Endometrioid Epithelial Ovarian Cancer Research Articles

Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer.

BackgroundThe Myc oncogene family has been implicated in many human malignancies and is often associated with particularly aggressive disease, suggesting Myc as an attractive prognostic marker and therapeutic target. However, for epithelial ovarian cancer (EOC), there is little consensus on the incidence and clinical relevance of Myc aberrations. Here we comprehensively investigated alterations in gene copy number, expression, and activity for Myc and evaluated their clinical significance in EOC.MethodsTo address inconsistencies in the literature regarding the definition of copy number variations, we developed a novel approach using quantitative polymerase chain reaction (qPCR) coupled with a statistical algorithm to estimate objective thresholds for detecting Myc gain/amplification in large cohorts of serous (n = 150) and endometrioid (n = 80) EOC. MYC, MYCN, and MYCL1 mRNA expression and Myc activity score for each case were examined by qPCR. Kaplan–Meier and Cox-regression analyses were conducted to assess clinical significance of Myc aberrations.ResultsUsing a large panel of cancer cell lines (n = 34), we validated the statistical algorithm for determining clear thresholds for Myc gain/amplification. MYC was the most predominantly amplified of the Myc oncogene family members, and high MYC mRNA expression levels were associated with amplification in EOC. However, there was no association between prognosis and increased copy number or gene expression of MYC/MYCN/MYCL1 or with a pan-Myc transcriptional activity score, in EOC, although MYC amplification was associated with late stage and high grade in endometrioid EOC.ConclusionA systematic and comprehensive analysis of Myc genes, transcripts, and activity levels using qPCR revealed that although such aberrations commonly occur in EOC, overall they have limited impact on outcome, suggesting that the biological relevance of Myc oncogene family members is limited to certain subsets of this disease.

Changes in ovarian cancer survival during the 20\xa0years before the era of targeted therapy

BackgroundThe survival of patients with ovarian cancer has improved because of surgery and chemotherapy. This study aimed to estimate the changes in survival rates among Korean women with ovarian cancer prior to the introduction of targeted therapy for ovarian cancer.MethodsData were obtained from the Korea Central Cancer Registry regarding patients who were diagnosed with epithelial ovarian cancer between 1995 and 2014. The relative survival rates were calculated for 5-year periods using the Ederer II method. Cox proportional hazard models were created to assess the associations of demographic and clinicopathological factors with ovarian cancer survival.ResultsDuring the study period, 22,880 women were diagnosed with epithelial ovarian cancer. The 5-year relative survival rate improved from 57.2% during 1995–1999 to 63.8% during 2010–2014 (P < 0.001). Survival outcomes improved between 1995 and 1999 and 2010–2014 for the serous and endometrioid carcinoma subtypes (P < 0.001). However, no improvements were observed for the mucinous and clear cell carcinoma subtypes (P = 0.189 and P = 0.293, respectively). Multivariate analysis revealed that younger age, early stage, recent diagnosis, primary surgical treatment, and non-serous histological subtype were favorable prognostic factors.ConclusionSurvival outcomes have improved for serous and endometrioid epithelial ovarian cancer in the last 20 years. However, no improvement was observed for patients with mucinous and clear cell carcinoma subtypes.

Stage- and Histologic Subtype-Dependent Frequency of Lymph Node Metastases in Patients with Epithelial Ovarian Cancer Undergoing Systematic Pelvic and Paraaortic Lymphadenectomy.

Tumor stage and distinct histological subtypes in epithelial ovarian cancer (EOC) show different prognostic outcome. The aim of this study is to evaluate whether the frequency of lymph node (LN) metastases in patients with different tumor stages and histological subtypes undergoing systematic pelvic and paraaortic lymphadenectomy is coincidentally divergent. Patients with EOC treated with upfront staging or debulking surgery between January 2000 and December 2016 were included. Systematic lymphadenectomy was performed in all consecutive patients with optimal debulking and without medical contraindications. Seven hundred sixty-two patients including 27.2% with early-stage EOC were included. The median number of removed LNs was 69, and metastases to LNs were found in 54.7%. No LN metastases were found in patients with low-grade endometrioid carcinoma, independently of tumor stage. LN metastases in early-stage low-grade serous (N = 5), mucinous (N = 31), and clear cell (N = 28) EOC were found in one (20%), zero, and one (3.6%) patient, respectively. LN metastases were detected in more than 10% of patients with all other histological subtypes. On multivariate analyses, overall survival was significantly impaired in patients with LN metastases, as compared with patients without LN metastases (p = 0.001). The risk of LN metastases in patients with EOC is dependent on stage and histological subtype. Patients with incidental finding of early mucinous or low-grade endometrioid EOC are at very low risk of retroperitoneal lymph node metastases. Reoperation for lymph node staging only should be discussed individually with caution.

Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000–2013

BackgroundWe sought to evaluate the impact of adjuvant chemotherapy on overall survival (OS) in patients with stage I endometrioid epithelial ovarian cancer (EEOC) or ovarian clear cell cancer (OCCC) using a national database. Patients and methodsThe Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I EEOC or OCCC from 2000 to 2013. We sought to identify predictors of chemotherapy use and to assess the impact of chemotherapy on OS in these patients. OS was compared using the log-rank test and the Cox proportional hazards model. ResultsIn all, 3552 patients with FIGO stage I EEOC and 1995 patients with stage I OCCC were identified. Of the 1600 patients (45%) with EEOC who underwent adjuvant chemotherapy, the 5-year OS rate was 90%, compared with 89% for those who did not undergo adjuvant chemotherapy (P = 0.807). Of the 1374 (69%) patients with OCCC who underwent adjuvant chemotherapy, the 5-year OS rate was 85%, compared with 83% (P = 0.439) for those who did not undergo adjuvant chemotherapy. Chemotherapy use was associated with younger age, higher substage, and more recent year of diagnosis for both the EEOC and OCCC groups. Only in the subgroup of patients with FIGO substage IC, grade 3 EEOC (n = 282) was chemotherapy associated with an improved 5-year OS—81% compared with 62% (P = 0.003) in untreated patients (HR: 0.583; 95% CI: 0.359–0.949; P = 0.030). In patients with OCCC, there was no significant effect of adjuvant chemotherapy on OS in any substage. ConclusionsAdjuvant chemotherapy was associated with improved OS only in patients with substage IC, grade 3 EEOC. In stage I OCCC, adjuvant chemotherapy was not associated with improved OS.

Phase II randomized trial of neoadjuvant (NA) chemotherapy (CT) with or without bevacizumab (Bev) in advanced epithelial ovarian cancer (EOC)‏ (GEICO 1205/NOVA TRIAL).

5508 Background: First line carboplatin(C)-paclitaxel(P) and Bev has proved to be an active combination after primary debulking surgery and improve overall survival in sub-optimal resected advanced EOC patients (pts). However, the role of Bev in the NA setting has not been well defined yet. Methods: We performed a phase II randomized open label multicentric study in pts with high grade serous or endometrioid EOC, FIGO stage III-IV, ECOG 0-2, considered unresectable in whom NA CT and interval debulking surgery (IDS) were planned. Main exclusion criteria were intestinal occlusion and contraindication for Bev. Pts were randomized to 4 courses of triweekly C AUC 6 and P 175 mg/m2 iv alone or with at least 3 courses of Bev 15 mg/kg i.v. every 3w in experimental arm. The primary endpoint was complete macroscopic response (CMR) rate at IDS. Secondary objectives were safety, surgical feasibility, optimal surgery rate (OSR), RECIST 1.1 and CA-125 GCIG response rate. Sample collection for translational research was taken at diagnosis and IDS. After surgery pts in both arms completed 3 additional cycles of CT and Bev, followed by maintenance Bev up to 15 mo. Results: Sixty-eight out of seventy-one evaluable pts. Clinical pts characteristics were well balanced, median age 60.0 y.o and a 33.8% stage IV. No differences in CMR were found at IDS (2/33 Control and 2/35 Bev). Bev arm was favoured in rate of surgical feasibility (66.7 vs 88.6%, p = 0.029), while no differences were found in OSR (63.6 vs 65.7%, p = 0.858) and in number of pts considered unresectable at time of IDS (2 vs 0). Median time from IDS to restarting Bev was 7.1 w. Median PFS was 20.3 mo in both arms, 20.13 mo in control arm and 20.36 mo in Bev arm, HR: 1.14 (IC 95%, 0.656 - 1.994). There were lower rates of serious adverse events (grade 3-4) in Bev arm (69.7 vs 42.9%, p = 0.026). 8 pts presented AE of special interest in Bev arm (3G2 proteinuria, 1G2/1G3 hypertension, 1G3 entero-vaginal fistulae, 1G3 entero-cutaneous fistulae, 1G3 deep venous thrombosis, 1G2 bleeding, 1G1 surgical dehiscence). Conclusions: NACT with Bevacizumab was feasible and improved the surgical outcomes at IDS in pts initially considered unresectable. Clinical trial information: 2012-003883-31.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Abstract 1833: Transcriptome characterization of high grade serous and endometrioid epithelial ovarian cancer tumors

