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Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC.Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERα target genes. Expression of this panel and ERα H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response.Results: Proliferation is ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3.Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802–12. ©2017 AACR.

Supplementary Materials, Methods, Figures and Table legends - PDF file 87K, Supplementary file giving details of supplementary materials and methods, figure legends and table legends

Supplementary Figure S2 - PDF file 84K, Phenotype of DCs following lysate-pulsing (i.e. HOCl-L, UVB-L or FTL), and activation with LPS and IFN-gamma. Unpulsed, mature (mDC) or immature DCs (iDC) served as controls. Data was presented as mean plus-minus SEM

Supplementary Table S1 - PDF file 191K, Cytokine and chemokine productions from DCs of ovarian cancer subjects that were loaded with HOCl-oxidized autologous whole tumor lysate and matured with LPS and IFN-gamma

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.

Supplementary Figure S3 - PDF file 128K, OCDC manufacturing process. Elutriated monocytes were obtained from subjects after leukapheresis and cultured in cell factories as described in Materials and Methods. HOCl-oxidized autologous tumor lysate was pulsed onto DCs for 16 to 20 hours, followed by activation and maturation with LPS and IFN-gamma for 6 to 8 hours. On day 5 of culture, matured lysate-pulsed DCs were harvested and cryopreserved until required

Supplementary File 3 contains the available pre- and post-treatment CA-125 data for our patient cohort.

Supplementary Figure S4 - PDF file 84K, A-B, Quantification of % Treg cells in subjects' pre- and post-vaccine PBMCs. C, fold-increase in serum cytokines and chemokines of subjects at EOS. Line indicated a 1 fold-increase from 1st OCDC vaccine to EOS

Supplementary Figure S1 - PDF file 81K, DCs pulsed with HOCl-L efficiently tumor-specific CD4+ and SIINFEKL-specific CD8+ T-cell responses in mice. A, representative dotplots showing the % of SIINFEKL-pentamer specific CD8+ T-cells (gated) in the spleens of mice following DC-lysate vaccinations. B, the % of CD3+CD4+ IFN-gamma secreting T-cells in response to live ID8-ova tumor cells was quantified in spleens 2 weeks after the 3rd vaccine. Data was the mean of 3 independent experiments with 5 mice in each experiment

Supplementary File 1 contains the genes included in the "EndoRx" NanoString code set.

This document contains the supplementary figures for the manuscript.

Supplementary Table S2 - PDF file 98K, Subject DC yield from leukapheresis

Bevacizumab; Folate receptor alpha; Platinum-resistant ovarian cancer Bevacizumab; Receptor de folato alfa; Cáncer de ovario resistente al platino Bevacizumab; Receptor de folat alfa; Càncer d'ovari resistent al platí Purpose Evaluate the antitumor activity and safety profile of the combination of mirvetuximab soravtansine and bevacizumab in patients with platinum-resistant ovarian cancer. Methods Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose most recent platinum-free interval was ≤6 months, were administered mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and bevacizumab (15 mg/kg), intravenously, once every 3 weeks. Eligibility included FRα expression by immunohistochemistry (IHC; ≥25% of cells with ≥2+ intensity). Prior bevacizumab and/or PARP inhibitor (PARPi) treatment were permitted. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. Results Ninety-four patients received combination treatment with mirvetuximab soravtansine and bevacizumab. Median age was 62 years (range, 39–81). Fifty-two percent had ≥3 prior therapies; 59% had prior bevacizumab; and 27% had prior PARPi. ORR was 44% (95% CI 33, 54) with 5 complete responses, median DOR 9.7 months (95% CI 6.9, 14.1), and median PFS 8.2 months (95% CI 6.8, 10.0). Treatment-related adverse events were consistent with the profiles of each agent, with the most common being blurred vision (all grades 57%; grade 3, 1%), diarrhea (54%; grade 3, 1%), and nausea (51%; grade 3, 1%). Conclusion The mirvetuximab soravtansine plus bevacizumab doublet is an active and well-tolerated regimen in patients with FRα-expressing platinum-resistant ovarian cancer. Promising activity was observed for patients regardless of level of FRα expression or prior bevacizumab. These data underscore the potential for mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this setting. This study was supported by ImmunoGen, Inc.

