Primary Epithelial Ovarian Cancer Patients Research Articles

A randomized controlled trial to compare short-term outcomes following infragastric and infracolic omentectomy at the time of primary debulking surgery for epithelial ovarian cancer with normal-appearing omentum

BackgroundOmentectomy is an important procedure in surgery for epithelial ovarian cancer, but the scope of omentectomy is not recommended in the guidelines. This study was performed to evaluate the benefits and risks of infragastric omentectomy in patients with epithelial ovarian cancer.MethodsThis trial is a single center prospective study. Primary epithelial ovarian cancer patients with normal-appearing omentum were randomly assigned to either the control or experimental group and underwent infracolic or infragastric omentectomy, respectively. The primary endpoint was progression-free survival. This trial is registered on Chinese clinical trial registry site (ChiCTR1800018771).ResultsA total of 106 patients meeting the inclusion criteria for ovarian cancer were included during the study period. Of these, 53 patients underwent infracolic omentectomy, whereas 53 patients received infragastric omentectomy. Multivariate analysis revealed that infragastric omentectomy could improve the detection rate of omental metastases (OR: 6.519, P = 0.005). Infragastric omentectomy improved progression-free survival significantly for those cases with higher than stage IIB disease (HR: 0.456, P = 0.041). Based on the short-term results, infragastric omentectomy did not cause more perioperative complications.ConclusionsCompared with infracolic omentectomy, infragrastric omentectomy may be a more appropriate surgical procedure for stage IIB-IIIC epithelial ovarian cancer patients with normal-appearing omentum.

Plasma exosomal miR-320d, miR-4479, and miR-6763-5p as diagnostic biomarkers in epithelial ovarian cancer.

Exosomal miRNA had been proved as the promising biomarkers for multiple cancers including epithelial ovarian cancer (EOC). This study aimed to validate the diagnostic accuracy of exosomal miR-320d, miR-4479, and miR-6763-5p for EOC. Exosomes isolated from the plasma by ultracentrifugation were verified using TEM, qNano and western blot. MiRNAs sequencing was used to screen out the differential exosomal miRNAs and miR-320d, miR-4479, and miR-6763-5p were selected as candidates, which were further verified by RT-qPCR in 168 healthy donors and 161 primary EOC patients. Besides, the diagnostic accuracy of these three exosomal miRNAs were evaluated using the receiver operating characteristic curve (ROC). MiRNAs sequencing revealed 95 differential exosomal miRNAs between EOC patients and healthy donors. Subsequently, exosomal miR-320d, miR-4479, and miR-6763-5p were significantly down regulated in EOC patients compared with healthy controls and benign patients. More importantly, these three miRNAs could serve as circulating diagnostics biomarkers for EOC, possessing areas under the curve (AUC) of 0.6549, 0.7781, and 0.6834, respectively. Moreover, these three exosomal miRNAs levels were closely associated with lymph node metastasis, meanwhile exosomal miR-320d and miR-4479 expression was related to tumor stage. Exosomal miR-320d, miR-4479, and miR-6763-5p might serve as potential biomarkers for EOC.

Development and validation of a nomogram to predict overall survival of epithelial ovarian cancer patients: a population-based study (381)

