Ovarian Cancer
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Cancer of the ovaries are the second most common group of gynaecologic cancers, and account for about 5% of all women's cancers. There are two main types; (i) epithelial tumours (carcinomas) which account for 90% of ovarian cancers, and (ii) non-epithelial tumours (eg. Stroma cell and germ cell tumours of the ovary). The epithelial ovarian cancers are usually found in women aged over 40, while the non-epithelial tumours are more common in girls and young women. Epithelial ovarian cancer has few early symptoms, a risk factor is having a family history of the disease. Taking the contraceptive pill is known to be protective against ovarian cancer.

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Latest Research Publications

Information Patients and the Public (21 links)

Information for Health Professionals / Researchers (12 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Androutsopoulos G, Adonakis G, Terzakis E, et al.
Endometrial cancer in a patient with rheumatoid arthritis.
Eur J Gynaecol Oncol. 2015; 36(1):91-3 [PubMed] Related Publications
BACKGROUND: Rheumatoid arthritis is a chronic, systemic, and autoimmune disease. In patients with rheumatoid arthritis, there is increased risk for site-specific malignancies. The authors present a case of endometrial cancer in a patient with rheumatoid arthritis and a review of the current literature.
CASE: The patient, a 60-year-old, postmenopausal Greek woman suffering from rheumatoid arthritis, presented with a complaint of abnormal uterine bleeding. She underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. Histopathology revealed endometrial cancer. The final diagnosis was Stage Ib endometrial cancer endometrioid type. She underwent postoperative adjuvant radiotherapy. She remains without evidence of disease, 16 months after initial surgery.
CONCLUSION: Although the present patient was diagnosed at early-stage disease and remains well 16 months after initial surgery, she needs a multidisciplinary treatment approach in order to achieve prolonged survival.

Related: Endometrial (Uterus) Cancer Endometrial Cancer

Lubin J, Pawałowska M, Markowska A, Bielas A
Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT)--case report.
Eur J Gynaecol Oncol. 2015; 36(1):88-90 [PubMed] Related Publications
Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare malignant disease, seen mostly in young women, with a very poor prognosis. There is no standard treatment for patients with this disease and most literature is limited to short series or case reports. This report describes the case of a 34-year-old woman with aggressive course of SCCOHT and poor outcome. What proved difficult was the process of establishing the diagnosis due to non-specific first symptoms of disease and consequently the combined treatment of surgery and chemotherapy with concurrent side effects.

Tanda ET, Budroni M, Cesaraccio R, et al.
Epidemiology of ovarian cancer in North Sardinia, Italy, during the period 1992-2010.
Eur J Gynaecol Oncol. 2015; 36(1):69-72 [PubMed] Related Publications
INTRODUCTION: The aim of this study was to analyze and describe the incidence and mortality trends of ovarian cancer in North Sardinia, Italy, in the period 1992-2010.
MATERIALS AND METHODS: Data were obtained from the tumor registry of Sassari province which makes part of a wider registry web, coordinated today by the Italian Association for Tumor Registries.
RESULTS: The overall number of ovarian cancer cases registered in the period under investigation was 600. The mean age of the patients was 62 years. The standardized incidence and mortality rates were 11.2/100,000 and 5.1/100,000 respectively. A substantially stable trend in incidence and mortality of ovarian cancer was evidenced. Relative survival at five years from diagnosis was 44.2%.
CONCLUSIONS: The incidence and mortality trends of ovarian cancer in North Sardinia remained relatively stable in the last decades, while prognosis remains relatively poor.

Fukuda T, Imai K, Yamauchi M, et al.
Primary peritoneal cancer: study of 14 cases and comparison with epithelial ovarian cancer.
Eur J Gynaecol Oncol. 2015; 36(1):49-53 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: Primary peritoneal carcinoma (PPC) is histologically similar to ovarian serous carcinoma, but its biochemical features remain obscure. The authors investigated and compared clinical findings, treatments, and outcomes of patients with PPS and those with epithelial ovarian cancer (EOC) patients.
MATERIALS AND METHODS: The authors retrospectively reviewed data from 14 patients with PPC and 219 patients with EOC treated at the present hospital from January 2005 to December 2012, including demographic data, pathologic findings, treatments, and outcomes.
RESULTS: Patients with PPC were significantly older (62.6 ± 8.4 years) than those with EOC (56.3 ± 11.3 years) (p = 0.045). There was no significant difference in serum CA-125 levels. The five-year survival rates did not differ significantly between patients with PPC (61.1%) and those with EOC (60.3%; p = 0.78); nor between patients with PPC and those with Stage III serous EOC (43.8%; p = 0.40).
CONCLUSIONS: Treatment strategies for EOC applied to PPC apparently led to similar survival patterns among the two patient groups. Cytoreductive surgery combined with pre/postoperative platinum-containing chemotherapy may be effective for PPC patients.

