Advanced Serous Ovarian Cancer Patients Research Articles

Clinical impact of CA-125 ELIMination rate constant K (KELIM) on surgical strategy in advanced serous ovarian cancer patients

ObjectivesThe modeled CA-125 elimination constant K (KELIM) is a pragmatic early marker of tumor chemosensitivity in ovarian cancer patients treated with neoadjuvant chemotherapy before interval surgery. The primary objective of...

162 - GPX3 supports ovarian cancer progression by manipulating the extracellular redox environment

Ovarian cancer is the most lethal gynecologic malignancy, as most cases remain undiagnosed until considerable metastasis has occurred throughout the peritoneal cavity, resulting in 5-year overall survival rates of less than 29%. Ascites accumulation in the abdominal cavity provides a tumor-supporting medium in which metastatic ovarian cancer cells gain access to nutrients, growth factors, and cytokines that promote survival and proliferation. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to maintain an optimal redox homeostasis of this medium to support ovarian cancer survival during transcoelomic metastasis. Using gene expression cluster analysis of the major antioxidant enzymes, we identified two distinct populations of high grade serous ovarian tumors (The Cancer Genome Atlas, TCGA) that specifically clustered into high and low GPX3 expression, an extracellular glutathione peroxidase previously reported to be highly expressed in clear cell ovarian cancer and in ascites of advanced serous ovarian cancer patients. Interestingly, high GPX3 expression was associated with poorer overall patient survival. To assess whether cell survival advantages are associated with high GPX3 expression, we generated stable OVCAR3 GPX3 knockdown cell lines using lentiviral shRNA constructs. Decreased GPX3 expression inhibited clonogenicity and cell viability of OVCAR3 cells in response to treatment with H2O2 and high-dose ascorbate. GPX3 depletion resulted in increased extracellular H2O2 accumulation following ascorbate treatment, as measured by Amplex Red. Investigating the iron and oxidation reduction potential (ORP) of a cohort of 11 ovarian cancer patient ascites samples revealed heterogeneity in ascites ORP between patients and a positive correlation between iron content and ORP. GPX3 was necessary for overall cell survival in ascites. However, this did not correlate with ascites iron content or ORP. Collectively, our data suggest that GPX3 is a necessary antioxidant responsible for protection of ovarian cancer cells during metastatic spread in the peritoneal cavity.

A Comparison of Survival Outcomes in Advanced Serous Ovarian Cancer Patients Treated With Primary Debulking Surgery Versus Neoadjuvant Chemotherapy

ObjectiveThe management of women with advanced-stage serous ovarian cancer includes a combination of surgery and chemotherapy. The choice of treatment with primary debulking surgery or neoadjuvant chemotherapy varies by institution. The objective of this study was to report 5-year survival outcomes for ovarian cancer patients treated at a single institution with primary debulking surgery or neoadjuvant chemotherapy.MethodsThis study included a retrospective chart review of 303 patients with stage IIIC or IV serous ovarian carcinoma diagnosed in Calgary, Canada. The patients were categorized into 1 of the 2 treatment arms: primary debulking surgery or neoadjuvant chemotherapy. The 5-year ovarian cancer–specific survival rates were estimated using Kaplan-Meier curves.ResultsAmong the 303 eligible patients, 142 patients (47%) underwent primary debulking surgery, and 161 patients (53%) were treated with neoadjuvant chemotherapy. Five-year survival was better for patients undergoing primary debulking surgery (39%) than for patients who received neoadjuvant chemotherapy (27%; P = 0.02). Women with no residual disease experienced better overall survival than those with any residual disease (47% vs. 26%, respectively; P = 0.0002). This difference was significant for those who had primary debulking surgery (P = 0.0004) but not for the patients who received neoadjuvant chemotherapy (P = 0.09). Women who received intraperitoneal chemotherapy had better overall survival as compared with patients who received intravenous chemotherapy (44% vs 30%, respectively; P = 0.002).ConclusionsOur findings suggest that among women with no residual disease, survival is better among those who undergo primary debulking surgery than treatment with neoadjuvant chemotherapy. The latter should be reserved for women who are deemed not to be candidates for primary debulking surgery.

TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma.

