current state of palliative care in the treatment of gynecologic cancers and its implications for the quality and cost of this treatment.

Objective To determine the outcomes associated with primary radiation therapy for medically inoperable, clinical stage I and II, endometrial adenocarcinoma (EAC). Methods A multi-institution, retrospective chart review from January 1997 to January 2009 was performed. Overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) and time to progression (TTP) were assessed using the Kaplan–Meier method. Disease-specific survival was analyzed using a competing risks approach. Results Seventy-four patients were evaluable. The median age and BMI were 65years (range 36–92years) and 46kg/m 2 (range 23–111kg/m 2 ), respectively. 85.1% had severe systemic disease, most frequently cardiopulmonary risk and morbid obesity. With a mean follow-up of 31months, 13 patients (17.6%) experienced a recurrence. The median PFS and OS were 43.5months and 47.2months, respectively. Overall, 35 women died, including 4 women who died of unknown cause. Of the remaining 31 women, 7 patients (9.5%) died of disease, while 24 died of other causes (32.4%). The hazard ratio comparing the risk of death due to other causes to the risk of death due to disease was 3.4 (95% CI 1.4–9.4, p=0.003). Among patients who are alive three years after diagnosis, 14% recurred and the conditional recurrence estimate did not exceed 16%. Conclusions Primary radiation therapy for clinical stage I and II EAC is a feasible option for medically inoperable patients and provides disease control, with fewer than 16% of surviving patients experiencing recurrence.

Objectives: Few studies have described genetic counseling and testing of specific minority patients at risk for ovarian cancer. The purpose of this study was to describe our experience with genetic counseling and testing of an African American (AA) population evaluated at a large, southeastern medical center. Methods: We reviewed an institutional review board-approved prospectively gathered database of all patients evaluated in an Ovarian Cancer Risk Assessment Clinic. Data evaluated included general demographics, family and personal history of cancer, frequency of genetic testing, frequency and types of deleterious mutations, and performance of risk-reducing salpingo-oophorectomy (RRSO). Results: From 2003 to 2014, 76/1004 patients (7.6%) evaluated in this clinic were AA. Sixty-four (84%) of these patients had a family history of ovarian and/or breast cancer, and 12 (16%) had a personal history of ovarian cancer. Thirty-six patients (47%) underwent genetic counseling only and 40 (53%) opted for genetic testing. Of the 40 women tested, 18 (45%) were found to have an abnormal genetic result. Six patients each had BRCA1 and BRCA2 deleterious mutations, respectively. Four patients had BRCA2 variant results, with three favoring polymorphism. RRSO was performed in six of 18 patients with BRCA mutations or variants, none of whom were noted to have ovarian or fallopian tube cancer at the time of surgery. None of the patients who did not undergo genetic testing or did not have a BRCA mutation or variant have developed ovarian cancer. Conclusions: This study demonstrates that in a region of the country where AAs represent 30% of the population, the number of AA patients as a proportion of all patients referred to an Ovarian Cancer Risk Assessment Clinic for genetic counseling remains low. Genetic testing was, however, performed at a rate comparable to Caucasians, suggesting barriers to genetic counseling and testing may be overcome once patients are evaluated in a dedicated clinic. Of the patients tested, the mutation and variant rate was high, although this may be representative of a more select series of at-risk patients. Efforts should continue to identify minority patients at risk for ovarian cancer and to refer them to dedicated genetic counseling clinics.