Poor Ovarian Cancer Research Articles

An updated meta-analysis of the prognostic value of decreased E-cadherin expression in ovarian cancer.

Decreased epithelial cadherin (E-cadherin) expression is hypothesized to be related to poor prognosis of ovarian cancer, but the predictive value is still inconsistent. We conducted an updated meta-analysis with a total of 16 studies enrolling 1720 patients to estimate the prognostic value of decreased E-cadherin expression in ovarian cancer. Reduced expression of E-cadherin was significantly associated to poor overall survival (HR = 1.74, 95% CI: 1.40–2.17) and progression-free survival (HR = 1.45, 95% CI: 1.12–1.86) with a large heterogeneity for overall survival. In addition, we found that decreased expression of E-cadherin was significantly correlated with International Federation of Gynecology and Obstetrics grade (HR = 3.74, 95% CI: 2.24–6.23), E-cadherin membranous (HR = 1.47, 95% CI: 1.01–2.14), pathologic grade (HR = 1.41, 95% CI: 1.01–1.97), residual tumor size (HR = 2.72, 95% CI: 1.99–3.72), and surgery (HR = 3.21, 95% CI: 1.19–8.67). Our finding suggests that decreased E-cadherin expression may be a predictor of poor ovarian cancer prognosis.

LAMP3 expression correlated with poor clinical outcome in human ovarian cancer.

Lysosome-associated membrane protein 3 belongs to the lysosome-associated membrane glycoprotein family, which is associated with lymph node, metastasis, poor overall survival, and resistance to chemotherapy and radiotherapy. Epithelial ovarian cancer is one of the most deadly global female gynecologic malignant tumors. Its clinical outcome is poor and most epithelial ovarian cancer patients tend to relapse because of drug resistance. However, lysosome-associated membrane protein 3 expression in epithelial ovarian cancer and its relationship between clinicopathologic factors remain poorly understood. To clarify the prognostic implications of lysosome-associated membrane protein 3 in epithelial ovarian cancer, we analyzed both messenger RNA and protein levels of lysosome-associated membrane protein 3 in ovarian carcinomas. Polymerase chain reaction results showed higher expression of lysosome-associated membrane protein 3 messenger RNA in epithelial ovarian cancer than in noncancerous tissues. Immunohistochemical results showed that high lysosome-associated membrane protein 3 cytoplasmic expression was significantly related to tumor grade ( p = 0.038), lymph node metastasis ( p = 0.049), metastasis ( p < 0.001), level of CA125 ( p = 0.030), and International Federation of Gynecology and Obstetrics (FIGO) ( p < 0.001). High lysosome-associated membrane protein 3 nuclear expression was significantly associated with tumor grade ( p = 0.046), tumor single or double (representative whether the tumor involving one or both ovaries) ( p = 0.016), metastasis ( p < 0.001), and FIGO stage ( p < 0.001). Survival analysis indicated that high lysosome-associated membrane protein 3 cytoplasmic expression (hazard ratio: 4.632, 95% confidence interval: 2.421-8.864; p < 0.001), patients' age (hazard ratio: 1.729, 95% confidence interval: 1.027-2.911; p = 0.039), and FIGO stage (hazard ratio: 2.049, 95% confidence interval: 1.113-3.774; p = 0.021) were significantly correlated with poor survival outcome of epithelial ovarian cancer patients.

Thresholds and timing of pre-operative thrombocytosis and ovarian cancer survival: analysis of laboratory measures from electronic medical records.

