Overall Survival In Ovarian Cancer Research Articles

Oncolytic virus immunotherapies in ovarian cancer: moving beyond adenoviruses.

Ovarian cancer is the 5th most common cancer in UK women with a high relapse rate. The overall survival for ovarian cancer has remained low for decades prompting a real need for new therapies. Recurrent ovarian cancer remains confined in the peritoneal cavity in >80% of the patients, providing an opportunity for locoregional administration of novel therapeutics, including gene and viral therapy approaches. Immunotherapy is an expanding field, and includes oncolytic viruses as well as monoclonal antibodies, immune checkpoint inhibitors, and therapeutic vaccines.Oncolytic viruses cause direct cancer cell cytolysis and immunogenic cell death and subsequent release of tumor antigens that will prime for a potent tumor-specific immunity. This effect may be further enhanced when the viruses are engineered to express, or coadministered with, immunostimulatory molecules. Currently, the most commonly used and well-characterized vectors utilized for virotherapy purposes are adenoviruses. They have been shown to work synergistically with traditional chemotherapy and radiotherapy and have met with success in clinical trials. However, pre-existing immunity and poor in vivo models limit our ability to fully investigate the potential of oncolytic adenovirus as effective immunotherapies which in turn fosters the need to develop alternative viral vectors. In this review we cover recent advances in adenovirus-based oncolytic therapies targeting ovarian cancer and recent advances in mapping immune responses to oncolytic virus therapies in ovarian cancer.

Development and Validation of an Individualized Immune Prognostic Signature in 3005 Ovarian Cancer Patients

Ovarian cancer (OV) is the most lethal gynecological cancer in women. We aim to develop a robust, individualized immune prognostic signature that can stratify and predict overall survival for ovarian cancer. The gene expression profiles of ovarian cancer tumor tissue samples were collected from 20 public cohorts, including 3005 cases totally. We used the immune genes provided by ImmPort database to develop an immune-based prognostic signature for OV (IPSOV) in the training set (n = 409). The signature was validated in seven independent validation sets (n = 606, 519, 634, 415, 194, 128, 100). Further, we compared IPSOV with nine reported ovarian cancer prognostic signatures as well as the clinical characteristics including stage, grade and debulking status. The IPSOV significantly stratified patients into low- and high-immune risk groups in the training set (HR = 2.52; 95% CI: 1.92-3.30; P = 1.88×10-11) and in the 7 validation sets (HR range: 1.70 [95%CI: 1.32-2.10; P = 1.40×10-5] to 2.20 [95%CI: 1.24-3.91; P = 0.007]). Significant interaction effects were identified for IPSOV and platinum, Gemcitabine and Topotecan chemotherapy. The IPSOV achieved the highest mean C-index (0.631) compared with the other signatures (0.516 to 0.602) and clinical characteristics (0.550 to 0.576). Further, we integrated IPSOV with stage, grade and debulking, which showed improved prognostic accuracy than clinical characteristics only. The proposed clinical-immune signature is a promising biomarker for estimating overall survival in ovarian cancer. Prospective studies are needed to further validate its analytical accuracy and test the clinical utility. Funding: This study was supported by the National Natural Science Foundation of China (81530088 and 81473070 to F.C.), National Key Research and Development Program of China (2016YFE0204900 to F.C.), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (14KJA310002 to F.C.). Conflict of Interest: None. Ethical Approval Statement: This study has been proved by the Nanjing Medical University institutional committee.

TIGIT ligands CD155, CD112, and galectin-9 are associated with immune infiltration and increased overall survival in ovarian cancer

TIGIT ligands CD155, CD112, and galectin-9 are associated with immune infiltration and increased overall survival in ovarian cancer

Prognostic value of HE4 in patients with ovarian cancer.

Background There is no consensus in the medical community about the prognostic role of preoperative serum levels of human epididymis protein 4 (HE4) in ovarian cancer (OC). The purpose of this meta-analysis was to establish whether preoperative serum levels of HE4 are associated with OC prognosis. Content Eligible studies were searched for in PubMed, ClinicalTrials.gov, CNKI and Wanfang Med Online. We performed a meta-analysis of 1315 OC cases from 14 published articles. Summary Our meta-analysis demonstrated that high HE4 was associated with poor overall survival (OS) (random effects model, hazard ratio [HR]=1.91, 95% confidence interval [CI]=1.40-2.614, p<0.0001; I2=52%, p=0.04) and; progression-free survival (PFS) (random effects model, HR=1.38, 95% CI=1.13-1.69, p=0.002; I2=85%, p<0.00001). However, subgroup analysis showed that high HE4 was not associated with poor OS (fixed effects model, HR=1.86, 95% CI=0.89-3.89, p=0.1; I2=34%, p=0.22) or PFS (random effects model, HR=1.34, 95% CI=0.95-1.88, p=0.1; I2=69%, p=0.007) for studies including only Asian populations. Outlook In conclusion, this meta-analysis shows that high HE4 was associated with poor OC OS and PFS overall. However, the association of high HE4 with poor OS and PFS was not observed for Asians. Large-scale, multi-center investigations should be performed.