Related: Carboplatin Paclitaxel

Machado-Linde F, Sánchez-Ferrer ML, Cascales P, et al.
Prevalence of endometriosis in epithelial ovarian cancer. Analysis of the associated clinical features and study on molecular mechanisms involved in the possible causality.
Eur J Gynaecol Oncol. 2015; 36(1):21-4 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To determine the prevalence of endometriosis in patients with epithelial ovarian cancer and explore the differences between women with endometrioid and clear-cell histologic subtypes with and without associated endometriosis.
MATERIALS AND METHODS: The medical charts of 496 patients with epithelial ovarian cancer at the Hospital Virgin de la Arrixaca (Murcia, Spain) between 1971 and 2010 were reviewed.
RESULTS: Endometriosis was present in 27 (5.4%) of the 496 cases (p < 0001), and was associated with the endometrioid histotype in 13/45 cases (29%) and with the clear cell histotype in 7/22 (32%). The prevalence of an association with endometriosis according to histologic type was 28.8% (13/45) for endometrioid carcinoma and 31.8% (7/22) for clear-cell carcinoma.
CONCLUSION: Both endometrioid and clear-cell ovarians tumours are associated with pelvic endometriosis. Patients with endometiosis associated ovarian cancer differ from non-endometiosis associated ovarian cancer in their clinical characteristics.

Ying HC, Xu HY, Lv J, et al.
MicroRNA signatures of platinum-resistance in ovarian cancer.
Eur J Gynaecol Oncol. 2015; 36(1):16-20 [PubMed] Related Publications
OBJECTIVES: The authors utilized a microRNA (miRNA) array to compare the differentially expressed miRNAs in platinum-resistant associated ovarian cancer cells.
MATERIALS AND METHODS: The differential expression of microRNA between COC1 (DDP-sensitive) and platinum-resistant COC1/DDP (DDP-resistant) tumor cell lines was determined using microarray. Expression levels were further validated by real-time quantitive polymerase chain reaction (qRT-PCR).
RESULTS: The authors identified that several miRNAs are altered in collected 86 samples of human ovarian cancer cell-lines, with four significantly deregulated miRNAs and 13 upregulated miRNAs. Of which, miR-141-3p was the most differentially expressed miRNA between COC1 group (1.7833 ± 0.7213) and COC1/DDP group (14.0433 ± 4.4895) (p < 0.05). Additionally, the product curve of PCR amplification indicated that miR-141-3p had a significant higher expression level in chemotherapy resistant group (n = 20) rather than in chemotherapy sensitive group (n = 20) (9.56 ± 1.04 vs. 1.59 ± 0.91, p < 0.05).
CONCLUSIONS: The present results suggest that miR-141-3p might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response.

Related: Carboplatin MicroRNAs

Gąsiorowska E, Michalak M, Warchoł W, et al.
Clinical application of HE4 and CA125 in ovarian cancer type I and type II detection and differential diagnosis.
Ginekol Pol. 2015; 86(2):88-93 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to assess the sensitivity and specificity of HE4 in detecting and differentiating between types I and II epithelial ovarian cancer (EOC) in comparison with CA125.
MATERIAL AND METHODS: We measured HE4 and CA125 serum concentrations in 206 samples taken from patients operated in Gynecologic Oncology Department due to ovarian tumors. Ovarian cancer was confirmed in 89 cases divided into type I and type II. 52 healthy patients without any gynecological disease formed the control group. The sensitivity and specificity for type I and type II EOC detection and differentiating between both types was evaluated for HE4 and CA125.
RESULTS: The HE4 and CA125 serum concentrations were significantly higher in type II than in type I EOC (p=0.008696, p=0.000243 respectively). The HE4 and CA125 sensitivity for type I and benign tumors differentiation was 63.16% for both of them and specificity was 87.29% vs 67.89% respectively. For CA125 these differences did not reach statistical significance. The HE4 sensitivity and specificity for type II and benign tumors differentiation were 87.14% and 96.61%, respectively and for CA125 these values were 82.86% and 94.07%, respectively.
CONCLUSIONS: Pretreatment analysis of HE4 serum concentration is superior to CA125 in differential diagnosis of ovarian cancer subtypes (I and II). HE4 is superior to CA125 in detecting ovarian cancer type II. Neither HE4 nor CA125 is an effective diagnostic tool for type I ovarian cancer detection. A new highly specific and highly sensitive tumor marker for type I EOC is needed.