BackgroundThrombocytosis has been associated with poor ovarian cancer prognosis. However, comparisons of thresholds to define thrombocytosis and evaluation of relevant timing of platelet measurement has not been previously conducted.MethodsWe selected Tumor Registry confirmed ovarian, primary peritoneal, and fallopian tube cancer cases diagnosed between 1995–2013 from the Vanderbilt University Medical Center. Laboratory measured platelet values from electronic medical records (EMR) were used to determine thrombocytosis at three thresholds: a platelet count greater than 350, 400, or 450 × 109/liter. Timing was evaluated with 5 intervals: on the date of diagnosis, and up to 1, 2, 4, and 8 weeks prior to the date of diagnosis. Cox regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for association with overall survival; adjustment included age, stage, grade, and histologic subtype of disease.ResultsPre-diagnosis platelet measures were available for 136, 241, 280, 297, and 304 cases in the five intervals. The prevalence of thrombocytosis decreased with increasing thresholds and was generally consistent across the five time intervals, ranging from 44.8–53.2 %, 31.6–39.4 %, and 19.9–26.1 % across the three thresholds. Associations with higher grade and stage of disease gained significance as the threshold increased. With the exception of the lowest threshold on the date of diagnosis (HR350: 1.55, 95 % CI: 0.97–2.47), all other survival associations were significant, with the highest reaching twice the risk of death for thrombocytosis on the date of diagnosis (HR400: 2.01, 95 % CI: 1.25–3.23).ConclusionsOur EMR approach yielded associations comparable to published findings from medical record abstraction approaches. In addition, our results indicate that lower thrombocytosis thresholds and platelet measures up to 8 weeks before diagnosis may inform ovarian cancer characteristics and prognosis.

Abstract 4632: Poor survival associated with NUAK1 overexpression in serous ovarian cancer may be explained by chemotherapy resistance

Abstract Objectives: The purpose of this study was to identify and validate novel gene transcripts associated with poor prognosis ovarian cancer. Methods: Clinical, pathologic, outcomes and transcriptomics data for 22,277 probesets were downloaded for each of 1,183 eligible patients representing six datasets. Cohorts 1 (n = 638) and 2 (n = 545) were used for discovery and validation, respectively. Associations with survival were evaluated using univariate Cox modeling with Wald test and Kaplan-Meier method with log rank test. Odds ratios were evaluated using the Mantel-Haenszel test. NUAK1 expression in ovarian cancer cell lines was examined using immunoblotting. Results: There were 293 (1.3%) probesets whose expression was associated with survival in serous ovarian cancer patients in cohort 1 that passed false discovery correction, and 19 of these, including NUAK1, validated in cohort 2 (q&amp;lt;0.05). Women with high versus low transcript expression of NUAK1 had worse survival (hazard ratio = 1.4, 95% confidence interval = 1.2-1.64) and increased odds of being diagnosed at advanced age with late stage disease in addition to experiencing suboptimal debulking and earlier disease progression. Higher levels of NUAK1 protein were observed in a panel of chemoresistant versus chemosensitive ovarian cancer cells lines. Conclusions: Overexpression of NUAK1, also known as AMPK-related protein kinase 5 (ARK5) and a survival factor in nutrient starved cells with low oxygen tension, was identified and validated to predict poor prognosis in a cohort of 1,183 serous ovarian cancer patients, and to be associated with chemoresistance using in vitro models of platinum and taxane resistance in human ovarian cancer. Citation Format: Neil T. Phippen, Nicholas W. Bateman, Guisong Wang, Chad A. Hamilton, George L. Maxwell, Kathleen M. Darcy, Thomas P. Conrads. Poor survival associated with NUAK1 overexpression in serous ovarian cancer may be explained by chemotherapy resistance. [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 4632. doi:10.1158/1538-7445.AM2015-4632

Abstract 4631: AKAP12 is elevated in paclitaxel-resistant ovarian cancer cells and correlates with poor ovarian cancer patient survival

