Advanced Stage Ovarian Cancer Patients Research Articles

Diaphragmatic peritonectomy during cytoreductive surgery in advanced stage ovarian cancer patients: more efforts from gynecologist can give more hope to the patient

Diaphragmatic peritonectomy during cytoreductive surgery in advanced stage ovarian cancer patients: more efforts from gynecologist can give more hope to the patient

879PD - Novel Pharmacogenetic Germline Candidates of Bevacizumab-Related Survival in the Icon7 Trial of Advanced Stage Ovarian Cancer

Aim: Bevacizumab improves progression-free survival in advanced stage ovarian cancer patients treated with carboplatin and paclitaxel. We evaluated the role of genetic variants in modifying the benefit of bevacizumab in ICON7, one of the key clinical trials to describe this benefit in ovarian cancer. Using a hypothesis-agnostic genome-wide association study (GWAS) approach, we evaluated association of genetic markers with survival. Methods: Germline DNA from 437 patients were genotyped using an Illumina Omni-Platform. In an interaction analysis, Cox proportional hazard models of overall survival generated P-values for bevacizumab-polymorphism interaction terms. We further described the interactions by assessing treatment arm-specific hazard ratios and 95% confidence intervals adjusted for clinical prognostic factors. Likelihood ratio tests were performed comparing models with and without the interaction term; an additive genetic inheritance model was assumed. Results: After quality control steps, 400 patient samples and 727,683 markers were evaluable. Median follow-up was 2.1 years, with 22% deaths. After adjusting for treatment arm, country, FIGO stage, and treatment initiation time relative to diagnosis, no single marker reached global GWAS significance. The top markers associated with overall survival were in the CD26 gene family, with the top genetic variants had an interaction P value of 2.3x10−6. For an increase in each minor allele, there was an increase in risk of death in patients treated with the standard chemotherapy arm (adjusted aHR, 2.55 (95%CI: 1.7-3.9). In contrast, in the bevacizumab-treatment arm, the corresponding aHR was 0.64 (95%CI:0.4-1.0). This family of molecules has been associated with angiogenesis and epithelial ovarian cancer through its link with CXC chemokine activity. Conclusions: Novel genetic markers in the CD26 family were associated with bevacizumab- related survival in the ICON7 trial. Validation in other bevacizumab treatment trials is warranted.

Nutritional Risk Index as a significant prognostic factor in advanced-stage epithelial ovarian cancer patients

Nutritional Risk Index as a significant prognostic factor in advanced-stage epithelial ovarian cancer patients

Diffusion of Intraperitoneal Chemotherapy in Women with Advanced Ovarian Cancer in Community Settings 2003–2008: The Effect of the NCI Clinical Recommendation

Purpose: A 2006 National Cancer Institute clinical announcement recommended the use of combined intravenous (IV) and intraperitoneal (IP) chemotherapy over IV chemotherapy alone for women with International Federation of Gynecology and Obstetrics (FIGO) stage 3 optimally debulked ovarian cancer due to significant survival benefit demonstrated in multiple randomized clinical trials. We examined uptake of IP chemotherapy in community practice before and after this recommendation.Methods: We identified 288 women with FIGO stage 2 or greater incident ovarian cancer diagnosed from 2003 to 2008 at three integrated delivery systems in the US. Administrative health plan data were used to determine patient characteristics and receipt of IV and IP chemotherapy within 12 months of diagnosis. We compared characteristics of women receiving IV chemotherapy alone vs. IP chemotherapy (with or without IV chemotherapy) and assessed temporal trends in IP chemotherapy use.Results: Overall 12.5% (n = 36) of women received IP chemotherapy during the study period. IP chemotherapy use was non-existent between 2003 and 2005. Use of IP chemotherapy occurred among 26.9% of women diagnosed in 2006 and plateaued at 20.4% of women diagnosed in 2008. IP recipients were younger (mean age 55.9 vs. 63.5 years, p = < 0.001) and more likely to have stage 3 ovarian cancer (77.8 vs. 50.4% p = 0.039) compared to their IV-only chemotherapy counterparts.Conclusion: Use of IP chemotherapy for newly diagnosed advanced stage ovarian cancer patients was uncommon in this community setting. Future research should identify potential patient, physician, and system barriers and facilitators to using IP chemotherapy in this setting.