Moradan S
Ovarian immature teratoma during pregnancy: a case report.
J Med Liban. 2014 Oct-Nov; 62(4):245-7 [PubMed] Related Publications
Germ cell tumors are derived from the primordial germ cells of the ovary and immature teratoma is the second most common germ cell malignancy. About 50% of pure immature teratomas of the ovary occur in women between the ages of 10 and 20 years, and they rarely occur in pregnancy. A 21-year-old woman, gravid 1, para 0, at 18 weeks of gestation, was incidentally diagnosed with a right ovarian mass 180 mm by 200 mm, 160 mm in diameter, during a prenatal ultrasound scanning. She underwent surgery by unilateral salpingo-oophorectomy and surgical staging. The result of pathology showed a stage 1a grade 1 immature teratoma of ovary. Her pregnancy continued until term. At 38 weeks she delivered with breech presentation a normal 2900 g male newborn by cesarean section. Although immature teratomas of ovary during pregnancy are rare, clinicians should consider their eventuality in younger pregnant women in asymptomatic cases.

Related: Breast cancer in pregnancy

Celik B, Didem Yalcin A, Esra Genc G, Gumuslu S
Proteomics pattern of peritoneal sApo-2L but not CD200 (OX-2) as a possible screening biomarker for metastatic ovarian, endometrial and breast carcinoma.
J BUON. 2015 Jan-Feb; 20(1):280-6 [PubMed] Related Publications
PURPOSE: The purpose of this study was to evaluate the soluble Apo-2L (sApo-2L) levels in the ascitic fluid and to study its potential in detecting malignant ascites and soluble CD200 (sCD200,sOX-2) levels so as to predict its clinical usage for detecting stage 4 metastatic endometrial, ovarian and breast cancer in serum samples.
METHODS: Ascitic fluid from 53 and blood from 25 subjects without known malignancy on admission were collected. There were 14 breast cancer (BC), 17 ovarian cancer (OC) and 19 endometrial cancer (EC) patients diagnosed later on. Blood samples for sApo-2L, sCD200, liver function tests and CEA, CA-19.9 and CA-125 were always taken and assayed in the morning.
RESULTS: Significantly low levels of sApo-2L were observed in peritoneal fluid from OC and EC patients compared to benign peritoneal fluid from control individuals. Positive correlation was observed between sApo-2L and aspartate aminotransferase (AST) in benign peritoneal fluid and sCD200, and creatinine and sCD200 and platelets in OC patients; also, sCD200 and CEA in EC patients and sCD200 and blood urea nitrogen (BUN) in healthy subjects.
CONCLUSIONS: Our data indicate that low proteomics pattern of sApo-2L but not sCD200 is a good biochemical marker. Further decline in the level of sApo-2L was seen in EC compared to OC. Since higher levels of sApo-2L were seen with higher levels of AST, the liver might be involved in its metabolism. The positive correlation detected between sCD200 and creatinine, platelets, CEA and BUN needs to be elucidated.

Related: Breast Cancer Endometrial (Uterus) Cancer Endometrial Cancer TNFSF10

How JA, Abitbol J, Lau S, et al.
The impact of qualitative research on gynaecologic oncology guidelines.
J Obstet Gynaecol Can. 2015; 37(2):138-44 [PubMed] Related Publications
OBJECTIVE: Inherent in the care provided to patients with cancer is an important psychosocial element which has been explored scientifically through qualitative research. The purpose of our study was to evaluate the availability of qualitative research in gynaecologic oncology and to measure its integration in gynaecologic oncology practice guidelines.
METHODS: We searched Medline, CINHAL, Scopus, and Web of Science databases to identify the availability of qualitative research conducted in the past 20 years on the three most prevalent gynaecologic cancers: endometrial, ovarian, and cervical cancer. National and international practice guidelines on management of gynaecologic cancers were selected using the National Guideline Clearinghouse website, the Society of Obstetricians and Gynaecologists of Canada website, and the Standards and Guidelines Evidence directory of cancer guidelines. Bibliometric analysis was used to determine the frequency of qualitative references cited in these guidelines.
RESULTS: One hundred thirteen qualitative research papers on gynaecologic cancers were identified focusing on psychological impacts, social dynamics, and doctor-patient interactions during cancer treatment and recovery. Among the 15 national and international clinical practice guidelines identified on management of gynaecologic cancer, there were a total of 2272 references, and of these only three references citing qualitative research were identified (0.1%) in only one of the 15 practice guidelines.
CONCLUSION: Although qualitative research is being carried out in gynaecologic oncology, its integration into clinical practice guidelines is essentially absent. Efforts to narrow the gap between qualitative research and clinical practice are essential in ensuring a comprehensive approach to the treatment of patients with gynaecologic cancer.