<b>Objectives:</b> To develop and validate a nomogram for the overall survival of epithelial ovarian cancer based on the National Union of Real- World Gynecological Oncology Research and Patient Management Platform (NUWA) in China. <b>Methods:</b> We enrolled patients with pathologically confirmed primary epithelial ovarian cancer in the NUWA platform between 2004 and 2018 as a training cohort to develop a nomogram. The cut-off for follow-up was December 2020. Patients with a history of other tumors or missing values of any variable were excluded. Variables were selected by univariate and multivariate Cox proportional hazard regression. Significant factors were applied to establish a nomogram to predict 3-year and 5-year survival, assessed by C-statistic and calibration curves. A testing cohort from SEER Database was applied to externally validate the nomogram by bootstrap resampling. Statistical analysis was conducted by SPSS version 26.0 (IL, USA) and R version 4.1.1 (www.r-project.org). <b>Results:</b> A total of 1262 primary epithelial ovarian cancer patients were filtered out from 5003 ovarian cancer patients in the NUWA platform. Total 10594 of 125682 patients in the SEER Database were screened out accordingly. Baseline age, histotype, histological grade, FIGO stage, longest diameter of the primary tumor, and residual disease after primary surgery were significant risk factors (<i>p</i><0.05). Compared with serous cancer, the hazard ratio (HR) of mucinous, endometrioid, clear cell, other epithelial cancer were 3.391 (95% CI: 2.201-5.223), 1.642 (95% CI: 1.045-2.580), 3.127 (95% CI: 2.134-4.582), and 2.071 (95% CI: 1.486-2.885), respectively. The HR of advanced stage and high grade of disease (FIGO stage III-IV vs I-II, High grade vs Low/moderate grade) were 1.921 (95% CI: 1.226-3.010) and 1.407 (95% CI: 1.048-1.889), respectively. Patients who received optimal (R1), suboptimal (R2) cytoreduction, and those who didn't receive primary debulking surgery had a higher risk of death compared to those without the residual disease (R0), with HRs of 5.530 (95% CI: 3.575-8.555), 7.757 (95% CI: 5.101-11.796) and 9.975 (95% CI: 5.831-17.063), respectively. For continuous variables, the HR of baseline age (years) was 1.024 (95% CI: 1.013-1.036), and the HR of the longest diameter of the primary tumor (cm) was 1.030 (95% CI: 1.007-1.054). The C-statistic values of the nomogram (Figure 1) in the training and testing cohorts were 0.771 (95% CI: 0.748-0.794) and 0.726 (95% CI: 0.718-0.734), respectively. The slopes of calibration curves of 3-year and 5-year survival in the training cohort were 1.165 (95% CI: 0.990-1.340) and 0.955 (95% CI: 0.920-0.990), respectively, whereas, in the testing cohort, these were 1.355 (95% CI: 1.108-1.602) and 1.374 (95% CI: 1.103-1.644), respectively. Fig. 1 <b>Conclusions:</b> The discrimination and goodness of fit of the nomogram indicated its predictive value for the survival of epithelial ovarian cancer in China. Furthermore, the nomogram also obtains certain values in external validation, which implies its feasibility in different populations.

Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics.

ObjectiveThe status of homologous recombination repair (HRR) gene mutations and their impact on the survival of patients with Chinese epithelial ovarian cancer (EOC) are still unclear. In this study, we retrospectively analyzed the mutations of HRR genes in tumor tissues and evaluated their values for predicting the survival of Chinese EOC patients.MethodsA total of 273 primary EOC patients from five different hospitals between 2015 and 2016 were recruited. All patients received staging surgeries or debulking surgeries combined with systemic platinum-based chemotherapy. DNA was extracted from formalin-fixed, paraffin-embedded sections and analyzed for mutations using a 21-gene panel (including 13 well-known HRR genes) by next-generation sequencing.ResultsHigh-grade serous carcinoma (HGSOC) accounted for 76.2% of the cohort. A total of 34.1% (93/273) cases had 99 deleterious mutations in 9 HRR genes, namely, BRCA1 (56/273, 20.5%), BRCA2 (20/273, 7.3%), ATM (5/273, 1.8%), RAD51C (5/273, 1.8%), RAD51D (5/273, 1.8%), BRIP1 (2/273, 1.8%), CHEK2 (2/273, 0.7%), FANCI (2/273, 0.7%), and RAD54L (1/273, 0.4%). There is a strong mutual exclusion between HRR genes. The mutation landscape revealed several unappreciated deleterious variants in BRCA1/2 and other HRR genes reported previously. Estimated according to the mutation allele frequency, about 4.8% of the patients had potential somatic HRR gene mutations, which might be underestimated. Moreover, HRR mutations mainly exist in HGSOC (83/208, 39.9%), clear cell (2/30, 6.7%), and endometroid subtypes (8/20, 40%), but not seen in other rare subtypes. BRCA1 mutations tend to be present in younger patients with family history or multiple primary foci. Patients with BRCA1/2 mutations tend to have a longer progression-free survival and overall survival, while other HRR mutation carriers tend to have a shorter progression-free survival, but no significant difference in overall survival.ConclusionThis study revealed the distribution of HRR gene mutations in Chinese EOC tissues. BRCA1/2 account for the majority of HRR gene mutations and predict long prognosis in HGSOC. Non-BRCA HRR mutations also account for a very important proportion and might be associated with poor prognosis in HGSOC. It is suggested that HRR gene mutations need to be detected in EOC tissues and germline status be further clarified in clinical algorithm for potential targeted therapy, genetic screening, and prognosis prediction.