Abstract Background: Little transcriptomic research has compared epithelial ovarian cancer (EOC) histological subtypes. We set out to characterize the transcriptomes of high-grade serous carcinomas (HGSC) and endometrioid carcinomas (EC), which make up around 70% and 20% of EOC tumors, respectively, and have some histopathological similarities. Methods: Fresh frozen tumors from EOC patients seen at the Mayo Clinic (30 EC and 62 HGSC) were used. 1ug RNA riboZero was used for library preparation using the Illumina TruSeq kit and sequenced on a HiSeq 2000 machine. Reads were aligned using TopHat2 followed by quantification of abundances using RSEM and differential expression analysis with edgeR. We analyzed transcriptomes, conducted pathway analyses, and summarized key candidate gene sets. Expressed SNVs (eSNVs) from the RNA-seq data were determined using GATK and RVboost. Results: The analysis found 699 genes with FDR &amp;lt; 1×10-5 for differential expression between HGSC and EC, with most genes being up-regulated in EC. The top most associated genes were TPH1, MAP2K6, KLK2, ADAM23, TESC and TRAF3IP2 (p&amp;lt;10-22). Pathway analysis of the genes up-regulated in EC revealed enrichment of the “basal cell carcinoma signaling pathway” (p = 1.2×10-5). Within 1 Mb of the 25 known EOC risk loci, we observed higher expression in HGSC for RSPO1 and HPSE (p &amp;lt;5×10-7). For genes functionally related to EOC, we observed in HGSC up-regulation (*p &amp;lt; 10-5, ⁁p&amp;lt;0.003) for FOXM1⁁, CDKN2A⁁, CCNE1*, CCND2⁁, PIK3CA*, BRCA2⁁, BIRC5⁁, MMP9⁁, FANCD2⁁, and MAML2⁁. In contrast, we found up-regulation in EC for MDM2*, KLK4*, BCL2⁁, CCND1*, ANXA4*, CDH1⁁, MMP7⁁, and MAML3⁁. We also identified 204 eSNVs (44 non-synonymous) associated with EC v HGSC subtype (p&amp;lt;10-4); this included an exonic TRAF3IP2 eSNV (66% EC, 13% HGSC, p = 4×10-7, chr6:111877117). Discussion: Using one of the largest sets of identically processed fresh-frozen EOC tumors, some patterns emerged among the numerous EC v HGSC transcriptomic differences. TPH1, up-expressed in EC, is regulated by SOX4 which was also up-regulated in EC. Two sets of genes related to Kallikreins serine proteases were differentially expressed, including KLK2 which is known to regulate EGFR and pro-inflammatory cytokines and is regulated by MYC. Lastly, TRAF3IP2 encodes for a protein involved in regulating cytokines through members of the NFKB pathway. Conclusions: These findings suggest important biological insights into one of the rarer EOC histologies and may aid in the development of targeted treatment options. Research is on-going to incorporate additional features (e.g., DNA methylation, copy number) into a “systems biology” framework to better understand the molecular differences between EOC histologies. Citation Format: Brooke L. Fridley, Junqiang Dai, Rama Raghavan, Chen Wang, Pengcheng Lu, Stacey Winham, Madalene Earp, Kate Lawrenson, Simon A. Gayther, Kimberly R. Kalli, Ellen L. Goode. Transcriptome characterization of high grade serous and endometrioid epithelial ovarian cancer tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1833.