A chemoresponse assay for prediction of platinum resistance in primary ovarian cancer

Recurrence following primary platinum-based chemotherapy remains a challenge in the treatment of patients with advanced-stage epithelial ovarian cancer. This study examines whether a chemoresponse assay can identify patients who are platinum-resistant prior to treatment. Women (n = 276) with International Federation of Gynecology and Obstetrics stage III-IV ovarian, fallopian, and peritoneal cancer were enrolled in an observational study, and the responsiveness of their tumors was evaluated using a chemoresponse assay. All patients were treated with a platinum/taxane regimen following cytoreductive surgery. Assay responses to carboplatin or paclitaxel were classified as sensitive, intermediate sensitive (IS), or resistant. Association of assay response with progression-free survival (PFS) was analyzed using the Kaplan-Meier method and a Cox regression model. Patients whose tumors were resistant to carboplatin were at increased risk of disease progression compared to those with nonresistant (sensitive + IS) tumors (median PFS: 11.8 vs 16.6 months, respectively, P < .001), and the association was confirmed after adjusting for other clinical factors (hazard ratio, 1.71; 95% confidence interval, 1.12-2.62; P = .013). Association of assay response to paclitaxel with PFS trended in multivariate analysis (hazard ratio, 1.28; 95% confidence interval, 0.84-1.95; P = .245). For tumors resistant to carboplatin, 59% were sensitive or IS to at least 1 other commonly used agent, demonstrating the ability of the assay to inform treatment decisions beyond the standard platinum/taxane regimen. Assay resistance to carboplatin is strongly associated with shortened PFS among advanced-stage epithelial ovarian cancer patients treated with carboplatin + paclitaxel therapy, supporting use of this assay to identify patients likely to experience early recurrence on standard platinum-based therapy.

Therapeutic vaccines and cancer: focus on DPX-0907

In an attempt to significantly enhance immunogenicity of peptide cancer vaccines, we developed a novel non-emulsion depot-forming vaccine platform called DepoVax™ (DPX). Human leukocyte antigen (HLA)-A2 restricted peptides naturally presented by cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. In a phase I clinical study, the safety and immune-activating potential of DPX-0907 in advanced-stage breast, ovarian, and prostate cancer patients were examined, following encouraging results in HLA-A2 transgenic mice. The DPX-0907 vaccine was shown to be safe and well tolerated, with injection-site reactions being the most commonly reported adverse event. Vaccinated cancer patients exhibited a 61% immune response rate, with higher response rates in the breast and ovarian cancer patient cohorts. In keeping with the higher immune efficacy of this vaccine platform, antigen-specific responses were detected in 73% of immune responders after just one vaccination. In 83% of responders, peptide-specific T-cells were detected at two or more time points post-vaccination, with 64% of these patients showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T-cell memory, with the ability to secrete multiple type 1 cytokines. The novel DPX formulation promotes multifunctional effector/memory responses to peptide-based tumor-associated antigens. The data support the capacity of DPX-0907 to elicit type-1 biased immune responses, warranting further clinical development of the vaccine. In this review, we discuss the rationale for developing DPX-based therapeutic cancer vaccine(s), with a focus on DPX-0907, aimed at inducing efficient anti-tumor immunity that may eventually be shown to prolong patient survival.

Cost-Effectiveness of Early-Initiated Treatment for Advanced-Stage Epithelial Ovarian Cancer Patients: A Modeling Study

Between diagnosis and primary treatment of patients with epithelial ovarian cancer (EOC), gaps of several weeks exist. Reducing these time intervals may benefit the patient and may lead to a reduction of costs. We explored the cost-effectiveness of early-initiated treatment of patients with suspected advanced-stage EOC compared with that of current treatment. A discrete event simulation was used to synthesize all available evidences and to evaluate the health care costs and effects (quality-adjusted life years [QALYs]) of the 2 treatment strategies over lifetime. Overall survival, progression-free survival, health-related quality of life, and costs of the separate events were assumed to remain equal. Other uncertainties were addressed using deterministic and probabilistic sensitivity analyses. The treatment times of current and early-initiated treatment were 27 and 24 weeks, respectively. Early-initiated treatment yielded 3.42 QALYs per patient, for a total expected health care cost of €25,654. Current treatment yielded 3.40 QALYs per patient, for a total expected health care cost of €25,607. This resulted in an incremental cost-effectiveness ratio of €2592 per QALY gained for early-initiated treatment compared with that for current treatment. For the willingness to pay for €30,000 or more per QALY, early-initiated treatment had a 100% probability of being cost-effective compared with current treatment under the previously mentioned assumptions. Given the current evidence, early-initiated treatment of patients with suspected advanced-stage EOC leads to additional QALYs and seems to be cost-effective compared with current treatment.