Identification of Stably Expressed Reference microRNAs in Epithelial Ovarian Cancer.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression and have been associated with the development of various cancers, including epithelial ovarian cancer (EOC). Accurate quantification of miRNA levels is important for determining their role in tumorigenesis and as biomarkers. Currently, U6 is widely used as a normalization control when investigating miRNAs in EOC; however, its variable expression across cancers has been reported. As only a few studies have been published to date on the identification of endogenous miRNA controls in EOC, our aim was to identify stable miRNAs based on global microarray profiling of 197 EOC patients and verify their stability in external datasets. We collected miRNA-microarray data from four datasets: the in-house "Pelvic Mass", and three public datasets with primary EOC patients: The Cancer Genome Atlas, GSE47841, and GSE73581. The expression stability of endogenous control candidates was evaluated by their coefficient of variation. All miRNA results in the used cohorts were produced by either Affymetrix or Agilent technologies, which show similar intra-platform patterns. Nonetheless, a clear difference in a cross-platform comparison was observed. We identified hsa-miR-92b-5p and hsa-miR-106b-3p as stable candidates shared between four datasets. Moreover, we investigated the stability performance of eight miRNAs that have been previously reported as stable endogenous controls in EOC and various performance was observed in four datasets. The selection of suitable endogenous miRNA normalization controls in EOC remains to be resolved, as variability in miRNA performance between platforms might have a crucial impact on the biological interpretation of data.

Cell-Free-DNA-Based Copy Number Index Score in Epithelial Ovarian Cancer-Impact for Diagnosis and Treatment Monitoring.

Simple SummaryThe prognosis of ovarian cancer is dependent on the tumor stage and the development of chemotherapy resistance. Using low-coverage cell-free tumor DNA sequencing, we were able to determine the chromosomal instability (CI) of tumors that are frequently found in patients with primary advanced and recurrent high-grade ovarian cancer from a blood sample. We were able to show that the CI could be used for the reliable detection of ovarian cancer in comparison to healthy controls. Moreover, we showed that the CI was significantly associated with the prognostic and predictive clinical measures in primary and recurrent ovarian cancer. The high diagnostic accuracy of the tumor CI derived from cfDNA analysis might lead to the optimization of main prognostic determinants in patients with ovarian cancer. As the CI is a characteristic feature in high-grade ovarian cancer, no upfront tumor tissue analysis is required to identify genomic alterations for targeted sequencing of cfDNA, if the herein described low-coverage sequencing and CNI-Score determination is used.Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment. Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set. Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively. Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

Eukaryotic initiation factor 3B is overexpressed and correlates with larger tumor size, advanced FIGO stage, and shorter overall survival in epithelial ovarian cancer patients.

BackgroundThis study aimed to detect the eukaryotic initiation factor 3B (EIF3B) expression and explore its correlation with clinical features and prognosis in epithelial ovarian cancer (EOC) patients.Methods A total of 230 primary EOC patients underwent surgery treatment were retrospectively reviewed. Immunohistochemical (IHC) assay was used to determine EIF3B expression in tumor and adjacent tissue specimens of all patients. According to the total IHC score, the expression of EIF3B was classified as low expression and high expression, and the latter was further divided into 3 grades: high+, high++, and high+++ expressions. Overall survival (OS) was calculated.ResultsEukaryotic initiation factor 3B expression was increased in tumor tissue compared with adjacent tissue. Tumor EIF3B high expression correlated with larger tumor size (>10 cm), lymphatic metastasis, and advanced International Federation of Gynecology and Obstetrics stage (FIGO) (III/IV). Besides, OS was decreased in patients with tumor EIF3B high expression compared with patients with tumor EIF3B low expression, and further analysis showed that the OS was shortest in patients with tumor EIF3B high+++ expression, followed by patients with tumor EIF3B high++ expression and patients with tumor EIF3B high + expression, and the longest in patients with tumor EIF3B low expression. Additionally, higher tumor EIF3B expression, peritoneal cytology (positive), ascites volume (>100 mL), differentiation (poor vs. well/moderate), tumor size (>10 cm), FIGO stage (III/IV vs. I/II), and cancer antigen 125 (>1000 U/mL) independently predicted shorter OS.ConclusionEukaryotic initiation factor 3B exhibits a clinical value for monitoring disease progression and predicting prognosis in EOC patients.