Prevalence study of germline BRCA1/2 mutation in Korean patients with high-grade serous and/or endometrioid epithelial ovarian, Fallopian tube, or primary peritoneal cancer.

e17043Background: To investigate the prevalence and clinically characterize the germline BRCA 1/2 mutation in Korean patients with high grade (HG) serous and/or endometrioid epithelial ovarian canc...

Tubal Ligation and Salpingectomy and the Risk of Epithelial Ovarian Cancer and Borderline Ovarian Tumors

Objective According to the recent theories on the ovarian cancer origin, any protective effect of tubal ligation may vary with histologic subtype of ovarian cancer. Furthermore, bilateral salpingectomy may represent an opportunity for surgical prevention of serous ovarian cancer. Design Nationwide register-based case–control study. Setting Denmark during 1982–2011. Population Cases were all Danish women diagnosed with epithelial ovarian cancer (n = 13 241) or borderline ovarian tumor (n = 3605) in the study period. Age-matched female population controls were randomly selected by risk set sampling. We required that cases and controls have no previous cancer and that controls have no previous bilateral oophorectomy. Methods Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders. Main outcome measures Epithelial ovarian cancer and borderline ovarian tumors stratified according to histology. Results Tubal ligation reduced overall epithelial ovarian cancer risk (odds ratios 0.87; 95% confidence interval 0.78–0.98). We observed significant risk variation according to histology (p = 0.003) with the strongest risk reductions associated with endometrioid cancer (odds ratios 0.66; 95% confidence interval 0.47–0.93) and epithelial ovarian cancer of “other” histology (odds ratios 0.60; 95% confidence interval 0.43–0.83). Tubal ligation was not associated with risk of borderline ovarian tumors. Finally, bilateral salpingectomy reduced epithelial ovarian cancer risk by 42% (odds ratios 0.58; 95% confidence interval 0.36–0.95). Conclusions We confirmed that tubal ligation reduces the risk of epithelial ovarian cancer and particularly endometrioid cancer. To our knowledge, this is the first observational publication to report on salpingectomy and ovarian cancer risk and our promising findings warrant further investigation.

Early pregnancy IGF-I and placental GH and risk of epithelial ovarian cancer: A nested case-control study.

Insulin-like growth factor-I (IGF-I) signaling may promote ovarian tumor development by exerting mitotic, antiapoptotic and proangiogenic effects. During pregnancy, maternal production of IGF-I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF-I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF-I and EOC in nonpregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort, we identified 1,045 EOC cases, diagnosed after recruitment (1975-2008) and before March 2011 and 2,658 individually matched controls. Placental GH and IGF-I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles and a doubling of hormone concentrations. Higher IGF-I was associated with a nonsignificant decrease in risk for invasive [ORT3 vs. T1 : 0.79 (0.62-1.02); ptrend = 0.07] and endometrioid tumors [ORT3 vs. T1 : 0.55 (0.28-1.07); ptrend = 0.07]. The protective association between higher IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis [ORT3 vs. T1 : 0.74 (0.57-0.96); ptrend = 0.03]. Our study provides the first data on placental GH and IGF-I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF-I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC.

High prevalence of atypical hyperplasia in the endometrium of patients with epithelial ovarian cancer.

The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P=.001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC.

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

Dairy food and nutrient intake in different life periods in relation to risk of ovarian cancer.

High lactose intake has been suggested to increase epithelial ovarian cancer (EOC) risk. We evaluated the association between lactose consumed during specific life periods (high school, premenopause, and postmenopause) and later risk of EOC. We assessed the association of dairy food and nutrient intake with risk of EOC during 28 years of follow-up including 764 cases in the Nurses' Health Study (NHS) and NHSII. Cox proportional hazards regression was used to model the hazard ratios (HRs) and 95% confidence intervals (CIs) for EOC across categories of dairy food or nutrient intake. We examined dietary intake in adulthood overall, as well as during premenopausal/postmenopausal years and high school. In analyses of the highest versus lowest cumulative average intake in adulthood, we observed a non-significant inverse association with skim milk intake (HR 0.76, 95% CI 0.54-1.06, p(trend) = 0.05), a non-significant inverse association with lactose intake (HR 0.87, 95% CI 0.69-1.11, p(trend) = 0.22) and no association with consumption of whole milk, dairy calcium, or dairy fat. Similar risk estimates were observed for dairy food/nutrient intake during high school, premenopause or postmenopause. Lactose intake in adulthood was inversely associated with risk of endometrioid EOC (HR 0.32, 95% CI 0.16-0.65, p(trend) < 0.001). These findings do not support the hypothesis that higher lactose intake increases EOC risk. The inverse association with endometrioid tumors deserves further study.

Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.

The relation between endometriosis and ovarian cancer – a review

Endometriosis is known to harbor characteristics substantiating its possible role as a precursor of ovarian cancer. To assess the quality of the literature regarding the association between endometriosis and ovarian cancer and to estimate the extent of this relation. An electronic literature search was conducted in PubMed and 1112 articles dealing with the relation between endometriosis and ovarian cancer were identified. Original articles based on case-control studies, cohort studies and cross-sectional studies were included. Studies consisting of populations with self-reported endometriosis were excluded, as were articles with fewer than 20 cases of ovarian cancer. Twenty-eight studies underwent detailed quality assessments based on the checklists developed by the Scottish Intercollegiate Guidelines Network (SIGN). Meta-analyses were conducted on selected subgroups of ovarian cancer with coexisting endometriosis. None of the 28 studies was given the highest possible rating using the SIGN checklists. The risk of ovarian cancer in women with endometriosis was reported to be a standardized incidence ratio of 1.43-8.95, a rate ratio of 1.6-2.88, an odds ratio of 1.34, with a prevalence of ovarian cancer in 2.0-17.0% of women with endometriosis. Conversely, the prevalence of endometriosis in women with ovarian cancer ranged from 3.4 to 52.6%. Meta-analysis results were weakened by heterogeneity. There is sufficient evidence to conclude that there is an increased risk of developing clear-cell and endometrioid epithelial ovarian cancer for women with histologically verified endometriosis. Nonetheless, prospective cohort studies assessing the relation between endometriosis and ovarian cancer will increase knowledge in this field.

Prognostic analysis of endometrioid epithelial ovarian cancer with or without endometriosis: a 12-year cohort study of Chinese patients

Clinicopathological characteristics and possible prognostic factors among women with endometrioid epithelial ovarian cancer (EEOC) with or without concurrent endometriosis were investigated. A search of medical charts at Peking Union Medical College Hospital from 2000 through 2012 identified patients with EEOC with or without endometriosis. Of 188 patients with EEOC, concurrent endometriosis was identified in 32 (17.0%). Patients with concurrent endometriosis were approximately 5 years younger, more likely to be premenopausal, more likely to have an early stage of EEOC, and less likely to have high-grade tumors compared to those without endometriosis. The univariate analysis showed that concurrent endometriosis was a significant prognostic factor for disease-free survival, but this association did not remain in the multivariate analysis. Women with EEOC and concurrent endometriosis showed distinct characteristics and had longer disease-free survival when compared to those without endometriosis.

Abstract 1441: Effect of chemotherapy on cytokine production by solid tumor cell lines.