Non-Gestational Ovarian Choriocarcinoma (NGOC) is an extremely rare ovarian tumor, with an incidence of less than 0.6% of malignant ovarian germ cell tumors. Its close pathologic resemblance to Gestational Ovarian Choriocarcinoma (GOC), however, requires special attention as the treatments differ greatly. NGOC typically affects patients in late adolescence or early reproductive years. As a result, NGOCs are often misdiagnosed as ectopic pregnancies due to their common presentation of bleeding, abdominal pain, adnexal mass, and positive serum beta-HCG. On pathologic examination, the tumor is indistinguishable from GOC, and only after review of tissue for paternal genetic components can the diagnosis of NGOC be made. Imaging studies often show highly vascular lesions with further investigation with computer topography (CT) sometimes showing metastatic lesions in the lungs, pelvis, vagina, and liver. These lesions are often hemorrhagic and can lead to catastrophic bleeding. Treatment is vastly different from GOC; NGOC requires treatment with both surgical resection and chemotherapy, with Bleomycin, Etoposide, and Cisplatin (BEP) being the most used regimen. With correct diagnosis and treatment, patients can often receive fertility sparing treatment with long term survival.

Purpose: Endometriosis, a largely benign, chronic inflammatory disease, is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors. We aimed to identify plasma miRNAs that can be used to differentiate patients with endometriosis and ovarian cancer from healthy individuals. Experimental Design: We conducted a two-stage exploratory study to investigate the use of plasma miRNA profiling to differentiate between patients with endometriosis, patients with endometriosis-associated ovarian cancer (EAOC), and healthy individuals. In the first stage, using global profiling of more than 1,000 miRNAs via reverse transcriptase quantitative PCR (RT-qPCR) in a 20-patient initial screening cohort, we identified 23 candidate miRNAs, which are differentially expressed between healthy controls (n = 6), patients with endometriosis (n = 7), and patients with EAOC (n = 7) based on the fold changes. In the second stage, the 23 miRNAs were further tested in an expanded cohort (n = 88) of healthy individuals (n = 20), endometriosis (n = 33), EAOC (n = 14), and serous ovarian cancer cases (SOC; n = 21, included as controls). Results: We identified three distinct miRNA signatures with reliable differential expression between healthy individuals, patients with endometriosis, and patients with EAOC. When profiled against the control SOC category, our results revealed different miRNAs, suggesting that the identified signatures are reflective of disease-specific pathogenic mechanisms. This was further supported by the fact that the majority of miRNAs differentially expressed in human EAOCs were mirrored in a double transgenic mouse EAOC model. Conclusion: Our study reports for the first time that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and EAOC cases. Clin Cancer Res; 19(5); 1213–24. ©2013 AACR.

Background The indications for nonemergent operations during pregnancy remain undefined. Many surgeons defer nonemergent operations until after delivery to minimize fetal risk. We wished to determine the outcome of delaying cholecystectomy in pregnant patients hospitalized for nonacute gallbladder disease. Methods After approval from the Institutional Review Board, a retrospective case review at a large-volume regional referral center for high-risk obstetrics was performed. All pregnant inpatients from November 2003 to November 2006 who were diagnosed by a general surgeon with symptomatic cholelithiasis, choledocholithiasis, gallstone pancreatitis, biliary dyskinesia or chronic cholecystitis were included. Results Fifty-eight patients met the criteria over the 3-year period. Nineteen patients who underwent cholecystectomy during pregnancy were compared with 39 who were observed for gallbladder disease. Patients who were observed during pregnancy and remained at our institution through delivery had a higher rate of pregnancy-related complications (36%). In three cases, complications during pregnancy were directly attributable to gallbladder disease (parenteral nutrition during pregnancy, two unplanned inductions). Two patients (3.4%) were hospitalized for gallbladder disease diagnosed during a previous pregnancy and did not undergo cholecystectomy. Although 71% of the patients who were observed continued to be followed up at this institution for their obstetric care, 56% of those were lost to follow-up for their gallbladder disease. Nine of 39 observed patients (23%) had multiple hospital admissions (range 2-5). Of the 19 patients undergoing cholecystectomy during pregnancy, 3 were performed in the first (16%), 9 in the second (47%), and 7 in the third trimester (37%). Operative complications resulting from laparoscopic cholecystectomy during pregnancy occurred in one patient (cystic duct stump leak, nonoperative management). All cholecystectomies were performed laparoscopically. Discussion Delaying cholecystectomy for the hospitalized pregnant patient with gallbladder disease results in increased short- and long-term morbidity. There was high loss to follow-up among patients who were observed during pregnancy. In contrast, cholecystectomy during pregnancy resulted in a low rate of complications, and all were completed laparoscopically. This suggests that operative intervention for nonemergent symptomatic gallbladder disease during pregnancy may be beneficial and reduce overall morbidity.