The Prevalence and associated Factors for Liver Metastases, Development and Prognosis in newly diagnosed Epithelial Ovarian Cancer: A large Population-Based Study from the SEER Database.

Background: Primary Epithelial Ovarian Cancer (EOC), a malignant gynecologic disease, is considered one of the leading causes of mortality in women. The development of Liver Metastases (LM) in women with primary ovarian cancer commonly results in a poorer prognosis. This retrospective population-based study aims to measure the prevalence, prognostic factors, and associated risk factors for epithelial ovarian cancer patients with liver metastases (EOCLM).Materials and Methods: The current study cohort of patients based on the Surveillance, Epidemiology, and End Results (SEER) database identified with primary ovarian cancer between the years 2010 and 2016. A chi-square test was employed to compare Metastatic differences among demographic and clinical factors. Univariable and multivariable logistic regression analysis models were used to predict related prognostic factors for LM development. 7-year Kaplan-Meier curves were applied to compare the survival patterns of patients with and without LM. The Multivariable Cox regression model was used to estimate potential risk factors associated with LM related deaths.Results: 33895 eligible primary EOC patients were identified. Among them 2635 (7.77%) patients were initially diagnosed with de novo LM, and 31260 (92.23%) without metastases disease to any site. Non-serous histology type; Malignant Brenner Carcinoma, NOS (OR 1.94; CI: 1.39-2.71; P<0.001), T3/T1 stage (OR 5.65; CI: 3.87-8.24; P<0.001), N1/N0 stage (OR 1.67; CI: 1.43-4.95; P<0.001), grade; G3/G1 (OR 2.16; CI: 1.29-3.59, P<0.001), and cancer antigen-125; Elevated/Normal (OR 1.79; CI: 1.19-2.69, P<0.001) were significantly associated with LM occurrence. The median survival of EOC patients with LM was 12.0 (95% CI: 11.0-14.0; P<0.001) months. Multivariable cox regression showed being unmarried (HR 1.16; CI: 1.04-1.30; P=0.001), non-serous histology types, Mucinous (HR 2.38; CI: 1.82-3.12; P<0.001), Clear cell (HR 1.83; CI: 1.32-2.55; P<0.001), Malignant Brenner Carcinoma, NOS (HR 1.44; CI:1.23-1.66; P<0.001), Carcinosarcoma NOS, (HR 1.44; CI: 1.11-1.88; P<0.001) and radiotherapy (HR 1.52; CI: 1.12-2.06; P<0.001), were positively related to death. Chemotherapy (HR 0.30; CI: 1.12-2.06; P<0.001) and surgery (HR 0.34; CI: 0.29-0.39; P<0.001) were related with reduced rate of death.Conclusion: The retrospective cohort study showed that women with primary EOC had some high-risk factors associated with LM. LM can intensely decrease the survival of EOC patients. The findings of our research provided estimates for LM occurrence prediction and potential prognostic factors of EOC with de novo LM development. These findings can be useful for follow-up strategies, guidelines for screening, and treatment of EOCLM.

HLA-G 3\u2032 untranslated region variants +3187G/G, +3196G/G and +3035T define diametrical clinical status and disease outcome in epithelial ovarian cancer

Expression of the non-classical human leukocyte antigen-G (HLA-G) promotes cancer progression in various malignancies including epithelial ovarian cancer (EOC). As single nucleotide polymorphisms (SNPs) in the HLA-G 3′ untranslated region (UTR) regulate HLA-G expression, we investigated HLA-G 3′UTR haplotypes arranged by SNPs in healthy controls (n = 75) and primary EOC patients (n = 79) and determined soluble HLA-G (sHLA-G) levels. Results were related to the clinical status and outcome. Although haplotype frequencies were similar in patients and controls, (i) sHLA-G levels were increased in EOC independent of the haplotype, (ii) homozygosity for UTR-1 or UTR-2 genotypes were significantly associated with metastases formation and presence of circulating tumor cells before therapy, whereas (iii) the UTR-5 and UTR-7 haplotypes were significantly associated with a beneficial clinical outcome regarding negative nodal status, early FIGO staging, and improved overall survival. Lastly, (iv) the ambivalent impact on clinical EOC aspects could be deduced to specific SNPs in the HLA-G 3′UTR: +3187G, +3196G and +3035T alleles. Our results give evidence that even if the genetic background of the HLA-G 3′UTR is identical between patients and controls, certain SNPs have the potential to contribute to diametrical clinical status/outcome in EOC.