Abstract Objective: Although most ovarian cancer patients respond initially to the standard of care involving carboplatinum/paclitaxel-based chemotherapy, the majority will recur with chemotherapeutically resistant disease. Unfortunately, no clinical biomarker(s) for predicting or monitoring chemotherapeutic resistance are available. We sought to identify shed and/or secreted proteins from paclitaxel-resistant human ovarian cancer cells and identify whether any of these correlate with ovarian cancer patient outcome. Methods: A proteomic analysis of secretomes from high grade serous ovarian cancer (HGSOC) cells (OV90) was compared to that from a syngeneic paclitaxel-resistant variant (OV90-TR) and a cancer cell line developed from a chemorefractory HGSOC patient. Associations between the identified candidates and patient outcome were assessed from publicly available transcript expression data (n = 545 ovarian cancer patients) and validated independently (n = 795 ovarian cancer patients). Results: Among the 81 differentially abundant proteins identified (q&amp;lt;0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated at the protein and transcript level in all models of paclitaxel-resistant HGSOC. Further, elevated AKAP12 transcript expression was found to significantly correlate with poor progression-free (Hazard Ratio = 1.487 (± 0.148), p = 0.0085 (± 0.002) and overall (Hazard Ratio = 1.22 (± 0.08), p = 0.009 (± 0.013) survival. Conclusions: These findings suggest that elevation and efflux of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells and that elevated AKAP12 expression correlates with poor ovarian cancer patient survival. Citation Format: Nicholas Bateman, Elizabeth Jaworski, Guisong Wang, Elizabeth Dubil, Charlotte Marcus, Kelly Conrads, Pang-ning Teng, Brian Hood, Chad Hamilton, Larry Maxwell, Kathleen Darcy, Thomas Conrads. AKAP12 is elevated in paclitaxel-resistant ovarian cancer cells and correlates with poor ovarian cancer patient survival. [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 4631. doi:10.1158/1538-7445.AM2015-4631

ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers

BackgroundAtaxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad3 related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response (DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. Our objective was to evaluate if ATM, ATR and DNA-PKcs expressions could predict response to therapy and clinical outcome in epithelial ovarian cancers. MethodsWe investigated ATM, ATR, and DNA-PKcs expressions in ovarian epithelial cancers [protein expression (n=194 patients), mRNA expression (n=156 patients)] and correlated to clinicopathological outcomes as well as expression of X-ray repair cross-complementing protein 1 (XRCC1), cell division cycle-45 (CDC45), cyclin-dependent kinase 1(CDK1) and Ki-67 in tumours. ResultsHigh ATM protein expression was associated with serous cystadenocarcinomas (p=0.021) and platinum resistance (p=0.017). High DNA-PKcs protein expression was associated with serous cystadenocarcinomas (p=0.006) and advanced stage tumours (p=0.018). High ATM protein (p=0.001), high ATM mRNA (p=0.018), high DNA-PKcs protein (p=0.002), high DNA-PKcs mRNA (p=0.044) and high ATR protein (p=0.001) expressions are correlated with poor ovarian cancer specific survival (OCSS). In multivariate Cox model, high DNA-PKcs (p=0.006) and high ATR (p=0.043) protein expressions remain independently associated with poor OCSS. ConclusionsATM, ATR and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer. General significanceThe data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are not only promising biomarkers but are also rational targets for personalized therapy in ovarian cancer.