Individual mutations in the tumor suppressor TP53 alter p53 protein function. Some mutations create a non-functional protein, whereas others confer oncogenic activity, which we term ‘oncomorphic’. Since mutations in TP53 occur in nearly all ovarian tumors, the objective of this study was to determine the relationship of oncomorphic TP53 mutations with patient outcomes in advanced serous ovarian cancer patients. Clinical and molecular data from 264 high-grade serous ovarian cancer patients uniformly treated with standard platinum- and taxane-based adjuvant chemotherapy were downloaded from The Cancer Genome Atlas (TCGA) portal. Additionally, patient samples were obtained from the University of Iowa and individual mutations were analyzed in ovarian cancer cell lines. Mutations in the TP53 were annotated and categorized as oncomorphic, loss of function (LOF), or unclassified. Associations between mutation types, chemoresistance, recurrence, and progression-free survival (PFS) were calculated. Oncomorphic TP53 mutations were present in 21.3% of ovarian cancers in the TCGA dataset. Patients with oncomorphic TP53 mutations demonstrated significantly worse PFS, a 60% higher risk of recurrence (HR=1.60, 95% confidence intervals 1.09, 2.33, p=0.015), and higher rates of platinum resistance (χ2 test p=0.0024) when compared with single nucleotide mutations not categorized as oncomorphic. Furthermore, tumors containing oncomorphic TP53 mutations displayed unique protein expression profiles, and some mutations conferred increased clonogenic capacity in ovarian cancer cell models. Our study reveals that oncomorphic TP53 mutations are associated with worse patient outcome. These data suggest that future studies should take into consideration the functional consequences of TP53 mutations when determining treatment options.

Abstract 1555: TP53 oncomorphic mutations are associated with resistance to platinum- and taxol-based standard chemotherapy in advanced serous ovarian cancer patients

Abstract Mutations in the tumor suppressor gene TP53 abrogate the tumor suppressive functions of the p53 protein, and some mutations endow the mutant protein with oncogenic activity. These specific mutations we term oncomorphic. Many studies have attempted to correlate p53 mutation status with patient outcomes; however the results have been controversial due to indiscriminate categorization of all TP53 mutations into one group. Using advanced ovarian cancer as a model, our objective was to determine the relationship of oncomorphic TP53 mutations with the development of chemoresistance in advanced serous ovarian cancer patients uniformly treated with platinum and taxol primary chemotherapy. Clinical, genetic, and protein expression data from 264 high-grade serous ovarian cancer patients were downloaded from The Cancer Genome Atlas (TCGA) data portal. Associations between mutation types, chemoresistance, and progression-free survival (PFS) were calculated for patients harboring oncomorphic TP53 mutations, loss of function mutations, or unclassified mutations. Using a large and uniform patient population, we demonstrate the phenomenon of oncomorphic mutations in ovarian cancer. Specifically, patients with oncomorphic TP53 mutations showed significantly worse PFS when compared with patients with unclassified TP53 mutations (Log-rank, p < 0.05). Patients with oncomorphic TP53 mutations displayed higher rates of platinum resistance (X2, p = 0.0024) and an almost 60% higher chance of recurrence (HR=1.59, 95% confidence intervals 1.09, 2.33, p = 0.016). Furthermore, tumors containing oncomorphic TP53 mutations displayed a unique protein expression profile distinct from tumors with LOF or unclassified mutations. Taken together, these data reveal that particular oncomorphic TP53 mutations are highly associated with worse patient outcomes. Importantly, not all TP53 mutations are equal, and future studies should segregate mutations based on functional consequence. These data may have important implications for the future treatment of patients based on which TP53 mutation is present. Citation Format: Pavla Brachova, Donghai Dai, Mathew Carlson, Michael Goodheart, Kristina Thiel, Eric Devor, Kimberly Leslie. TP53 oncomorphic mutations are associated with resistance to platinum- and taxol-based standard chemotherapy in advanced serous ovarian cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1555. doi:10.1158/1538-7445.AM2014-1555

A new perspective on estrogen receptor beta in ovarian cancer progression

O the gynecological malignancies, epithelial ovarian cancer is the leading cause of death in the great majority of developed countries with more than 140,000 women dying from this cancer across the world in 2008. The importance of estrogen signaling in the development and progression of ovarian cancer has been assumed to be less significant than in breast or endometrial malignancies, although preclinical studies and clinical data have shown that not only normal ovaries but also many malignant ovarian tumors can be considered as endocrine related, and hormone-dependent. Estrogens exert their action through two estrogen receptors (ERα and ERβ) that are encoded by separate genes. In the healthy ovary, the levels of ERβ are high and predominate over ERα, being ERβ1, -β2, and -β5 the most represented isoforms. The majority of ovarian tumors also express ERβ, but few studies have examined the prognostic role of ERβ isoforms in ovarian cancer. We have recently shown a strong statistical association of cytoplasmic ERβ2 immunoreactivity with an unfavorable outcome in advanced serous ovarian cancer patients, a finding also reported in familial and sporadic breast cancer. The functional role of cytoplasmic ERβ2 is far from being elucidated, however preliminary data from our ongoing studies suggest that cytoplasmic protein accumulation may confer pro-survival advantages to ovarian cancer cells by inhibiting apoptotic pathways.