Next-generation sequencing-based genomic profiling analysis reveals novel mutations for clinical diagnosis in Chinese primary epithelial ovarian cancer patients

BackgroundOvarian cancer (OC) is one of the most malignant gynecological tumors, associated with excess death rate (50–60%) in ovarian cancer patients. Particularly, among newly occurred ovarian cancer patients, 70% of clinical cases are diagnosed at the advanced stage, which definitely delay the timely treatment and lead to high mortality rate within 5 years post diagnosis. Therefore, identification of sensitive gene markers, as well as development of reliable genetic diagnosis, are important for the early detection and precise therapy for OC patients. This study aims to identify novel genetic mutations and develop a feasible clinical approach for early OC diagnosis.MethodsThe OC tissue-derived DNA sample was acquired from 31 OC patients, and the somatic gene mutations will be identified after comparison with normal samples, using Genome-wide analysis and next-generation sequencing.ResultsA total of 463 somatic mutations, which were considered as potential pathogenic sites, were assigned to 473 genes. Among them, 15 genes (TP53, TTN, MUC16, OR4N2, BRCA1, CAD, CCDC129, INSR, NAV3, NELL2, NRAS, OBSCN, PGLYRP4, RBM15B and TRPC7) were mutated on at least two sites. These genes were mapped to RNA sequencing (RNAseq) data, and a total of 117 genes had an absolute fold- change ≥ 2 and p ≤ 0.01. Five genes were mutated in at least two OC patients. Gene ontology (GO) classification indicated that a majority of genes participated in biological processes. Kyoto Enrichment of Genes and Genomes (KEGG) enrichment pathway analysis revealed that the genes were mainly involved in the regulation of metabolic signaling pathways.ConclusionsTaken together, this study identified several novel genetic alterations pathway for early clinical diagnosis and provided abundant information for understanding molecular mechanisms of the OC occurrence and development.

Evaluation of trace elements associated with antioxidant enzymes in blood of primary epithelial ovarian cancer patients

Epithelial ovarian cancer (EOC) has been associated with oxidative stress (OS) due to epithelial inflammation which makes ovaries more vulnerable to the deleterious effects of reactive oxygen species (ROS). However, antioxidant enzymes (AOEs) such as manganese-superoxide dismutase (Mn-SOD), copper,zinc-superoxide dismutase (Cu,Zn-SOD) and glutathione peroxidase (GPx1) protect cells against the biological damage of ROS-induced OS and support cancer prevention by maintaining normal cell cycle progression, inhibiting proliferation, tumor invasion, angiogenesis, inflammation or inducing apoptosis.In the present study, we aimed to measure the levels of trace elements [manganese (Mn), copper (Cu), zinc (Zn) and selenium (Se)] which are structurally and/or functionally associated with the AOEs by inductively coupled plasma/mass-spectrometry (ICP/MS) in blood samples of patients with EOC (M, n = 26) and compare the data with healthy subjects (C, n = 46). Serous EOC (M1, n = 18) data were also evaluated according to the tumor grading [well or moderately well differentiated (G 1-2) vs. poorly differentiated or undifferentiated (G3)] and staging of disease [stage I-II (SI-II) vs. stage III (SIII)]. We obtained; i) The Mn and Se levels of M were significantly lower than C, ii) only Mn levels were changed [(G3(Mn) < G 1-2 (Mn)] in M1, iii) significant correlations were observed between [Cu and Zn levels (r = 0.701, p = 0.036) in G 1-2 and (r = 0.686, p = 0.041) in G3; Cu and Se levels (r = 0.960, p = 0.000) in G3; Mn levels and Mn-SOD expression (r = 0.551, p = 0.006) in M, (r = 0.857, p = 0.007) in G 1-2 and (r = 0.690, p = 0.056) in G3; Se levels and erythrocyte GPx1 activity (r = 0.660, p = 0.053) in G 1-2 ; Se levels and erythrocyte Cu,Zn-SOD activity (r = 0.693, p = 0.038) in G3]. The study revealed that trace elements, particularly low Mn and Se levels along with high Cu/Se ratios might be of value in all histologic subtypes of EOC. Although Mn level was important in terms of discriminating tumor grades, positive correlation between Cu-Se levels was also remarkable in patients with G 1-2 tumors of M1. Moreover, high erythrocyte Cu/Se ratios might be a favourable marker for EOC.