Distinct molecular signature of recurrent ovarian tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients

Seventypercentofovariancancerpatientsdieduetoconsecutiveepisodesofrecurrencesresultingfromthere-growth of ovarian tumor cells resistant to conventional chemotherapies. In an effort to identify chemoresistance mechanisms, we comparedtheexpressionofgenesintumorcellsisolatedfromtheascitesofadvanced-stageserousovariancancerpatientsprior to(chemonaive,CN)andafterchemotherapytreatments(chemoresistant/recurrent,CR).Anovel,recentlypublishedmethodwas used for the isolation of tumor cells from the ascites of CN and CR patients. Illumina HT-12 platform was used to assess the differentialexpressionofgenes(DEGs)betweentheisolatedtumorcellsfromtheascitesofCNandCRpatients.Theidentification ofDEGswasachievedbycomparingthegeneticsignaturesofCNversusCRsamplesbyameanexpressionratio(foldchange)of 2 and P < 0.05. Validation of selected genes was performed by quantitative Real Time Polymerase Chain Reaction (qRT-PCR). The dominant canonical pathways in the CR versus CN tumor cells were determined by Ingenuity Pathway Analysis. Gene expressionanalysisrevealeddifferentialexpressionof414genes,with179genesupregulatedand235downregulatedintheCR group. There were significant differences in gene expressions encoding for proteins involved with cancer stem cells, cell-cell adhesion, embryonic development, tumor suppression, immune surveillance, retinoic acid and energy metabolism in tumor cells isolated from CR compared to CN patients. Pathway analysis revealed that changes in cell cycle pathways, prominently those involved with mitosis and polo-like kinase (PLK1), G2/M DNA damage and proteins linked with cell cycle checkpoint regulation associated with chemoresistance. This preliminary molecular profiling, on a small number of patient samples, suggests an importantdiscriminationofgenesintheisolatedtumorcellsderivedfromtheascitesofCNandCRpatients.Thistypeofstudyon a larger cohort of samples may have important clinical implications for the development of therapeutic strategies to overcome chemoresistance and associated recurrences in ovarian cancer patients.

Preliminary results of a triple peptide escalating dose vaccination phase I/II clinical trial as consolidation treatment in women affected by ovarian cancer

Ovarian cancer remains one of the most lethal malignancies in developed countries and recently no improvement in disease free survival (DFS) and overall survival (OS) has been numbered for conventional therapies. Immunotherapy could be employed as consolidation treatment after standard therapies in patients in which disease and immune suppression is minimal. Furthermore, epitope spread and new adjutants have been found to significantly increase the efficacy of novel immunotherapic strategies.This Phase I/II study aimed to improve vaccine potency and enhance immune response of two mucins (MUC-1 and CEA) and Erb-B2 tumour associated antigens (TAAs), with the co-administration of a new adjuvant combination: Montanide ISA51 plus GM-CSF. Keyhole Limpet Hemocyanin (KLH) was adopted as immunological tracker.Ten disease-free HLA-A2 aplotype high-risk serous advanced stage ovarian cancer patients underwent a two-groups safety clinical trial vaccination protocol at “Sapienza” University of Rome from 2007 to 2010. CEA, Erb-B2 and MUC1 expression rates on primary tumours were 40%, 30% and 100%, respectively. Group A (8 patients) received 100μg of each peptide per dose accordingly to the immunohistochemically antigen expression, whereas GroupB (2 patients) was vaccinated with all the peptide regardless TAAs expression at the dose of 500μg each. Vaccination schedule included 6 consecutive peptide vaccine administrations and a recall dose at 3 months from the sixth dose. Results revealed the vaccine to be safe and feasible in ovarian cancer patients. Side effects accounts for ECOG scale 1-2 levels signs (itch, erythema and tumescence at injection site) and symptoms (fever, fatigue and malaise), for both the dose-administered. Good compliance was found to vaccine schedule in all patients enrolled. Secondary endpoints results revealed a 5 years 50% (3/6 patients) DFS and a 83% (5/6 patients) OS in FIGO stages IIIc-IV ovarian cancer patients (60%; 6/10 patients). Moreover, immunological and clinical correlation analysis revealed a significant increased IFNγ CD8+ specific T-cells production along with vaccination steps (χ2=6.67; p<0.009) in the subgroup of patients who did not recur vs. controls (mean follow up: 845.1 days; range 55-1523). The highest number of vaccine induced specific CD8+ cells were found at the end of the 6 doses although high levels of T-cells could be also re-induced by the recall boost. A significantly higher specific immune response was observed in the group B.