The Prognostic Value of CXCR4 in Ovarian Cancer: A Meta-Analysis

ObjectiveRecent reports have shown that C-X-C chemokine receptor 4 (CXCR4) is expressed in ovarian cancer and plays an important role in metastasis. However, the prognostic value of CXCR4 in ovarian cancer remains controversial and has not been emphasized. The aim of this study is to evaluate the prognostic significance of CXCR4 in ovarian cancer by performing a meta-analysis.MethodsWe systematically searched for studies evaluating the relationship between CXCR4 expression and the outcome of ovarian cancer patients. Only articles in which CXCR4 expression was detected by immunohistochemical staining were included. Hazard ratios (HRs) and relative risk (RR) with 95% confidence intervals (CIs) were pooled as effect size (ES) across studies for overall survival (OS) and progression-free survival (PFS).ResultsA total of 729 patients from 7 studies (6 articles) were included in this meta-analysis. Our results showed that high CXCR4 expression was significantly associated with poor prognosis in terms of OS (ES, 2.81; 95% CI, 1.16–6.80; p = 0.022) and PFS (ES, 8.48; 95% CI, 2.13–33.70; p = 0.002) in ovarian cancer patients. The association between high CXCR4 expression and poor ovarian cancer prognosis in OS was also statistically significant in subgroups of Asian and III-IV patients constituting 70%.ConclusionsThe present meta-analysis indicated that high CXCR4 expression was associated with poor prognosis in ovarian cancer. More studies, especially larger scale and well-matched researches, are warranted to clarify the prognostic effect of CXCR4 on the outcome of ovarian cancer.

YAP Promotes Ovarian Cancer Cell Tumorigenesis and Is Indicative of a Poor Prognosis for Ovarian Cancer Patients

YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we found that strong YAP expression was associated with poor ovarian cancer patient survival. Specifically, we showed for the first time that high YAP expression levels were positively correlated with TEAD4 gene expression, and their co-expression was a prognostic marker for poor ovarian cancer survival. Hyperactivation of YAP by mutating its five inhibitory phosphorylation sites (YAP-5SA) increased ovarian cancer cell proliferation, resistance to chemotherapeutic drugs, cell migration, and anchorage-independent growth. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes in ovarian cancer cells both in vitro and in vivo. Our results suggested that YAP caused these effects by promoting an epithelial-to-mesenchymal transition. Thus, YAP promotes ovarian cancer cell growth and tumorigenesis both in vitro and in vivo. Further, high YAP and TEAD4 expression is a prognostic marker for ovarian cancer progression and a potential target for ovarian cancer treatment.

Association of Reduced Immunohistochemical Expression of E-cadherin with a Poor Ovarian Cancer Prognosis - Results of a Meta-analysis

E-cadherin is a transmemberane protein which is responsible for adhesion of endothelial cells. The aim of our study was to assess existing evidence of associations between reduced expression of E-cadherin and prognosis of ovarian cancer with a discussion of potential approaches to exploiting any prognostic value for improved clinical management. We conducted a meta-analysis of 9 studies (n=915 patients) focusing on the correlation of reduced expression of E-cadherin with overall survival. Data were synthesized with random or fixed effect hazard ratios. The studies were categorized by author/year, number of patients, FIGO stage, histology, cutoff value for E-cadherin positivity, and methods of hazard rations (HR) estimation, HR and its 95% confidence interval (CI). Combined hazard ratios suggested that reduced expression of E-cadherin positivity was associated with poor overall survival (OS), HR=2.10, 95% CI:1.13-3.06. The overall survival of the E-cadherin negative group with ovarian cancer was significant poorer than the E-cadherin positive group. Upregulation of E-cadherin is an attractive therapeutic approach that could exert significant effects on clinical outcome of ovarian cancer.

A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival

BackgroundKLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival.ResultsIn silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site.ConclusionsWe provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.

Prognostic role of the recepteur d'origine nantais (RON) expression in ovarian cancer patients