Adenosine triphosphate-based chemotherapy response assay predicts long-term survival of primary epithelial ovarian cancer.

The aim of this study is to analyze the long-term relapse-free survival and overall survival outcomes of primary ovarian cancer patients using adenosine triphosphate-based chemotherapy response analysis. In total, 162 primary epithelial ovarian cancer patients who underwent chemotherapy response assay for carboplatin, cisplatin, and paclitaxel by adenosine triphosphate-based chemotherapy response analysis prior to chemotherapy between December 2006 and November 2016 were retrospectively reviewed. Chemosensitivity with single or combined three agents and clinical characteristics of patients were studied to understand their correlation with long-term relapse-free survival and overall survival. Median follow-up time was 61.4 (range 1 - 130) months. Univariate analysis showed the paclitaxel-sensitive group (HR = 0.625, 95%CI = 0.393 to 0.994), combined carboplatin and paclitaxel-sensitive group (HR = 0.574, 95%CI = 0.352 to 0.937), and combined carboplatin, cisplatin, and paclitaxel-sensitive group (HR = 0.489, 95%CI = 0.295 to 0.810) were highly associated with better relapse-free survival than their corresponding non-sensitive groups. The carboplatin-sensitive group (HR = 0.533, 95%CI = 0.303 to 0.939), cisplatin-sensitive group (HR = 0.433. 95%CI = 0.251 to 0.748), and combined carboplatin- and cisplatin-sensitive group (HR = 0.286, 95%CI = 0.142 to 0.576) were highly associated with better overall survival than their corresponding non-sensitive groups. Combined carboplatin, cisplatin, and paclitaxel chemosensitivity, together with International Federation of Gynecology and Obstetrics (FIGO) stage were independent predictors for relapse-free survival. Single or combined chemosensitivity of cisplatin and/or carboplatin, together with residual tumor size and FIGO stage, were significant independent predictors for overall survival on a multivariate hazard model. Paclitaxel sensitivity is a prognostic factor of long-term relapse-free survival in patients with epithelial ovarian cancer, but platinum sensitivity is a more important prognostic factor for long-term overall survival.

Distinct Clinical Courses of Epithelial Ovarian Cancer with Mutations in BRCA1 5' and 3' Exons.

This study aimed to determine the effect of different BRCA1 exonal mutations on the clinical course of epithelial ovarian cancer (EOC). Clinicopathological variables and survival outcomes were compared among 53 primary EOC patients with pathogenic BRCA1 mutations in exons 1-11 (5' mutations) and in exons 12-24 (3' mutations). BRCA1 5' exonal mutations were found in 35 (66.0%) patients. The median follow-up period was 40 months. Clinicopathological variables remained unchanged between the two groups. Patients with 5' mutations had a significantly longer progression-free survival than those with C-terminal mutations (p=0.034), better predicting progression-free survival [2.923 (1.402-6.093), p=0.004], but not overall survival in cases of multiple relapses (p=0.497). N-terminal BRCA1 mutations in EOC patients are associated with favourable primary progression-free survival, a trend observed only in primary progression-free survival, not in overall survival.

PAX8 is a potential marker for the diagnosis of primary epithelial ovarian cancer.