Highlights • Ovarian cancer patients receiving bevacizumab treatment can experience significant adverse events. • We report a case of vertebral artery dissection associated with bevacizumab treatment.

Dendritic cells are the professional antigen-presenting cells of the innate immune system with the potential to generate robust antigen-specific T cell immune responses. Immunotherapeutic strategies have attempted to monopolize on this ability of dendritic cells to deliver antigens as a means of therapeutic vaccination in individuals with advanced malignancies. Since the publication of the first clinical trial in melanoma patients in 1995, therapeutic dendritic cell cancer vaccines have been extensively studied in numerous phase I and II trials. While advances have been encountered (especially with prostate cancer), there are still considerable challenges that need to be addressed in future clinical trials. In this review, we describe the current methodology and highlight trials which have contributed to the development of dendritic cell vaccines. We then review strategies to optimize dendritic cell vaccines in order to improve antitumor responses in cancer patients.

Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo. Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC. Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.

Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012.1 While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 years.1,2 Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer.3,4 By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer.

Despite advances in surgery and chemotherapy, epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy 1. Due to lack of a specific prodromal symptomatology as well as effective screening strategies, the vast majority of EOC patients present with advanced stage disease will ultimately die from their disease 1. Furthermore, while up to 80% of patients will respond to conventional primary platinum/taxane chemotherapy, greater than 60% will experience disease recurrence, and current reports indicate discouraging response rates of 20% in women with resistance to platinum-based chemotherapy 2. Preventive strategies, including improvements in early detection of disease as well as in preventing disease recurrence, are, therefore, crucial to improving prognosis. Ovarian cancer prevention can be defined by two main strategies: 1) early detection of cancer in at-risk patients and 2) prevention of recurrent disease in patients with an established diagnosis of cancer. Through the use of screening tools, such as serum biomarkers and medical imaging, early disease detection offers the promise of identifying cancer while still localized and potentially curable 3. Secondary preventive approaches aim to maintain patients without evidence of active disease and thereby extend their disease-free survival. Surveillance methods including serial biomarker measurements as well as therapeutic vaccinations have been examined for their impact on survival outcomes. Finally, risk stratification is critical to the success of any cancer prevention strategy; capitalizing on risk-reducing behaviors and intensive screening is most likely to improve individuals at greatest risk for disease-related morbidity and mortality. Current research in the early detection of ovarian cancer largely focuses on biomarker discovery, using transcriptome analysis, proteomics, epigenomics, metabolomics and glycomics of differentially expressed molecules between women with disease and healthy controls. Biomarkers already approved by the FDA (i.e., CA125 and HE4) or those under investigation, including osteopontin, MUC1 and mesothelin, offer hope for women at risk for disease development, especially those with predisposing genetic mutations 4. As part of this effort, we have generated site-specific biotinylated recombinant antibodies secreted by yeast (Biobodies 5) to costand time-effectively generate antibodies for developing screening tools for large populations of women 6. In addition, biomarkers, especially tumor associated antigens, may also serve as targets for vaccination 7.

With advances in surgical techniques and chemotherapeutic agents, mortality rates from epithelial ovarian cancer (EOC) have slightly decreased over the last 30 years. However, EOC still ranks as the most deadly gynecologic cancer with an overall 5-year survival rate of 45%. Prognosis is especially disappointing for women with platinum-resistant disease, where 80% of patients will fail to respond to available therapies. Emerging treatment strategies have sub-sequently focused on targets which are integral to tumor growth and metastasis. In this review, we will focus on those innovative agents currently under investigation in clinical trials.

MUC1 (CA15-3) and MUC16 (CA125) tumor-associated antigens are upregulated in ovarian cancer and can be detected in patients’ sera by standardized tests. We postulated that increased MUC1 and MUC16 antigens augment antibody responses in platinum-resistant ovarian cancer patients and that the frequency and intensity of these responses can be used as immune biomarkers of treatment response and disease outcome. We measured MUC1 and MUC16 tumor expression by immunohistochemistry (IHC), assessed serum antigenic levels and quantitated circulating antibodies by ELISA in a cohort of 28 ovarian cancer patients with platinum-resistant or platinum-refractory ovarian cancer, and treated with intraperitoneal (IP) interleukin-2 (IL-2). MUC1 and MUC16 were overexpressed in tumor samples and showed differential distribution profiles. Serum MUC1 (CA15-3) measurements were elevated in all patients and significantly correlated with increased risk of death (P = 0.003). MUC1-specific IgM and IgG anitbodies were found in 92 and 50% of cases, respectively. Patients with progressive disease had higher mean anti-MUC1 IgG than responders at both early (P = 0.025) and late (P = 0.022) time points during IP IL-2 treatment. Anti-MUC1 IgM antibodies inversely correlated with overall survival at both early (P = 0.052) and late (P = 0.009) time points. In contrast to MUC1, neither soluble MUC16 nor MUC16-specific antibodies were significantly associated with clinical response or overall survival in this study. Increased serum MUC1 and high anti-MUC1 antibody levels are prognostic for poor clinical response and reduced overall survival in platinum-resistant or platinum-refractory ovarian cancer.