Chemokine Network and Overall Survival in TP53 Wild-Type and Mutant Ovarian Cancer.

Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. Because chemokine network is involved in OC progression, we evaluated associations between chemokine expression and survival in tumor suppressor protein p53 (TP53) wild-type (TP53WT) and mutant (TP53m) OC datasets. TP53 was highly mutated in OC compared to other cancer types. Among OC subtypes, CXCL14 was predominantly expressed in clear cell OC, and CCL15 and CCL20 in mucinous OC. TP53WT endometrioid OC highly expressed CXCL14 compared to TP53m, showing better progression-free survival but no difference in overall survival (OS). TP53m serous OC highly expressed CCL8, CCL20, CXCL10 and CXCL11 compared to TP53WT. CXCL12 and CCL21 were associated with poor OS in TP53WT serous OC. CXCR2 was associated with poor OS in TP53m serous OC, while CXCL9, CCL5, CXCR4, CXCL11, and CXCL13 were associated with better OS. Taken together, specific chemokine signatures may differentially influence OS in TP53WT and TP53m OC.

Correlation between NM23 protein overexpression and prognostic value and clinicopathologic features of ovarian cancer: a meta-analysis.

The prognostic value and clinicopathological features of NM23 (non-metastasis 23) have previously been assessed, but the results are controversial. Here, we attempted to clarify the correlation between NM23 expression and its prognostic value and the clinicopathological features in ovarian cancer (OC). The relevant studies were identified using PubMed, Embase, and Web of Science. We calculated the pooled odds ratio (OR) with 95% confidence intervals (CIs) for overall survival (OS), progression-free survival (PFS), and clinicopathological features. We used OS to evaluate the prognostic value of NM23 expression in patients with OC. Subgroup analyses were used to explore the source of heterogeneity. We included 10 studies involving 894 patients in our assessment of the association between NM23 expression and OS for OC. Our data indicated that NM23 expression was not associated with improved OS (OR 0.83, 95% CI 0.41-1.68, P=0.61) or PFS (OR 0.7, 95% CI 0.39-1.24, P=0.22). Elevated NM23 expression was associated with differentiation grade (OR 0.35, 95% CI 0.2-0.6, P=0.0002) and N status (OR 0.33, 95% CI 0.14-0.78, P=0.01), whereas there was no significant difference between NM23 expression and tumor stage (OR 1.1, 95% CI 0.45-2.66, P=0.84). Subgroup analysis did not reveal any potential source of heterogeneity. No obvious publication bias was found. In OC, there is poor statistical significance between NM23 expression and OS and PFS, but NM23 expression is related to differentiation grade and N status. This meta-analysis reveals that NM23 expression is a potential factor of poor prognosis in OC. The prognostic role of NM23 in different OC stages in combination with the clinical characteristics suggests a novel approach for developing future therapeutic targets.

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.

Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.

Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589-601. ©2017 AACR.

Ovarian cancer recurrence and early detection: may HE4 play a key role in this open challenge? A systematic review of literature.

Despite the improvement in overall survival for ovarian cancer (OC) patients, a fraction of patients with advanced-stage disease fails to respond to primary therapy and relapses in 70% of cases. For this reason, new predictive and monitoring tools are needed to identify OC recurrence and new biomarkers were studied, among which human epididymis 4 (HE4), primarily expressed in the reproductive and respiratory tracts, is one of the most promising, reporting a good sensitivity and specificity in detecting OC, overcoming the traditional role of carbohydrate antigen 125 (CA-125). In this review, we aim to discuss the latest evidence reported in the literature about the use of HE4 to monitor ovarian cancer treatment and to detect OC recurrence. We searched MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, IBECS, BIOSIS, Web of Science, SCOPUS, congress abstracts, and Grey literature (Google Scholar; British Library) from January 1952 to June 2017. The search identified seven papers in line with eligibility criteria for this systematic review; all of them demonstrated a good performance of HE4 in OC recurrence. The challenge to anticipate the diagnosis of OC recurrence and to translate this early diagnosis of relapse in a survival and quality of life improvement is still open, and as reported in this review, HE4 may play a key role in this scenario. More studies are needed to validate and reinforce the role of HE4 in ovarian cancer recurrence and in its early detection.