Expression of the Glioma-Associated Oncogene Homolog 1 (Gli1) in Advanced Serous Ovarian Cancer Is Associated with Unfavorable Overall Survival

Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, glioblastoma, melanoma as well as pancreas, colorectal, and prostate carcinomas. Here we investigated the role of the transcription factor Gli1 in ovarian cancer. To this end, the expression profile of Gli1 was examined in normal ovaries, ovarian tumors, and ovarian cancer cell lines, and the in vitro effects of a specific Hh-pathway blocker, KAAD-cyclopamine, or a specific Gli1 inhibitor (GANT58) on cell proliferation and on Hh target gene expression were also assessed. Results obtained showed that epithelial cells in ovarian cancer tissue express significantly higher levels of nuclear Gli1 than in normal ovarian tissue, where the protein was almost undetectable. In addition, multivariate analysis showed that nuclear Gli1 was independently associated to poor survival in advanced serous ovarian cancer patients (HR = 2.2, 95%CI 1.0–5.1, p = 0.04). In vitro experiments demonstrated Gli1 expression in the three ovarian carcinoma cell lines tested, A2780, SKOV-3 and OVCAR-3. Remarkably, although KAAD-cyclopamine led to decreased cell proliferation, this treatment did not inhibit hedgehog target gene expression in any of the three ovarian cancer cell lines, suggesting that the inhibition of cell proliferation was a nonspecific or toxic effect. In line with these data, no differences on cell proliferation were observed when cell lines were treated with GANT58. Overall, our clinical data support the role of Gli1 as a prognostic marker in advanced serous ovarian cancer and as a possible therapeutic target in this disease. However, our in vitro findings draw attention to the need for selection of appropriate experimental models that accurately represent human tumor for testing future therapies involving Hh pathway inhibitors.

Significance of hyaluronan binding protein (HABP1/P32/gC1qR) expression in advanced serous ovarian cancer patients

BackgroundTo evaluate various risk factors related to the overall survival (OS) and progression free survival (PFS) in 131 patients with stage III–IV ovarian serous carcinoma. MethodsAll patients underwent primary debulking surgery followed by a standard chemotherapeutic treatment regimen. Hyaluronan binding protein (HABP1) expression was evaluated using immunohistochemical-staining and assessed using western-immunoblotting analyses. A log-rank test was used to compare OS and PFS between cisplatin sensitive versus resistant patients. Multivariate analyses were used to identify risk factors associated with OS and PFS. ResultsHABP1 over-expression was correlated to histological-differentiation, residual-tumor-size, serum CA-125 levels and International Federation of Gynecology and Obstetrics (FIGO) stage. Multivariate analyses demonstrated that increased expression of HABP1 was associated with cisplatin resistance. HABP1 low-expression resulted in an increased five-year OS and PFS. Cox proportional hazards test identified that high expression of HABP1 led to increased risk for stage III/IV serous ovarian cancer via poor OS and PFS. This was similar for cisplatin resistant patients. Thus, increased HABP1 immunoreactivity in ovarian cancer may lead to a shortening in disease-free intervals of patients. ConclusionHAPBP1 over-expression in primary ovarian carcinomas is related to a decrease in OS and PFS and may be utilized as a prognostic marker for stage III/IV patients.

Cytoplasmic expression of estrogen receptor beta (ERβ) predicts poor clinical outcome in advanced serous ovarian cancer

Objective In this study we investigated the prognostic value of estrogen receptor α (ERα), ERβ and progesterone receptor (PR) expression in 58 untreated advanced serous ovarian cancer patients. The study also included 12 macroscopically and histopathologically normal ovaries. Materials and methods Protein expression was evaluated by immunohistochemistry, and antibody staining detected in both the nuclear and cytoplasmic compartments was taken into account. Immunopositivity was analyzed in relation to tumor clinicopathological variables, disease-free survival (DFS), and overall survival (OS). Results Epithelial cells in ovarian cancer tissue showed significantly lower levels of nuclear ERβ and PR, but not ERα, than in normal ovarian tissue. In the case of ERβ, however, while normal ovarian epithelium exhibited almost exclusively strong nuclear staining, ovarian cancer tissue mostly showed cytoplasmic immunopositivity. Nuclear ERα and ERβ expression were not associated with clinical outcome. Conversely, any cytoplasmic ERβ expression was an independent unfavorable prognostic factor for DFS, a finding approaching statistical significance also for OS. These data suggest that, in advanced serous ovarian cancer, cytoplasmic ERβ signaling may be more important for patient survival than its nuclear signaling. In the case of PR, positivity was an independent favorable prognostic factor for DFS. Conclusions These novel findings, that need to be confirmed in a large prospective trial, suggest that additional prognostic, and possibly therapeutic opportunities may be available in advanced serous ovarian cancer.