Liu L, Chang S, Sun J, et al.
Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts.
Cancer Lett. 2015; 361(1):147-54 [PubMed] Related Publications
We have synthesized multifunctional oxygen and paclitaxel loaded microbubbles (OPLMBs) for ultrasound mediated delivery of combination therapy in an ovarian cancer xenograft model. In comparison with other therapeutic options, intravenous injection of OPLMBs followed by ultrasound mediation yielded a superior therapeutic outcome. Immunohistochemical analyses of the dissected tumor tissue confirmed the increased tumor apoptosis and the reduced VEGF expression after treatment. Western Blot tests further confirmed the decreased expressions of HIF-1α and P-gp. Our experiment suggests that ultrasound mediation of OPLMBs may provide a promising drug delivery strategy for the combination treatment of ovarian cancer.

Related: Apoptosis HIF1A Paclitaxel VEGFA

Bristow RE, Chang J, Ziogas A, et al.
Sociodemographic disparities in advanced ovarian cancer survival and adherence to treatment guidelines.
Obstet Gynecol. 2015; 125(4):833-42 [PubMed] Related Publications
OBJECTIVE: To estimate whether race or ethnic and socioeconomic strata are independently associated with advanced-stage ovarian cancer-specific survival after adjusting for adherence to National Comprehensive Cancer Network treatment guidelines.
METHODS: The design was a retrospective population-based cohort study of patients with stage IIIC-IV epithelial ovarian cancer identified from the Surveillance, Epidemiology, and End Results-Medicare database (1992-2009). Quartile of census tract median household income was used as the measure of socioeconomic status (quartiles 1-4). A multivariable logistic regression model was used to identify characteristics predictive of adherence to National Comprehensive Cancer Network guidelines for surgery and chemotherapy. Cox proportional hazards models and propensity score matching were used for survival analyses.
RESULTS: A total of 10,296 patients were identified, and 30.2% received National Comprehensive Cancer Network guideline-adherent care. Among demographic variables, black race (adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.22-1.92) and low socioeconomic status (quartile 1, adjusted OR 1.32, 95% CI 1.14-1.52) were independently associated with nonguideline care. Stratified multivariate survival analysis using the propensity score-matched sample (n=5,124) revealed that deviation from treatment guidelines was associated with a comparable risk of disease-related death across race-ethnicity: whites (adjusted hazard ratio [HR] 1.59, 95% CI 1.48-1.71), blacks (adjusted HR 1.66, 95% CI 1.19-2.30), Asian or Pacific Islanders (adjusted HR 1.52, 95% CI 0.99-1.92), and Hispanics (adjusted HR 1.91, 95% CI 0.98-3.72). Across socioeconomic status, deviation from treatment guidelines was also associated with a comparable risk of ovarian cancer mortality for quartile 1 (adjusted HR 1.69, 95% CI 1.47-1.95), quartile 2 (adjusted HR 1.63, 95% CI 1.42-1.87), quartile 3 (adjusted HR 1.51, 95% CI 1.32-1.73), and quartile 4 (adjusted HR 1.57, 95% CI 1.38-1.79).
CONCLUSION: Adherence to treatment guidelines for advanced-stage ovarian cancer is associated with equivalent survival benefit across racial or ethnic and socioeconomic strata. Ensuring equal access to standard treatment is a viable strategic approach to reduce survival disparities.

Related: USA

Cybulski M, Jarosz B, Nowakowski A, et al.
Cyclin A correlates with YB1, progression and resistance to chemotherapy in human epithelial ovarian cancer.
Anticancer Res. 2015; 35(3):1715-21 [PubMed] Related Publications
BACKGROUND: Cyclin A is a cell-cycle regulatory gene and its overexpression promotes tumor cell growth. Y-Box-binding protein 1 (YB1) is a transcription/translation factor involved in tumor growth, invasion, and drug resistance. We investigated whether an association exists between protein products of these genes in epithelial ovarian cancer (EOC) specimens and clinicopathological parameters, patient response and EOC sensitivity to platinum-based first-line chemotherapy.
PATIENTS AND METHODS: Cyclin A and YB1 expression were analyzed by immunohistochemistry in 54 human primary EOC tissues. Immunolabeling of both proteins was graded according to their staining intensity (scale 0-3) and the proportion of immunostained cancer cells (scale 0-4) to obtain a staining index (SI; value=0-12).
RESULTS: Significantly higher cyclin A immunostaining (SI≥4) in EOC specimens was discovered in patients with advanced (International Federation of Gynaecology and Obstetrics (FIGO) III and IV, p=0.003), poorly differentiated (G3, p<0.001) tumors, and tumors of those with residual disease>1 cm (p=0.001). YB1 immunostaining was significantly higher in EOCs from patients with suboptimal debulking (p=0.025). Over-expression of cyclin A (SI≥9) in EOCs was significantly linked with poorer patient response (p=0.001) and higher resistance of tumors to platinum-based first-line chemotherapy (p=0.007), while immunolabeling of YB1 in EOCs was not significantly associated with either of these variables (p>0.05). Cyclin A expression was significantly and positively correlated with that of YB1 (R=0.588, p<0.001).
CONCLUSION: Increased cyclin A expression in EOC is related to a more aggressive tumor behavior and predicts the response of patients to first-line platinum-based chemotherapy.