The present study aimed to investigate the clinical significance of paired-box 8 (PAX8) in primary epithelial ovarian cancer (PEOC). Using immunohistochemical (IHC) staining, the expression of PAX8 in 60 patients with PEOC, 20 patients with ovarian benign lesions and 10 patients with metastatic ovarian cancer (MOC), was examined based on the clinicopathological profiles of the patients. The correlation between PAX8 expression and the clinicopathological parameters or prognosis of patients was statistically analyzed. PAX8 was revealed to be highly expressed in PEOC, but not in MOC, as indicated by IHC staining. The rate of positivity of PAX8 in PEOC was 92% (57/60) with no significant difference of PAX8 expression found between the various pathological types of PEOC (P=0.871). The rate of positivity of PAX8 in ovarian benign tumors was 85%, demonstrating no significant difference in comparison with that of PEOC (P=0.761). PAX8 staining and statistical analysis revealed that the higher the grade of PEOC, the less the cancer cell had differentiated (P=0.033) and the more the cancer had advanced according to International Federation of Gynaecological Oncologists (FIGO) staging (P=0.003). Survival rate statistics showed that PEOC patients with higher PAX8 expression exhibited a shorter postoperative survival rate (P=0.009). PAX8 was specifically expressed in PEOC, and its expression level was associated with the degree of cancer cell differentiation, FIGO stage, and survival rate, indicating that PAX8 is a potential marker for the diagnosis of PEOC.

MAGE-A family serves as poor prognostic markers and potential therapeutic targets for epithelial ovarian cancer patients: a retrospective clinical study

Objective: The aim of our study is to investigate the expression pattern and prognostic significance of melanoma-associated antigens-A (MAGE-A) family in primary epithelial ovarian cancer (EOC) patients.Study design: The expression of MAGE-A family members, including MAGE-A1, -A2, -A3, -A4, -A6, -A10 and -A12 was immunohistochemically detected in 82 cases of primary EOC and 10 cases of pericarcinoma ovarian tissues. The association between MAGE-A family expression and the clinicopathological parameters as well as the prognosis of primary EOC patients was analyzed.Results: MAGE-A family expressed in 48.8% of primary EOC tissues, but not expressed in pericarcinoma ovarian tissues. MAGE-A expression was associated with the pathological types, FIGO stage, and pre-operative serum CA125 level. Overall survival of EOC patients with positive MAGE-A family expression was significantly shorter than those patients with negative MAGE-A expression. Multivariate analysis showed that although MAGE-A family expression can affect the overall survival, it was not an independent prognostic marker for EOC patients.Conclusions: Molecular assessment of MAGE-A family members could be helpful to improve the prognostic evaluation and to provide a new potential therapeutic target for primary EOC patients.

Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.

Germline mutations in BRCA1 gene have been reported in up to 20% of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60% of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8%). Further 10/263 (3.8%) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100%) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients—results from the OVCAD study

Patients with epithelial ovarian cancer (EOC) are at high risk of tumor recurrence. Human epididymis protein 4 (HE4) has been shown to be overexpressed in EOC. The primary aim of our study was to evaluate the role of HE4 in predicting recurrence in EOC patients. Furthermore, we assessed the role of HE4 in predicting recurrence after second-line chemotherapy. We retrospectively analyzed data of 92 out of 275 primary EOC patients of the multicenter project "Ovarian Cancer: Diagnosis of a silent killer" (OVCAD). The concentrations of HE4 and CA125 were determined preoperatively and 6months after the end of platinum-based first-line chemotherapy (FU) using ELISA and Luminex technique, respectively. The role of HE4 and CA125 for prediction of recurrence was determined using receiver operating characteristics (ROC) curves. Out of 92 patients included, 70 (76%) were responders and 22 (23%) non-responders in terms of response to platinum-based first-line chemotherapy. Median HE4 concentrations at follow-up (FU) differed between responders and non-responders (60.5 vs. 237.25pM, p = 0.0001), respectively. The combined use of HE4 and CA125 at FU with cut-off values of 49.5pM and 25U/ml for HE4 and CA125, respectively, for predicting recurrence within 12months after first-line chemotherapy performed better than HE4 or CA125 alone (area under the curve (AUC) 0.928, 95% confidence intervals (CI) 0.838-1, p < 0.001). HE4 at FU could predict recurrence within 6months after second-line chemotherapy (AUC 0.719, 95% CI 0.553-0.885, p = 0.024). The combination of both elevated biomarkers revealed significantly worse estimated median progression-free survival (PFS; hazard ratio (HR) 8.14, 95% CI 3.75-17.68, p < 0.001) and slightly worse PFS in those in whom only one biomarker was elevated (HR 1.46, 95% CI 0.72-2.96, p = 0.292) compared to those patients in whom no biomarker was elevated. For the estimated median overall survival (OS), our analysis revealed similar results. HE4 in combination with CA125 performed better than CA125 and HE4 alone in predicting recurrence within 12months after first-line chemotherapy.