A SEER-Medicare analysis of the impact of metformin on overall survival in ovarian cancer

ObjectiveDetermine whether metformin use is associated with improved survival in patients with ovarian, fallopian tube or primary peritoneal cancer. MethodsAll patients with a diagnosis of first epithelial ovarian cancer from 2007 to 2011 in the combined SEER-Medicare database were identified from the SEER registry primary site codes. Comorbidities, procedures and cancer treatment ICD-9 and HCPCS codes were used to search the Medicare claims files. Medication use was determined with National Drug Codes using the Medicare Part D event files. The primary outcome, overall survival, was assessed between metformin users and non-users using a Cox Proportional Hazards survival model. To control for confounding, metformin users were matched to non-metformin users using propensity scores. Effect of dosage on survival was assessed using discrete time survival analysis with pooled logistic regression (PLR). ResultsThere were 2291 cases that met our inclusion criteria. Of these, 180 (7.9%) had been on metformin. The median age was 73years, with the majority of the population being White (83.5%) and treated with primary surgery (74.1%). Metformin use was not associated with overall survival in the entire cohort (HR 0.96, 95% CI 0.75–1.23) or in the matched sample cohort (HR 0.88, 95% CI 0.66–1.17). However, exploratory regression with time-varying coefficients suggests a protective metformin effect for women alive after 30months follow-up (HR=0.37, 95% 0.16–0.87). ConclusionNo statistically significant association was observed between metformin use and overall survival in a matched cohort of 360 ovarian cancer patients. However, exploratory modeling suggests metformin use may be protective in a certain subgroup of patients.

Objective response rate is a possible surrogate endpoint for survival in patients with advanced, recurrent ovarian cancer

ObjectiveEvaluate literature to assess response rate as a surrogate endpoint of survival in ovarian cancer (OC). MethodsSystematic review consistent with PRISMA criteria, identified randomized, controlled trials reporting overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in recurrent OC. MEDLINE® and Embase® searches (year 2000–March 23, 2015) were augmented by bibliographic screening. Proposed surrogate measures (independent variables) were ORR and disease control rate. True clinical outcomes (dependent variables) were median OS and PFS. Analyses were performed on unweighted and weighted data using correlation analysis, linear regression, and surrogate threshold effect (STE). Smaller STE indicates greater predictive precision with magnitude of STE dependent on variance of prediction. ResultsThirty-nine studies were included for review, representing 9223 platinum-sensitive and resistant patients. Objective response rate (r=0.82; P<0.001) was a better predictor than disease control rate (r=0.58; P<0.001) and strongly correlated with PFS (r=0.85; P<0.0001). Weighted-regression analysis demonstrated that for each 10% increase in ORR, PFS increased by 1.20months and OS by 2.83months. Regression analysis of treatment effects (odds ratio of response, hazard ratio of survival) suggests that a 10% increase in odds ratio of ORR would result in 2.5% reduction in the hazard ratio of OS. Based on weighted data, STE indicated that an ORR of ≥1% is needed to achieve nonzero OS benefit. ConclusionThis systematic review supports ORR as a possible surrogate clinical trial endpoint for OS in recurrent OC with at least second-line therapy.

Prognostic value of abnormally expressed lncRNAs in ovarian carcinoma: a systematic review and meta-analysis.

Ovarian cancer (OC) is the most deadly gynecological cancer and it is urgently needed to find a new marker for the progress of OC. Many long noncoding RNAs (lncRNAs) have been reported to be aberrantly expressed in ovarian carcinoma, and may serve as prognostic markers. Therefore, we conducted this meta-analysis to gain a better understanding of the prognostic value of lncRNAs in patients with varian carcinoma. We systematically searched PubMed, EMBASE, and Web of Science. A total of 13 eligible studies, including 10 on clinicopathological features, 13 on prognosis were identified. Pooled hazard ratios (HRs) or odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects models. Our results revealed that the increased expressions of 8 lncRNAs were associated with poor prognosis and the decreased expressions of 5 lncRNAs were related to poor prognosis in ovarian carcinoma. High HOTAIR expression was associated with shorter overall survival in ovarian cancer (pooled HR: 2.05, 95% CI: 1.51-2.77, P < 0.001). In conclusion, our meta-analysis suggested that LncRNAs could function as potential prognostic markers for ovarian cancer patients and high expression HOTAIR was associated with shorter overall survival in ovarian cancer.