Hypothesis:Conservative surgical management of ovarian neoplasms can result in favorable oncologic and obstetric outcomes.Methods:All reproductive-age women (18-45 years old) with stage IA to stage IIC ovarian neoplasms (N = 161) were retrospectively identified from a single institution's tumor registry between 1990 and 2007. Operative, pathological, outpatient, and delivery records were reviewed to confirm histological findings, stage, extent of surgical resection, adjuvant treatment, oncologic outcomes, and pregnancy outcomes.Results:Women who underwent conservative surgical management for ovarian neoplasms (n = 61 [37.9%]) were identified, including those with low malignant potential (LMP, n = 36), epithelial (n = 12), germ cell (n = 6), and sex cord (n = 7) tumors. Thirteen women conceived 23 pregnancies, producing a pregnancy rate of 25.0% overall and of 68.4% for those attempting conception. Women with LMP tumors conceived most pregnancies and had the highest number of antenatal complications. Of those receiving adjuvant chemotherapy (n = 8), 12.5% were able to conceive after their treatment and with no reported congenital anomalies. Pregnancy after a diagnosis of ovarian neoplasm did not impact disease recurrence (0% vs 7.7%, P = 0.56) or survival (100% vs 100%, P = 1.0).Conclusions:Conservative surgery may be an acceptable option for reproductive-age women with early-stage ovarian neoplasms. We report pregnancy and oncologic outcomes for a cohort of women managed conservatively for LMP, epithelial, germ cell, and sex cord ovarian neoplasms.

To determine if cervical intraepithelial neoplasia grade 3 (CIN-3) and cervical cancer are associated with adverse obstetrical outcomes.Women with diagnoses of CIN-3 and cervical cancer were first identified from the University of Pittsburgh Medical Center (UPMC) Network Cancer Registry by using respective ICD-3 codes. Identified records were then linked to the Magee Obstetrical Maternal and Infant (MOMI) database to identify women who subsequently delivered pregnancies at Magee-Womens Hospital. Women with cervical disease were compared with women without known disease to determine the impact of cervical disease on various maternal and neonatal outcomes. The latter group consisted of those women who delivered singleton pregnancies at our institution, as determined by the MOMI database, but who did not have any matching records in the UPMC Cancer Registry. Statistical significance was defined by a p value0.05.We identified CIN-3 (n = 52) and cervical cancer patients (n = 83) who later had documented pregnancies delivered at Magee-Womens Hospital between 1989 and 2006. Women with cervical cancer and CIN-3 were at greater risk to deliver small-for-gestational age (SGA) neonates compared with women without known cervical disease (RR 1.54, 95% confidence interval [CI] 1.0-2.46). A secondary analysis of risk factors for SGA neonates demonstrated a significant association with cervical cancer (p = 0.04). After accounting for variables known to be risk factors for SGA, cervical cancer was associated with a 1.9-fold increased risk of a SGA delivery (OR 1.9, 95% CI 1.1-3.4).Cervical cancer is a risk factor for delivery of an SGA neonate in a subsequent pregnancy.

Background Pregnancy after cytoreductive surgery and intraperitoneal chemotherapy is rare. Case We present the case of a 25-year-old woman with appendiceal carcinoid tumor treated with intraperitoneal cisplatin for peritoneal recurrence after a fertility-sparing cytoreductive procedure. Five years after her procedure, she conceived with the help of assisted reproductive technologies and delivered a viable term fetus via cesarean delivery. She subsequently had a successful second pregnancy and is currently alive without evidence of her disease. Conclusion Conception is possible after tumor debulking and intraperitoneal chemotherapy. In unique clinical situations, fertility-sparing surgery may be considered in young patients who desire future pregnancy.