Feldheiser A, Yosef AB, Braicu EI, et al.
Surgery at primary versus relapsed epithelial ovarian cancer: a study on aspects of anaesthesiological management.
Anticancer Res. 2015; 35(3):1591-601 [PubMed] Related Publications
BACKGROUND: Primary cytoreductive surgery (CS) for epithelial ovarian cancer (EOC) is well-established. CS at relapse remains controversial, with an unclear morbidity profile.
PATIENTS AND METHODS: We analyzed 121 patients with EOC who underwent CS. Two groups were identified by timing of surgery due to primary disease and due to recurrent disease.
RESULTS: CS for primary versus recurrent EOC led to no differences in haemodynamic management, such as transfusion rates, application of vasopressors, ICU and hospital length of stay, or mortality. The risk for postoperative ileus was higher in patients with relapsed versus primary EOC. This might be attributed to patients being operated due to preoperative ileus and a higher small bowel resection rate at CS for relapse.
CONCLUSION: CS for EOC relapse does not seem to be more challenging in terms of perioperative management compared to that at initial diagnosis. The major surgical morbidity profile was comparable apart from a higher risk for postoperative ileus at relapse.

Yoneyama K, Ishibashi O, Kawase R, et al.
miR-200a, miR-200b and miR-429 are onco-miRs that target the PTEN gene in endometrioid endometrial carcinoma.
Anticancer Res. 2015; 35(3):1401-10 [PubMed] Related Publications
Endometrioid endometrial carcinoma (EEC) is a common malignancy of the female genital tract. However, no adequate biomarker is currently available for predicting the prognosis of this cancer. Recent studies have revealed dysregulated expression of several microRNAs (miRNAs) in various cancer tissues, and therefore, these cancer-associated miRNAs (also called onco-miRs) could be promising prognostic biomarkers of cancer progression or metastasis. In this study, in order to identify onco-miRs and their possible targets involved in EEC, we performed microarray-based integrative analyses of miRNA and mRNA expression in specimens excised from EEC lesions and adjacent normal endometrial tissues. Using integrated statistical analyses, we identified miR-200a, miR-200b and miR-429 as highly up-regulated onco-miRs in EECs. Conversely, we detected expression of a tumor-suppressor gene, phosphatase and tensin homolog (PTEN), which was predicted in silico using a miRNA-targeting mRNA prediction algorithm, as a target of the three miRNAs and which was down-regulated in EECs. Furthermore, these miRNAs were validated to target PTEN experimentally using luciferase assays and real-time polymerase chain reaction. These results suggest that the occurrence of EEC is, at least in part, mediated by miRNA-induced suppression of PTEN expression.

Related: Endometrial (Uterus) Cancer Endometrial Cancer MicroRNAs PTEN

Caposole MZ, Aruca-Bustillo V, Mitchell M, Nam B
Benign metachronous bilateral ovarian and mediastinal teratomas with an elevated alpha-fetoprotein.
Ann Thorac Surg. 2015; 99(3):1073-5 [PubMed] Related Publications
Teratomas are a common form of non-seminomatous germ cell tumor histologically composed of tissues derived from multiple cell lines of the primary embryonic germ cell layers. There are few cases reported in the literature that describe multiple locations with recurrence of benign teratomas, none of which describe an elevated AFP. We describe a case of metachronous bilateral recurrent ovarian and mediastinal teratomas with a curiously elevated α-fetoprotein. We may be describing a novel syndrome of recurrent metachronous teratomas. Because of the uncertainty of this case, the patient will require close follow-up over the next several years.

Damak T, Ben Hassouna J, Chargui R, et al.
Borderline tumors of the ovary.
Tunis Med. 2014; 92(6):411-6 [PubMed] Related Publications
BACKGROUND: Borderline tumors of the ovary (BOT) were described for the first time by Taylor in 1929. These lesions have a more favorable outcome than do other ovarian cancers. Their prognosis and treatment are still subject of discussion since they occurred more often in young women where the sparing fertility surgery is always considered primarily.
AIM: Evaluate the management of patients with borderline ovarian tumors.
METHODS: A retrospective study was conducted in 40 patients with borderline ovarian tumors treated between January 1, 1991 and December 31, 2004.
RESULTS: Median follow-up was 43 months, mean age was 44 years. Initial surgery was conservative in 17 patients and radical in 23 cases. Six patients had residual disease. Serous, mucinous and mixte tumors were observed in 18, 21 and 1 cases respectively. Staging was I, II, III in 26, 5, and 9 cases respectively with two pseudomyxomas. Adjuvant Chemotherapy was given in 3 patients. There was a recurrence in 13 patients and seven died. The 5-year overall survival rate was 78 %. Prognostic factors with an impact on survival rate were age, stage of the disease, histological subtype and residual tumor. Factors with a negative impact on recurrence were age, type of surgery and residual disease. With Cox multivariate analysis, residual tumor is an independent factor for overall survival, on the other hand age and type of surgery were significant for recurrence free survival.
CONCLUSION: Careful staging followed by complete and radical surgery is mandatory. Unilateral salpingo-oophorectomy with omentectomy and multiple peritoneal biopsies and washing could be indicated in patients with child bearing age. Radical surgery after pregnancy is advised.