Neutrophil-to-Lymphocyte Ratio Is a Potential Prognostic Biomarker in Patients with Ovarian Cancer: A Meta-Analysis.

Background and Aims Plenty of studies were conducted to explore the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer with contradictory results. This study aims to summarize the prognostic significance of NLR in patients with ovarian cancer. Methods A literature search in PubMed, Cochrane Library, and Embase was conducted. The endpoints were progression-free survival (PFS) and overall survival (OS). Results Eleven studies involving a total of 2,892 patients were identified. The results indicated that patients with high NLR had shorter PFS compared to patients with low NLR in ovarian cancer (HR = 1.55, 95% CI = 1.15–2.08, p = 0.004, and I2 = 61%). Similarly, high NLR was related to shorter OS (HR = 1.51, 95% CI = 1.03–2.23, p = 0.04, and I2 = 85%). Moreover, high NLR was significantly associated with shorter PFS when the NLR cut-off was less than 3.3 (p = 0.03) or when treatment is operation (p = 0.002). In addition, high NLR was distinctly related to worse OS in Asian people (p = 0.04) or operation (p = 0.04). Conclusion High NLR was associated with shorter PFS and shorter OS in ovarian cancer. NLR is potentially a promising prognostic biomarker in patients with ovarian cancer.

MON-P072: Involuntary Weight Loss Between Surgery and a day of 1st Cycle of Chemotherapy is an Independent Adverse Prognostic Factor for overall Survival in Ovarian Cancer

MON-P072: Involuntary Weight Loss Between Surgery and a day of 1st Cycle of Chemotherapy is an Independent Adverse Prognostic Factor for overall Survival in Ovarian Cancer

Calreticulin expression: Interaction with the immune infiltrate and impact on survival in patients with ovarian and non-small cell lung cancer

ABSTRACTLoss of expression of calreticulin (CALR) has been detected by immunohistochemistry in a fraction of non-small cell lung cancers (NSCLC) and has been demonstrated to have a major negative prognostic impact on overall patient survival. Here, we analyzed the impact of CALR expression levels detected by microarray finding a positive correlation between CALR and the expression of a metagene indicating the presence of cytotoxic T lymphocytes (CTL) in NSCLC and ovarian cancer. In addition, we detected a positive correlation with a metagene suggestive of activated dendritic cell (aDC) infiltration in ovarian cancer. Combination of two parameters (CALR + DC (dendritic cell) in NSCL and CALR + aDC in ovarian cancer) or three parameters (CALR + CTL + DC in NSCL and CALR + CTL + aDC in ovarian cancer) had a significant impact on overall patient survival in NSCL (Adenoconsortium) and ovarian cancer (TCGA collection), allowing the stratification of patients in high-risk and low-risk groups. In addition, CALR and aDC alone have a significant impact on overall survival in ovarian cancer. In contrast, in mammary, colorectal and prostate cancer, CALR had no impact on patient survival if analyzed alone or in combination with the immune infiltrate. In addition, CALR correlates with CTL infiltrate in three cancer types (colorectal, breast, ovarian). Altogether, these results support the contention that, at least in some cancers, loss of CALR expression may negatively affect immunosurveillance, thereby reducing patient survival.

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.

CLINICAL IMPLICATIONS OF INSULIN-LIKE GROWTH FACTORS (IGF) AND IGF-BINDING PROTEINS INVESTIGATION IN PATIENTS WITH OVARIAN NEOPLASMS