Preoperative Fluorine 18 Fluorodeoxyglucose Tumoral Uptake Ratio Between Upper and Lower Abdomen in Primary Advanced-Stage Ovarian Cancer

The objective of this study was to assess whether the ratio of upper abdomen (UA) to lower abdomen (LA) (relative to the umbilicus) standardized fluorine 18 fluorodeoxyglucose uptake, as measured by preoperative positron emission tomography and computed tomography, is predictive of recurrence, survival, and suboptimal cytoreduction (residual tumor >1.0 cm) in advanced-stage ovarian cancer (AOC). Positron emission tomography/computed tomography before surgical staging was performed in 159 AOC patients. The ratio between the highest maximum standardized uptake value (SUV(max)) in the UA and the LA was expressed as UA/LA SUV(max). Clinicopathological characteristics and follow-up information were collected retrospectively. Cox proportional hazards analysis was used to identify prognostic factors for recurrence and survival. Logistic regression analysis was used to identify predictors of suboptimal cytoreduction. The median age and follow-up period were 55 years (range, 27-80 years) and 32 months (range, 1-92 months), respectively; 133 and 26 patients had stage III and IV disease, respectively. There were 120 and 54 cases of recurrence and disease-specific death, respectively. Multivariate analysis showed that recurrence was associated significantly with high UA/LA SUV(max) (P < 0.05; hazard ratio [HR], 4.902; 95% confidence interval [CI], 2.521-9.531) and suboptimal cytoreduction (P < 0.05; HR, 2.431; 95% CI, 1.561-3.788), and that disease-specific death was significantly associated with high UA/LA SUV(max) (P < 0.05; HR, 2.777; 95% CI, 1.270-6.075), suboptimal cytoreduction (P < 0.05; HR, 1.951; 95% CI, 1.080-3.524), and histology (P < 0.05; HR, 4.134; 95% CI, 1.676-10.196). Upper abdomen/lower abdomen SUV(max) was the only independent predictor of suboptimal cytoreduction (P < 0.05; odds ratio, 4.644; 95% CI, 1.676-12.862). High preoperative UA/LA SUV(max) was significantly associated with poor prognosis and may be predictive of suboptimal cytoreduction in AOC. This parameter may be considered in the treatment of AOC patients.

Which patients benefit most from primary surgery or neoadjuvant chemotherapy in stage IIIC or IV ovarian cancer? An exploratory analysis of the European Organisation for Research and Treatment of Cancer 55971 randomised trial