Hu J, Hu Y, Hu Y, Zheng S
Intake of cruciferous vegetables is associated with reduced risk of ovarian cancer: a meta-analysis.
Asia Pac J Clin Nutr. 2015; 24(1):101-9 [PubMed] Related Publications
BACKGROUND: Epidemiological studies on the association between cruciferous vegetable (CV) consumption and the risk of ovarian cancer have demonstrated inconsistent results. We conducted a meta-analysis on CV consumption and ovarian cancer risk.
METHODS: The relevant studies were identified by searching the Medline (Pubmed), Embase and Web of Science databases. The references of related articles and reviews up to October 2013 were also screened. The pooled relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest CV consumption levels were calculated using a random-effects model. The heterogeneity and publication bias were also evaluated.
RESULTS: Eight studies (4 case-control studies and 4 cohort studies) were identified and included in this meta-analysis. When all studies were pooled together, there was a significantly inverse association between CV consumption and the risk of ovarian cancer (RR: 0.89; 95% CI: 0.81-0.99). No significant heterogeneity or publication bias was found.
CONCLUSIONS: The findings from this study suggest that the consumption of CVs may reduce the risk of ovarian cancer. Further investigations are needed to confirm the clinical effect of CVs on ovarian cancer.

Guillemette S, Serra RW, Peng M, et al.
Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4.
Genes Dev. 2015; 29(5):489-94 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Hereditary cancers derive from gene defects that often compromise DNA repair. Thus, BRCA-associated cancers are sensitive to DNA-damaging agents such as cisplatin. The efficacy of cisplatin is limited, however, by the development of resistance. One cisplatin resistance mechanism is restoration of homologous recombination (HR), which can result from BRCA reversion mutations. However, in BRCA2 mutant cancers, cisplatin resistance can occur independently of restored HR by a mechanism that remains unknown. Here we performed a genome-wide shRNA screen and found that loss of the nucleosome remodeling factor CHD4 confers cisplatin resistance. Restoration of cisplatin resistance is independent of HR but correlates with restored cell cycle progression, reduced chromosomal aberrations, and enhanced DNA damage tolerance. Suggesting clinical relevance, cisplatin-resistant clones lacking genetic reversion of BRCA2 show de novo loss of CHD4 expression in vitro. Moreover, BRCA2 mutant ovarian cancers with reduced CHD4 expression significantly correlate with shorter progression-free survival and shorter overall survival. Collectively, our findings indicate that CHD4 modulates therapeutic response in BRCA2 mutant cancer cells.

Related: Cisplatin BRCA2

Kannan K, Coarfa C, Chao PW, et al.
Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma.
Proc Natl Acad Sci U S A. 2015; 112(11):E1272-7 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.

Related: AKT1 AKT2

Suzuki M, Matsushima-Nishiwaki R, Kuroyanagi G, et al.
Regulation by heat shock protein 22 (HSPB8) of transforming growth factor-α-induced ovary cancer cell migration.
Arch Biochem Biophys. 2015; 571:40-9 [PubMed] Related Publications
Accumulating evidence suggests that heat shock proteins (HSPs) are implicated in progression of cancer. HSP22 (HSPB8), a small HSP, is recognized to be ubiquitously expressed in various tissues. However, the expression and the role of HSP22 in ovarian cancer remain to be clarified. In the present study, we investigated the involvement of HSP22 in transforming growth factor (TGF)-α-induced migration of ovarian cancer cells. The expression of HSP22 was detected in a serous ovarian cancer cell line, SKOV3.ip1. The migration was reduced by down-regulation of HSP22 expression. The TGF-α-induced migration was reduced by SB203580 (a p38 MAP kinase inhibitor), SP600125 (a SAPK/JNK inhibitor) and Y27632 (a Rho-kinase inhibitor). However, down-regulation of HSP22 had little effect on the TGF-α-induced phosphorylation of p38 MAP kinase, SAPK/JNK and MYPT, a target protein of Rho-kinase. The HSP22 expression was further analyzed in 20 resected specimens of human ovarian serous carcinoma. The expression of HSP22 was detected in all the twenty tissues (8.24-109.22 pg/mg protein), and the cases with highly expression of HSP22 showed a tendency to acquire the progressive ability. Our results strongly suggest that HSP22 acts as a positive regulator in TGF-α-induced migration of ovarian cancer cells, subsequently directing ovarian cancer toward progression.