Abstract Tumor microenvironment strongly influences cancer progression, regulating several cellular processes and cancer immune surveillance. Albeit the influence of cytokines from immune cells on tumor progression has already been described, little is known on the role of cancer cells on the production of these cytokines, especially in response to chemotherapy. To address this aspect of tumor biology, we exposed the serous epithelial ovarian cancer (EOC) cell line A2780, the clear cell EOC cell line TOV21G, the endometrioid EOC cell line MDAH-2774 (further referred as 2774), the breast cancer (BC) cell line MDA-MB 231, and the non-small cell lung carcinoma (NSCLC) cell line A549 to cisplatin (CI), cyclophosphamide (CY), doxorubicin (DO), and paclitaxel (PA) for 5 days, at their IC50 range, prior to cytokine measurement by ELISA in cell's conditioned media (CM). Cytokines (IL-17, IFN-γ, CXCL-1, and TGF-β) were measured in the pool of CM from 3 well after 3 and 5 days of exposure to each drug or untreated cells (UT). Results were normalized by the mean protein content of wells and are expressed in pg/mL/μg of protein. Cytokines’ level varied among UT cell lines, probably reflecting tumor heterogeneity. IL-17 secretion was higher in 2774, MDA-MB 213 and A549 (4.6, 8.9, and 10.6, respectively). UT TOV21G cells did not secrete IL-17. In response to CI, IL-17 levels decreased; whereas response to the other drugs greatly varied. INF-γ levels showed the lesser variation among cell lines (0.01 - 0.2). Upon exposure to the drugs, IFN-γ secretion tend to increase by all drugs in A2780 and 2774 lines, and in TOV21G exposed to CY; however it was strongly decreased by PA in this line and in A549. EOC cells A2780 and 2774 were the only lines secreting CXCL-1 in UT condition (∼0.015 on D5). CXCL-1 secretion in most conditions either was unaltered or decreased. However, CI was the only drug that induced its secretion in A2780, TOV21G and MDA-MB 231. As this chemokine has already been described as a factor promoting tumor cell migration and invasion, the relation between CI and CXCL-1 is worth of further analysis. Worth noticing, TGF-β was highly secreted by NSCLC cells (42.7 on D5); all other cells’ level was &amp;lt; 0.96 on D5. The most striking change was in A540 where all drugs decreased its levels, especially CI (0.73 on D5). Similar data were observed in A2780 cells, which is not in concordance with our previous data. This finding highlights the importance of precisely define drug dose in cancer therapy and its impact on patients’ clinical outcome, as the assays were conducted under distinct CI concentration. Overall, our data corroborated the great heterogeneity among different cancers and its response to chemotherapy, also highlighting the importance to consider the effect of different drugs on tumor immune surveillance, therefore introducing a novel aspect in predicting tumor responsiveness to conventional antineoplastic drugs, and ultimately to control cancer progression. Citation Format: Alice L. Herlinger, Iuri C. Valadão, Mariana C. de Souza, Maria das Graças MO Heniques, Celso Caruso-Neves, Leticia BA Rangel. Effect of chemotherapy on cytokine production by solid tumor cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1441. doi:10.1158/1538-7445.AM2013-1441

Clinical Presentation of Endometrioid Epithelial Ovarian Cancer with Concurrent Endometriosis: A Multicenter Retrospective Study

Endometrioid epithelial ovarian cancer (EEOC) is frequently diagnosed in conjunction with endometriosis and is suggested to arise during the process of endometriosis. This study evaluates the clinical manifestations, including endometriosis-related symptoms and their relationships according to the coexistence of endometriosis. Using medical records, a retrospective analysis was conducted on 221 patients treated for EEOC at four tertiary educational hospitals between 2000 and 2008. The initial presenting symptoms, particularly those related to endometriosis, were examined in relation to the coexistence of endometriosis or other clinical variables. Endometriosis was identified in 82 (37.1%) of the 221 patients with EEOC. The most common symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea (18.1%) and dyspareunia (13.6%). Notably, dysmenorrhea and dyspareunia were frequently observed in patients with endometriosis. Among 210 patients identified with pretreatment serum CA-125, 54 (25.7%) displayed normal CA-125 levels (<35 units/mL) and 23.3% and 29.9% of patients without and with endometriosis had normal CA-125 levels, respectively (P = 0.381). Additionally, 32.6% of the patients with early-stage EEOC displayed normal CA-125 levels. In this large series of patients with EEOC, the main presenting symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea and dyspareunia. Dyspareunia and dysmenorrhea were more frequently detected in patients with endometriosis. Normal CA-125 levels cannot be applied as a marker to exclude EEOC, particularly at the early stages.

Wnt-Signaling genes and their potential as tumor markers for epithelial ovarian cancer

The Wnt/beta-catenin-signaling pathway has been increasingly implicated in a variety of cancers, including epithelial ovarian cancer (EOC). However, the nature of Wnt-signaling defects other than beta-catenin are unknown. The frizzled protein sFRP4 has putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Fibroblast growth factors (FGF) have been described to interact with beta-catenin, TGF-beta and steroid receptors. FGF9 has recently been proposed to be a key downstream target contributing to the cancer phenotype of endometrioid EOC carrying Wnt-pathway defects.