BackgroundTo investigate whether biomarkers consisting of baseline characteristics of advanced stage ovarian cancer patients can help in identifying subgroups of patients who would benefit more from primary surgery or neoadjuvant chemotherapy. MethodsWe used data of the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial in which 670 patients were randomly assigned to primary surgery or neoadjuvant chemotherapy. The primary outcome was overall survival. Ten baseline clinical and pathological characteristics were selected as potential biomarkers. Using Subpopulation Treatment Effect Pattern Plots (STEPP), biomarkers with a statistically significant qualitative additive interaction with treatment were considered as potentially informative for treatment selection. We also combined selected biomarkers to form a multimarker treatment selection rule. FindingsThe size of the largest metastatic tumour and clinical stage were significantly associated with the magnitude of the benefit from treatment, in terms of five-year survival (p for interaction: 0.008 and 0.016, respectively). Stage IIIC patients with metastatic tumours ⩽45mm benefited more from primary surgery while stage IV patients with metastatic tumours >45mm benefited more from neoadjuvant chemotherapy. In stage IIIC patients with larger metastatic tumours and in stage IV patients with less extensive metastatic tumours both treatments were equally effective. We estimated that by selecting treatments for patients based on largest metastatic tumour and clinical stage, the potential five-year survival rate in the population of treated patients would be 27.3% (95% confidence interval (CI) 21.9–33.0), 7.8% higher than if all were treated with primary surgery, and 5.6% higher if all were treated with neoadjuvant chemotherapy. InterpretationAlthough survival was comparable after primary surgery and neoadjuvant chemotherapy in the overall group of patients with ovarian cancer in the EORTC 55971 trial, we found in this exploratory analysis that patients with stage IIIC and less extensive metastatic tumours had higher survival with primary surgery, while patients with stage IV disease and large metastatic tumours had higher survival with neoadjuvant chemotherapy. For patients who did not meet these criteria, both treatment options led to comparable survival rates.

An evaluation of molecular markers that predict maximal surgical cytoreduction: A Gynecologic Oncology Group trial

Objective: To evaluate molecular and clinical markers previously linked to overall survival for their ability to predict residual disease status following primary surgical cytoreduction in advanced-stage epithelial ovarian cancer (EOC) patients enrolled in GOG trials.

Abstract 646: Identification of novel epigenetic biomarkers for platinum-based chemotherapy resistance in high grade serous ovarian cancer.

Abstract Platinum-based chemotherapy has been standard of care for advanced stage ovarian cancer (OC) patients since the last 3 decades. However, majority of patients relapse within 6 months with drug-resistant disease, which entitle OC among the most lethal gynecological malignancy. Besides ‘’classic’’ clinicopathological features of the primary tumor, no biological parameters have shown clinically predictive and prognostic value for chemoresponse in OC. In the present study, we are focusing on the identification of novel DNA methylation markers in response to platinum-based chemotherapy in high grade serous OC. To accomplish this aim, we performed next generation sequencing on methylation-enriched genomic DNA, isolated from frozen OC patient material from responders (more than 18 months progression free survival) and non-responders (less than 6 months progression free survival) to platinum chemoresponse (n=10 in each group). Subsequent robust biostatistics and comparative expression data analysis revealed a list of significantly differentially methylated genes of which a number were checked by methylation specific PCR (MSP) on a large platinum sensitive and resistance OC cell line panel. Gene ontology analysis showed that these genes are frequently associated with cell-fate determination, lineage commitment, transcriptional factor binding and ions-transporter system. Selected candidate methylation markers are currently being validated by pyrosequencing. Moreover, these selected markers are in-silico validated with publically available methylation and expression databases. Next, selected candidate methylation markers will be validated by quantitative-MSP on an independent OC patient cohort. Ultimately, this study will provide a DNA methylation profile for identifying those patients that may benefit from platinum-based chemotherapy in combination with epigenetic treatment modalities. Citation Format: Tushar Tomar, Nicolette G. Alkema, Tim De Meyer, Wim van Criekinge, Harry G. Klip, Gert Jan Meersma, Ate GJ van der Zee, Steven de Jong, G. Bea A. Wisman. Identification of novel epigenetic biomarkers for platinum-based chemotherapy resistance in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 646. doi:10.1158/1538-7445.AM2013-646

A phase II clinical trial of polyethylene glycol-conjugated L-asparaginase in patients with advanced ovarian cancer: Early closure for safety

The anti-angiogenic activity of L-asparaginase (L-ASP) and the sensitivity of ovarian cancer cell lines to L-ASP has been previously demonstrated by preclinical findings. The aim of this clinical trial was to translate those findings and evaluate the activity of polyethylene glycol-conjugated L-asparaginase (PEG-ASP or pegaspargase) in advanced ovarian cancer. Women with recurrent ovarian cancer and good end-organ function were enrolled in an open-label phase II trial of PEG-ASP at a dose of 2,000 IU/m2 by intravenous infusion every 2 weeks. Patients were evaluated for response every 8 weeks and for toxicity on an ongoing basis. Early stopping rules for toxicity and activity were included. Four patients were enrolled and received a total of 7 treatment cycles. The study ended accrual by invoking an early stopping rule, after excessive toxicity was identified in patients. Drug-related toxicities included grade 2 pancreatitis, fatigue, neutropenia, hypoalbuminemia, weight loss, dehydration, decreased fibrinogen and 1 case of grade 3 hypersensitivity reaction during cycle 2. One patient died during the study. No patients were evaluable for response. PEG-ASP was poorly tolerated in this group of advanced-stage ovarian cancer patients and no conclusions regarding activity may be drawn. Further studies of PEG-ASP in ovarian cancer patients are not recommended.