ObjectiveThe aim of the study was to investigate the potential clinical relevance of immunohistochemically assessed RON expression in a large, single institution series of primary untreated advanced ovarian cancer patients. MethodsImmunohistochemical analysis was performed by using the polyclonal rabbit anti-RON-β antibody (C-20, clone sc-322, Santa Cruz, California). Results were expressed as the total proportion of immunostained tumor cells (RON positivity), or the percentage of cells showing strong staining of RON expression (H-RON positivity). ResultsIn the overall series RON positive immunoreaction was observed in 103/141 cases, while H-Ron positivity was detected in 577141 (40.4%) cases. No association between RON and H-RON expression with response to first-line treatment was documented. During the follow up period, progression and death of disease were observed in 111 (78.7%) and 76 (53.9%) cases, respectively. Cases with strong H-RON expression has a shorter overall survival (median=35 months) than cases with low RON levels (median=59 months) (X2=−2.1, p value=0.032). In multivariate analysis, only platinum resistance, and extent of residual tumor retained an independent negative prognostic role for OS, with the percentages of H-RON positively immunostained cells showing a borderline statistical significance (p value=0.0643). The unfavourable role of elevated percentages of H-RON expression was maintained only in the subgroup of platinum resistant recurrent ovarian cancer patients (X2=3.89, p value=0.048) compared to the platinum sensitive ones (X2=1.98, p value=0.16). ConclusionsThe assessment of RON expression deserves further attention as a parameter helpful to identify poor prognosis ovarian cancer patients potentially candidates to investigational agents.

Class III β-Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients

Overexpression of beta III tubulin has been involved in paclitaxel resistance in several experimental models. We investigated the role of beta III tubulin as predictor of clinical outcome in ovarian cancer patients given platinum/paclitaxel treatment. We also investigated whether beta III tubulin expression could be modified after the selective pressure represented by chemotherapy in vivo. The study was designed to include a series of consecutive ovarian cancer patients with unresectable disease at time of first surgery, who underwent interval debulking surgery with pathologic assessment of response to treatment with platinum/paclitaxel chemotherapy. Immunostaining was done on formalin-fixed, paraffin-embedded tissue sections from pretreatment and posttreatment tissue biopsies by using the polyclonal rabbit anti-class III beta-tubulin antibody. beta III Tubulin immunoreaction was observed in 51 of 62 (82.2%) cases. beta III Tubulin positivity was neither associated with clinicopathologic variables nor with pathologic response to chemotherapy. Significantly lower percentages of beta III tubulin positivity were observed in posttreatment (range, 5-80%; median, 20%) versus pretreatment (range 10-100%; median, 40%) tissue biopsies (P = 0.0011). Cases with high beta III tubulin expression showed a worse overall survival with respect to cases with low beta III tubulin expression (median overall survival, 25 versus 46 months; P = 0.002). Multivariate analysis showed that high content of beta III tubulin remains independently associated with a worse prognosis. Assessment of beta III tubulin could be useful to identify poor prognosis ovarian cancer patients candidates to more aggressive and/or targeted therapy.

FISH analysis of BRCA1 copy number in paraffin-embedded ovarian cancer tissue samples

We investigated the BRCA1 gene copy number in unselected ovarian malignancies. Both additional genes (amplification) as well as deletion (loss of heterozygosity, LOH) are often thought to have a role in the initiation or progression of cancer. In addition, if there were little change, deletion studies might help identify BRCA1 mutation carriers. Forty-seven paraffin-embedded ovarian tissue blocks obtained between 1984 and 1997 were used for this study. A sample was “deletion-positive” when BRCA1-deleted cells in the tumor area were significantly different from the benign area. Twenty-five (53%) cases were found to be “deletion-positive”. The average age of onset of “deletion-positive” patients was 50.8 years and of “deletion-negative” 57.8 years ( P < 0.05). There was no statistical difference between groups in the staging, histology, or prognosis. A Kaplan–Meier study did show a trend towards poorer survival for “deletion-positive” patients. FISH permits unique molecular characterization of malignancies at a cellular level. Double amplification of HER-2 and c- myc predicts poor ovarian cancer survival. There appears to be a definite role for BRCA1 deletion in reducing the age of ovarian cancer onset and possibly in overall survival. Further FISH studies of this and other patient sets using additional molecular markers are needed.

Feasibility of an accelerated multi-cycle high-dose chemotherapy regimen including high-dose thiotepa for patients (Pts) with poor risk ovarian cancer (OC)

Feasibility of an accelerated multi-cycle high-dose chemotherapy regimen including high-dose thiotepa for patients (Pts) with poor risk ovarian cancer (OC)