Related: TGFA

Kodaz H, Hacibekiroglu I, Turkmen E, et al.
Increased dose single-agent gemcitabine in platinum-taxane resistant metastatic ovarian cancer.
Tumori. 2015 Jan-Feb; 101(1):36-40 [PubMed] Related Publications
CONCLUSION: In platinum–taxane resistant epithelial ovarian cancer (EOC), we aimed to determine the effectiveness.
PATIENTS AND METHODS: Between 2004 and 2013, patients afflicted with platinum–taxane resistant EOC and who were administered a 30-minute i.v. infusion of single-agent gemcitabine at a dose of 1,250 mg/m2 on the 1st, 8th and 15th days, every 28 days, were examined retrospectively.
RESULTS: Twenty-six patients with platinum–taxane resistant EOC were included in the study. The overall survival (OS) was 48 months. The median survival after becoming platinum–taxane resistant was 16 months for the study population. Median time to progression (TTP) and median survival after becoming platinum–taxane resistant for patients who received second-line treatment were 3.3 months and 16 months, respectively; for patients who received third-line treatment with gemcitabine, these were 3.7 months and 19 months, respectively. Administration of gemcitabine as second- and third-line chemotherapy in platinum–taxane resistant EOC, provides similar TTP and OS outcomes (p = 0.4, p = 0.9) with a similar response and toxicity rate.
CONCLUSIONS: Second- and third-line gemcitabine at a dose of 1,250 mg/m2 on days 1, 8 and 15 every 28 days as a 30-minute i.v. infusion in platinum–taxane resistant EOC is an effective treatment option with a tolerable and manageable toxicity.

Related: Gemcitabine

Redondo A, Castelo B, Pinto A, et al.
Prolonged response to aflibercept in ovarian cancer relapse: a case report.
Tumori. 2015 Jan-Feb; 101(1):e29-31 [PubMed] Related Publications
VEGF-targeted therapies have shown activity in ovarian cancer, and one of them, bevacizumab, has been recently approved in this disease. Aflibercept is an antiangiogenic soluble fusion protein that inhibits VEGF-mediated signaling. In ovarian cancer, phase II trials with aflibercept have shown a significant benefit in the control of malignant ascites but with a lower response rate than expected.We report the case of a patient with relapsed ovarian cancer treated with aflibercept in fourth line, who experienced a prolonged response during more than two years with good tolerance. The duration of response to aflibercept was longer than that of the three previous lines of therapy (including the initial carboplatin-paclitaxel regimen) and ascites did not reappear. Further clinical research with this drug in ovarian cancer to identify patients who benefit most is warranted.

Related: Angiogenesis Inhibitors Carboplatin Paclitaxel Signal Transduction VEGFA

Wang H, Bao W, Jiang F, et al.
Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ.
Cancer Lett. 2015; 360(2):269-79 [PubMed] Related Publications
P53 mutation plays a pivotal role in tumorigenesis of endometrial cancer (EC), here we report that the gain-of-function mutant p53-R248Q targets the proteasome activator REGγ to promote EC progression. Increased p53 expression significantly correlated with high pathological grade and lymph node metastasis in EC specimens. Manipulation of p53-R248Q in EC cells caused coincident changes in REGγ expression, and chromatin immunoprecipitation coupled with PCR further indicated that p53-R248Q bound to the REGγ gene promoter at a p53 responsive element. Silencing of REGγ in EC cells attenuated the cell proliferation, migration and invasion abilities, whereas overexpression of p53-R248Q rescued these activities. Overexpression of REGγ also induced an epithelial-mesenchymal transition phenotype. Moreover, a mouse xenograft tumor model showed that REGγ promoted tumor growth, further demonstrating a p53-R248Q-REGγ oncogenic pathway. Finally, examination of EC and normal endometrium specimens confirmed the oncogenic role of REGγ, in that REGγ was more highly overexpressed in p53-positive specimens than in p53-negative specimens. Our data suggest that REGγ is a promising therapeutic target for EC with the p53-R248Q mutation.