142 TAS-2913 is a Mutant Selective EGFR Inhibitor for NSCLC: Characterization Against EGFR T790M in Cell and Xenograft Models

activation of ErbB3 and to sensitize platinum-resistant cells to subsequent chemotherapy. Materials and Methods: Cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines were acquired from ATCC. Primary ascites cells were isolated from advanced stage ovarian cancer patients who had undergone prior therapy. Cells were propagated in vitro and cell viability assays were performed in the presence of platinum-based drugs, taxanes, or MM-121. Heregulin stimulation and inhibition of signaling by MM-121 were evaluated by quantitative western blotting and reverse phase protein arrays. Drug sensitivity and signaling were assessed for A2780 and A2780cis using subcutaneous xenografts. Basal heregulin levels were measured by ELISA and mRNA-based methods. Results: Consistent with our hypothesis that platinum resistance can be mediated by ligand-driven ErbB3 signaling, basal heregulin levels were increased in A2780cis cells relative to A2780 cells, and growth of A2780cis (but not A2780) xenografts was sensitive to MM-121. Interestingly, patientderived ascites cells exhibited differential sensitivity to paclitaxel and platinum-based drugs, and cells collected serially from the same patient over the course of treatment provided evidence of acquired resistance. Ascites cells responded differently to heregulin stimulation and inhibition by MM-121, suggesting that only a subset of cells develop resistance through this mechanism. In most cases, cells that are responsive to heregulin are also responsive to MM-121, and MM-121 sensitizes some of these cells to paclitaxel treatment. Conclusion: Platinum resistance is associated with increased heregulin expression or responsiveness to heregulin in cell lines and primary ascites cells. MM-121 could potentially play a role in overcoming platinum resistance or in sensitizing cells to subsequent chemotherapy. As only a subset of cells use this mechanism, a biomarker-based strategy to identify patients could be useful. A Phase 2 randomized open label study of MM-121 in combination with paclitaxel versus paclitaxel alone is currently enrolling patients with advanced ovarian cancer.

Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients

BackgroundGlycodelin is a cell surface glycoprotein offering a unique gender specific carbohydrate configuration. Sialylated carbohydrate structures, which are unusual for mammals, characterize Glycodelin isolated from amniotic fluid (Glycodelin A, GdA). Glycodelin in general exerts multiple, partly opposing functions ranging from immunosuppression to cell differentiation. As these markedly influence tumorigenesis, this study aimed to clarify whether expression of different Glycodelin isoforms is related to clinicopathological characteristics and prognosis of ovarian cancer patients. Further the use of Glycodelin as a serum marker in benign and malignant ovarian diseases was evaluated.MethodsOvarian cancer specimens (n = 152) were stained for Glycodelin with carbohydrate and peptide specific antibodies. Associations between Glycodelin expression and histological grading, FIGO stage as well as patient’s prognosis were examined. Glycodelin was correlated to expression of gonadotropin receptors and mucin-1, which are discussed as ovarian cancer tissue markers. In addition, Glycodelin serum concentrations were analyzed in patients suffering from benign (n = 73) or malignant (n = 38) ovarian neoplasias.ResultsGlycodelin A was found to be an independent prognostic marker for poor prognosis in advanced ovarian cancer patients. GdA staining correlated with gonadotropin receptor (FSHR and LHCGR) and with hCG expression. Gd expression showed a positive correlation with a tumour-associated epitope of mucin 1 (TA-MUC1). Further, compared to ovarian cancer, serum Gd was increased in patients with benign ovarian tumors.ConclusionGlycodelin A might be related to tumor aggressiveness and poor clinical outcome in advanced epithelial ovarian cancer. Glycodelin serum levels found in patients suffering from benign ovarian tumors, might contribute to a more global attenuation during progression of these precursor lesions.