Актуальность. Сигнальная система инсулиноподобных факторов роста (ИФР) играет важную роль в возникновении и прогрессии различных злокачественных опухолей, в том числе рака яичников, поэтому ее компоненты рассматриваются в качестве потенциальных диагностических и прогностических маркеров заболевания и мишеней для молекулярно-направленной терапии. Цель – сравнительная оценка содержания ИФР-I и II и ИФР-связывающих белков (ИФРСБ) 1, 2 и 3 в сыворотке крови и опухолях больных различными новообразованиями яичников, анализ их взаимосвязи с клинико-морфологическими особенностями рака яичников и оценка клинических перспектив определения данных маркеров для диагностики и прогноза заболевания. Материал и методы. Содержание ИФР-I, II и ИФРСБ-1, 2, 3 определено в сыворотке крови и экстрактах опухолей 74 больных раком, 14 пограничными и 16 доброкачественными опухолями яичников с помощью наборов для прямого иммуноферментного анализа Mediagnost (Германия). В контрольную группу вошли 77 практически здоровых женщин. Результаты. Выявлено 3 потенциальных серологических маркера рака яичников – ИФРСБ-2, ИФРСБ-1 и ИФР-I. Наилучшее соотношение диагностической чувствительности и специфичности продемонстрировано для ИФРСБ-2: при пороговом уровне 370 нг/мл эти показатели равны 87 и 79% соответственно. Выявленные диагностические маркеры влияют также на прогноз общей выживаемости больных раком яичников, причем низкий уровень ИФР-I имеет независимое неблагоприятное прогностическое значение по данным многофакторного анализа. На прогноз заболевания влияет также содержание ИФР-II и ИФРСБ-1 в ткани опухоли.Заключение. Выявлены нарушения баланса ИФР/ИФРСБ у больных раком яичников и показано, что отдельные компоненты этой системы могут рассматриваться в качестве диагностических и прогностических маркеров данного заболевания.

The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and overall survival in ovarian cancer

BackgroundOvarian cancer is mostly diagnosed in the elderly woman who is likely to have comorbid disease and to take several comedications on a regular basis. Aim of this study was to evaluate the influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival. Patients and methodsIn this individual participant data meta-analysis the original data of three phase II/III studies of the North-Eastern German Society of Gynecological Oncology (NOGGO) were analyzed using multivariate logistic and Cox regression. ResultsOverall, 1213 patients with recurrent ovarian cancer were included in these analyses. An increasing amount of medication was associated with overall grade III/IV toxicity (p<0.001; OR 1.120), and hematological (p<0.001; OR 1.056) and non-hematological (p<0.001; OR 1.134) toxicities. Prior discontinuation of chemotherapy was not influenced by an increasing amount of medication (p=0.196). There was no association of polypharmacy with overall survival (p=0.068). ConclusionAs polypharmacy does not influence survival ovarian cancer patients taking several comedications may be included in clinical trials and should not be deprived of adequate cancer treatment. However, a thorough monitoring is mandatory due to the increased risk of toxicities.

Abstract 4636: Investigation of exome variants associated with overall survival in ovarian cancer

Abstract Many germline genetic variants have been found to be associated with susceptibility to epithelial ovarian cancer (EOC), but currently few associations have been identified for EOC outcomes such as overall survival. In the absence of evidence for common germline markers, it is possible that rare variants not captured in GWAS arrays may be associated with overall survival. We hypothesize that rare variants, either individually or combined across a gene, may be associated with overall survival in EOC. We utilized data from two genotyping projects of the Ovarian Cancer Association Consortium (OCAC) that used commercial exome-based arrays. The primary sample, genotyped on the Affymetrix Axiom Exome Array at 227,892 standard and custom variants, consisted of 14 independent EOC studies (4293 cases; 2257 deaths). The secondary sample, genotyped on the Illumina Infinium HumanExome BeadChip at 114,620 variants, consisted of six additional EOC studies (1744 cases; 1027 deaths). Both sets were analyzed using Cox proportional hazards regression to determine the association of each variant with overall survival time. Meta-analysis was conducted across samples at 73,203 overlapping variants. Gene-level tests of over 18,000 genes were also conducted using burden tests and Sequencing Kernel Association Tests (SKAT) adapted for Cox proportional hazards models. Gene-level tests were conducted separately for the primary and secondary cases and then were meta-analyzed. Models were adjusted for age, site, and three principle components. Six individual variants had meta-analysis p-values &amp;lt; 1.0E-4, five of which were rare (MAF &amp;lt; 0.003). Common variant rs8170 (MAF = 0.2) in BABAM1 encoding BRISC and BRCA1 A complex member 1 - previously reported to be associated with EOC risk_showed evidence of association with overall survival (Pmeta = 1.5E-5) and consistent estimates of effect size across both samples (HR1 = 1.18, HR2 = 1.19). In imputed genotype data from over 18,000 subjects from OCAC genotyped on the COGS array, this association reaches genome-wide significance (HR = 1.15, P = 4.7E-9). Five genes had gene-level meta-analysis p-values &amp;lt; 1.0E-4, including top ranked ATG2B (p = 1.1E-6), an autophagy gene important for apoptosis; zinc finger protein PEG3 (p = 1.8E-5), playing a role in autophagy and down-regulated in EOC; helicase-like transcription factor HLTF (p = 1.9E-5), involved in post-replication DNA repair; mitochondrial fission regulator 1-like gene FAM54B (p = 3.1E-5); and T-cell surface glycoprotein CD1E (p = 8.8E-5). With over 6000 EOC cases in the primary and secondary samples, this is the largest genome-wide assessment of rare variant genetic associations with EOC overall survival. Variant rs8170 in BABAM1, a necessary component of the BRCA1 complex, is associated with overall survival. Single variant and gene-level analyses provide complementary approaches, suggesting additional candidates that warrant follow-up study. Citation Format: Stacey J. Winham, Brooke L. Fridley, Melissa C. Larson, Zachary Fogarty, Andrew Berchuck, Yian Ann Chen, Hui-Yi Lin, Georgia Chenevix-Trench, Jenny Permuth-Wey, Thomas A. Sellers, Ailith Pirie, Ellen L. Goode, Ovarian Cancer Association Consortium. Investigation of exome variants associated with overall survival in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4636. doi:10.1158/1538-7445.AM2015-4636