Related: Endometrial (Uterus) Cancer Endometrial Cancer Signal Transduction TP53

Bauckman K, Haller E, Taran N, et al.
Iron alters cell survival in a mitochondria-dependent pathway in ovarian cancer cells.
Biochem J. 2015; 466(2):401-13 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
The role of iron in the development of cancer remains unclear. We previously reported that iron reduces cell survival in a Ras/mitogen-activated protein kinase (MAPK)-dependent manner in ovarian cells; however, the underlying downstream pathway leading to reduced survival was unclear. Although levels of intracellular iron, ferritin/CD71 protein and reactive oxygen species did not correlate with iron-induced cell survival changes, we identified mitochondrial damage (via TEM) and reduced expression of outer mitochondrial membrane proteins (translocase of outer membrane: TOM20 and TOM70) in cell lines sensitive to iron. Interestingly, Ru360 (an inhibitor of the mitochondrial calcium uniporter) reversed mitochondrial changes and restored cell survival in HEY ovarian carcinoma cells treated with iron. Further, cells treated with Ru360 and iron also had reduced autophagic punctae with increased lysosomal numbers, implying cross-talk between these compartments. Mitochondrial changes were dependent on activation of the Ras/MAPK pathway since treatment with a MAPK inhibitor restored expression of TOM20/TOM70 proteins. Although glutathione antioxidant levels were reduced in HEY treated with iron, extracellular glutamate levels were unaltered. Strikingly, oxalomalate (inhibitor of aconitase, involved in glutamate production) reversed iron-induced responses in a similar manner to Ru360. Collectively, our results implicate iron in modulating cell survival in a mitochondria-dependent manner in ovarian cancer cells.

Related: Mitochondrial Mutations in Cancer

Bitler BG, Aird KM, Garipov A, et al.
Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.
Nat Med. 2015; 21(3):231-8 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.

Related: AKT1 Signal Transduction ARID1A EZH2 gene

Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies.
Lancet. 2015; 385(9980):1835-42 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk.
METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.
FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005).
INTERPRETATION: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.
FUNDING: Medical Research Council, Cancer Research UK.

Kato K, Usami T, Takeshima N
Secondary debulking surgery for isolated para-aortic nodal recurrence in ovarian cancer involving the division of the left renal vein.
Gynecol Oncol. 2015; 137(1):188-9 [PubMed] Related Publications
OBJECTIVE: To present a case that involved para-aortic lymphadenectomy in the aortocaval and retrocaval region involving the division of the left renal vein (LRV).
METHODS: A 36-year-old woman presented with ovarian cancer and isolated nodal recurrence located in the aortocaval and retrocaval region above and below the renal vein. Cytoreduction of para-aortic lymph nodes involving the division of the LRV was performed.
RESULTS AND CONCLUSION: Division of the LRV facilitates the separation of the lymph nodes from the renal artery or inferior vena cava under direct vision. No intra- or early postoperative complications, including renal dysfunction, occurred. Further analyses with long-term follow-up are warranted to evaluate this surgical method.

Coenegrachts L, Garcia-Dios DA, Depreeuw J, et al.
Mutation profile and clinical outcome of mixed endometrioid-serous endometrial carcinomas are different from that of pure endometrioid or serous carcinomas.
Virchows Arch. 2015; 466(4):415-22 [PubMed] Related Publications
Clinical outcome of 23 patients with mixed endometrioid and serous endometrial carcinomas (mixed EEC-SC) was compared to that of pure endometrioid (EEC) and pure serous (SC) carcinomas. Hotspot mutation frequencies in KRAS, PIK3CA, PTEN, and TP53 and microsatellite instability (MSI) status were determined in mixed EEC-SC, as well as in their EEC and SC microdissected components separately, and alterations were compared to frequencies in pure EEC and SC. Relapse-free (RFS) and overall survival (OS) differed significantly between mixed EEC-SC and pure EEC and SC, revealing that outcome of mixed EEC-SCs was intermediate to that of pure EEC and pure SC. PTEN mutations were absent in pure SC, but occurred in 20 % of pure EEC, and 13 % of mixed EEC-SC. In contrast, TP53 mutations were more frequent in pure SC (17 %) and mixed EEC-SC (22 %) than in pure EEC (2 %). Mutations in mixed EEC-SC were shared by the two microdissected components in 30 %, whereas in 35 %, some mutations were component-specific. Mutation analysis confirms similarities between the EEC and SC components of mixed EEC-SC with pure EEC and pure SC, respectively. However, PTEN and KRAS mutations were more frequent in the SC component of mixed EEC-SC than in pure SC, while TP53 mutations were more frequent in the EEC component of mixed EEC-SC than in pure EEC. Presence of different clonal mutation pattern between EEC and SC components of mixed EEC-SC raises the possibility of divergent tumor heterogeneity or biclonal origin in some cases.

Related: Endometrial (Uterus) Cancer Endometrial Cancer

Mabuchi S, Kuroda H, Takahashi R, Sasano T
The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer.
Gynecol Oncol. 2015; 137(1):173-9 [PubMed] Related Publications
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development. Here, we highlight the recent progress that has been made in our understanding of the PI3K/AKT/mTOR pathway and discuss the potential of therapeutic agents that target this pathway as treatments for ovarian cancer and the obstacles to their development.

Related: AKT1 Signal Transduction

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