First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients

BackgroundDepoVaxTM is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907.MethodsA phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol.ResultsDPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines.ConclusionsThe novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent.Trial RegistrationClinicalTrials.gov NCT01095848

857 MicroRNA Predictor of Early Relapse in Advanced Stage Ovarian Cancer Patients

857 MicroRNA Predictor of Early Relapse in Advanced Stage Ovarian Cancer Patients

Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on multifunctional T-cell responses in ovarian, breast, and prostate cancer patients.

2588 Background: To increase the efficacy of peptide cancer vaccines, we developed a novel vaccine platform called DepoVax, an adjuvanted water-free depot formulation with the ability to generate enhanced immune responses. Naturally processed HLA-A2 restricted peptides that are selectively presented by breast, ovarian and prostate cancer cell lines, but not by normal HLA-A2+ cells, were used as antigens with a proprietary adjuvant and a T helper peptide epitope to create a therapeutic cancer vaccine, DPX-0907. Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose volume cohorts in a three immunization clinical protocol. Results: DPX-0907 proved to be safe with no serious adverse effects related to the vaccine reported. Of those evaluable for immunogenicity, all breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated immune response to one or more of seven antigenic peptides, resulting in a 61% response rate. Immune responses correlated with achievement of CR, PR or SD to last treatment. No difference in immune response rate or magnitude was seen between the two dose groups. DPX-0907 displayed strong immune induction potential, with 73% of immune responders showing responses with just one dose of vaccine. In 83% of responders, immune responses were detected at ≥2 time points post vaccination and 64% had a persistent immune response at one month post last vaccination. Immune monitoring showed peptide-specific CD8 T cells, and these T cells were able to secrete multiple Th1 cytokines indicating their multifunctionality, a feature attributable to cells that mediate protective responses. Conclusions: These data support the ability of DPX-0907 to elicit Th1 dominated, specific immunity and support the rationale for further testing in immunologically competent cancer patients. The novel DepoVax formulation may promote multifunctional memory responses with peptides from other tumor associated antigens.

Abstract 3641: The predictive and prognostic roles of DNA damage response genes in epithelial ovarian cancer

Abstract Background: Despite platinum-based chemotherapy, 5-year survival of advanced stage ovarian cancer patients is only 15-30%. Exposure to platinum-based chemotherapeutics induces double strand DNA breaks (DSBs) and subsequently leads to activation of the DNA damage response (DDR). Therefore inhibition of components of the DDR may lead to better response to therapy. Aim of this study was to investigate in a large series of ovarian cancer patients the predictive and prognostic role of the activation status of four DDR-proteins- ATM, a key controller in the DDR, and three ATM substrates, including Chk2, 53BP1 and γ-H2AX, of which the latter is a direct readout for DNA damage. Methods: Expression of phospho-ATM, Chk2, phospho-Chk2, 53BP1, phospho-53BP1 and γ-H2AX was immunohistochemically assessed in 309 patients with chemo-naive ovarian cancer. Expression levels were related to clinicopathological characteristics and survival. Response to platinum-based chemotherapy was analyzed by defining two populations with either an optimal therapy response or a very poor therapy response. Both groups consisted of patients with advanced stage ovarian cancer, &amp;gt;2 cm residual disease after primary surgery and were all treated with platinum-based chemotherapy. The responder group had a well-defined PFS of more than 18 months while the non-responder group had a PFS of less than 6 months. Results: In the two well-defined groups with the largest contrast regarding response to treatment, positive γ-H2AX expression (OR=0.193; p=0.036) and positive Chk2 expression (OR=0.149; p=0.011) were related to a good response to platinum-based chemotherapy. In advanced stage patients, phospho-53BP1 expression was independently related to a worse disease-specific survival (HR=1.905; p= 0.044). Conclusion: High DDR protein expression in advanced stage ovarian cancers suggests a high degree of genomic instability, while the negative prognostic impact of phospho-53BP1 may be due to enhanced repair capacity of chemotherapy-induced DSBs on the long term. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3641. doi:1538-7445.AM2012-3641