Abstract 990: Metastasis suppressor CD82/KAI1 expression is dependent on functional SWI/SNF ARID1A/B

Abstract CD82/KAI1 was one of the first metastasis suppressors identified and is capable of inhibiting the metastatic process in orthotopic tumor models. The expression of the CD82/KAI1 is down-regulated during tumor progression in many tumor types including prostate, breast, lung, bladder, and pancreatic cancers, and this down regulation appears to be at the level of transcription or post-transcription. The gene is not mutated, deleted or silenced by promoter methylation. CD82/KAI1 is also down regulated in advanced gynecologic cancers where CD82/KAI1 loss is associated with the poor overall survival in ovarian cancer. The mechanisms controlling the level of CD82/KAI1 expression remains unclear particularly the widespread loss in advanced cancers. The p53 tumor suppressor (TP53) can directly activate the CD82/KAI1 gene by interacting with the 5-prime upstream region of the CD82/KAI1 gene. Mutant TP53 is unable to bind this promoter site and fails to support CD82/KAI1 transcription. Taken together these data support a direct relationship between TP53 and CD82/KAI1 genes and suggested that the loss of TP53 function, which is common in many types of advanced cancer can lead to downregulation of CD82/KAI1, which then may result in metastases. However many cancers without TP53 mutation also exhibit loss of CD82/KAI1 suggesting that the mechanism for CD82/KAI1 loss is not completely explained by mutant TP53. Furthermore the mutant TP53 state and CD82/KAI1 loss is not strongly correlated in ovarian cancer. In some sarcomas the mechanism of CD82/KAI1 loss is related to the increase of the gp-78 E3 ligase and increased proteasomal degradation. Therefore the regulation of CD82/KAI1 in cells is likely complex. The AT Rich DNA binding protein ARID1A gene is frequently mutated in endometrial and ovarian cancers. In order to explore the functions of ARID1A in these cancers we complemented mutant ARID1A in the ACI-98 endometrial cancer cell line. We utilized a doxycycline inducible system and catalogued the protein changes following ARID1A complementation using LC MS/MS. Among the most differentially expressed proteins was CD82/KAI1. Levels of CD82 were dramatically increased following ARID1A induction. ACI-98 cells were found to be TP53 wild-type and CD82 expression null. QRT-PCR assays confirmed the dramatic increase in CD82/KAI1 mRNA levels and western blots also confirmed restoration of CD82/KAI1 protein following Doxycycline induced ARID1A restoration. We performed ChIP and confirmed that ARID1A was bound to the CD82/KAI1 promoter region close to the TP53 interaction area. Interestingly ACI-98 cells are mutant in both ARID1 homologs A and B. Ectopic expression of ARID1B was also able to restore expression of CD82/KAI1. These data suggest that the SWI/SNFARID1A/B complex is necessary for chromatin remodeling and expression of the CD82/KAI1 gene. Citation Format: Rusheeswar Challa, Yutaka Shoji, Kelly A. Conrads, Brian L. Hood, Guisong Wang, Kathleen M. Darcy, Chad A. Hamilton, George Larry Maxwell, Thomas P. Conrads, John I. Risinger. Metastasis suppressor CD82/KAI1 expression is dependent on functional SWI/SNF ARID1A/B. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 990. doi:10.1158/1538-7445.AM2014-990