Evaluation of leptin serum concentrations during surgery and first-line chemotherapy in primary epithelial ovarian cancer patients.

Aim of the studyThe available data on serum leptin levels in ovarian cancer present contradictory results. The majority of authors report lower leptin levels in those patients in comparison to healthy individuals. However, there is no data regarding leptin concentrations during therapy in women with primary epithelial ovarian cancer.Material and methodsBlood samples were collected at the time of diagnosis, after initial surgery, and after first-line chemotherapy. Leptin serum concentrations were analysed using ELISA technique. Additionally, parallel measurements of CA125 levels were performed.ResultsFifty-three patients with primary epithelial ovarian cancer met the inclusion criteria and were included in our study. Our analysis revealed a significant difference in mean preoperative serum leptin concentrations between early and advanced ovarian cancer patients (p < 0.0001). We identified statistically significant elevation of mean serum leptin levels (p < 0.001) after complete macroscopic cytoreduction and after first-line chemotherapy in advanced ovarian cancer cases.DiscussionIn this cohort, a significant elevation of postoperative serum leptin levels after complete macroscopic cytoreduction were shown. Moreover, elevation of leptin levels corresponded with remission after chemotherapy. Further studies are needed to determine if leptin can be a potential marker of surgery completeness as well as a marker in chemotherapy response evaluation.

Abstract 3156: MicroRNA let-7a is a possible new marker for predicting the effect of paclitaxel in epithelial ovarian cancer

Abstract MicroRNA let-7 is a family of small non-coding RNAs post-transcriptionally regulating the expression of genes that are involved in cell proliferation, apoptosis and therapy response. Let-7 is shown in vitro to affect the sensitivity of cancer cells to platinum. Let-7a, a member of the let-7 family, is also found to induce ovarian cancer cell resistance to paclitaxel (taxol). The purpose of this study is to investigate the relationship of let-7a expression and survival outcomes of epithelial ovarian cancer patients treated with different chemotherapy. Levels of let-7a and RNU48 (an endogenous control for normalization) were analyzed using the Taqman® microRNA assays in 178 primary epithelial ovarian cancer patients who received chemotherapy after debulking surgery. Survival analysis was performed to assess the associations of let-7a expression with disease outcomes and chemotherapy. Patients with poor response to platinum with taxol had significantly higher let-7a expression than those with complete response, while no difference in let-7a expression between responders and non-responders treated with platinum without taxol. We also found that in patients treated with platinum without taxol, high let-7a was associated with better survival. The Hazard Ratios (HRs) for death were 0.55 (95% CI: 0.29-1.05) and 0.52 (95% CI: 0.29-0.96) when comparing patients with medium or high let-7a to those with low let-7a, respectively (p for trend = 0.033). Similar HRs for disease progression were 0.49 (95% CI: 0.27-0.91) and 0.48 (0.26-0.89), respectively (p for trend = 0.020). These associations became less significant when patient age at surgery, disease stage, tumor grade and histological type were adjusted in the analysis. However, in patients treated with platinum and taxol, high let-7a expression was associated with poor survival. The HRs for death were 1.70 (95% CI: 0.50-5.81) for medium and 3.87 (95% CI: 1.28-11.66) for high let-7a (p for trend = 0.009). The HRs for disease progression were 2.85 (95% CI: 0.99-8.22) for medium and 3.48 (95% CI: 1.25-9.67) for high let-7a (p for trend = 0.016). These associations remained significant after the analyses were adjusted for patient age at surgery, disease stage, tumor grade and histological type. These results suggest that let-7a may play different roles in disease outcome when patients received different combinations of chemotherapy, and the microRNA may serve as a marker for selecting patient who will respond to taxol treatment. This finding may have significant implication in the treatment of epithelial ovarian cancer with regard to reducing treatment cost and minimizing drug toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3156. doi:10.1158/1538-7445.AM2011-3156

Assessment of superoxide dismutases in tissue and blood samples of primary epithelial ovarian cancer patients

Assessment of superoxide dismutases in tissue and blood samples of primary epithelial ovarian cancer patients