Advanced Stage Ovarian Cancer Patients Research Articles

Abstract 3641: The predictive and prognostic roles of DNA damage response genes in epithelial ovarian cancer

Abstract Background: Despite platinum-based chemotherapy, 5-year survival of advanced stage ovarian cancer patients is only 15-30%. Exposure to platinum-based chemotherapeutics induces double strand DNA breaks (DSBs) and subsequently leads to activation of the DNA damage response (DDR). Therefore inhibition of components of the DDR may lead to better response to therapy. Aim of this study was to investigate in a large series of ovarian cancer patients the predictive and prognostic role of the activation status of four DDR-proteins- ATM, a key controller in the DDR, and three ATM substrates, including Chk2, 53BP1 and γ-H2AX, of which the latter is a direct readout for DNA damage. Methods: Expression of phospho-ATM, Chk2, phospho-Chk2, 53BP1, phospho-53BP1 and γ-H2AX was immunohistochemically assessed in 309 patients with chemo-naive ovarian cancer. Expression levels were related to clinicopathological characteristics and survival. Response to platinum-based chemotherapy was analyzed by defining two populations with either an optimal therapy response or a very poor therapy response. Both groups consisted of patients with advanced stage ovarian cancer, >2 cm residual disease after primary surgery and were all treated with platinum-based chemotherapy. The responder group had a well-defined PFS of more than 18 months while the non-responder group had a PFS of less than 6 months. Results: In the two well-defined groups with the largest contrast regarding response to treatment, positive γ-H2AX expression (OR=0.193; p=0.036) and positive Chk2 expression (OR=0.149; p=0.011) were related to a good response to platinum-based chemotherapy. In advanced stage patients, phospho-53BP1 expression was independently related to a worse disease-specific survival (HR=1.905; p= 0.044). Conclusion: High DDR protein expression in advanced stage ovarian cancers suggests a high degree of genomic instability, while the negative prognostic impact of phospho-53BP1 may be due to enhanced repair capacity of chemotherapy-induced DSBs on the long term. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3641. doi:1538-7445.AM2012-3641

Abstract 3518: Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer

Abstract Introduction: Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies, and two-thirds of patients present with stage III and IV disease. Unfortunately, the vast majority of advanced-stage ovarian cancer (OC) patients will relapse, require ongoing treatment, and eventually succumb to chemotherapy-resistant disease. The aim of this study was to test cellular therapy in combination with cytokines (IL-2 and/or pegylated-IFNα-2b) in a xenograft mouse model of OC. Methods: SKOV3-AF2 OC cells (1x106) were injected intraperitoneally (IP) into athymic nude mice (n=40). Day-7 post OC cell injection, mice were IP injected with mononuclear cells (MC; 5x106) and cytokine combinations [IL-2 (4,000 U) ± pegylated-IFNα-2b (IFN; 12,000 U); n=5 per group]. Cytokine injections were continued weekly for IFN and thrice weekly for IL-2. Mice were sacrificed when they became moribund due to tumor burden at which time solid tumor and ascitic fluid was measured and collected. Total RNA was isolated from tumor samples and reverse transcription (RT) reactions were performed. Gene expression of Survivin, DNA mismatch repair homolog (MLH1), cysteine-rich 61 (CCN1), and suppressor of cytokine signaling 1 (SOCS1), which have been shown to play roles in the pathobiology of OC, was analyzed by quantitative (q)RT-PCR using Taqman probes. Results: The in vivo model demonstrated that mice tolerated all the treatment combinations well (PBS, IL-2, IFN, IL-2+IFN, MC, MC+IL-2, MC+IFN, MC+IL-2+IFN) without significant weight loss or other cytotoxicities. Mice receiving MC+IL-2 treatment showed improved survival at 9-weeks post-tumor cell injection (60%, p<0.05) vs. mice without treatment (20%), IL-2 (0%), or MC (20%). There was no significant survival advantage in mice receiving MC+IFN (40%) or MC+IL-2+IFN (20%). Harvested tumors consisted of poorly differentiated surface epithelial carcinoma, growing in solid nests and sheets of large cells with a moderate amount of amphophilic or clear cytoplasm. Tumor cells focally were pleomorphic and multinucleated. Mitoses were frequent with abnormal forms present indicating a high rate of proliferation. We found that all tumors analyzed expressed Survivin, MLH1, CCN1, and SOCS1; however, there was no significant correlation of gene expression level (> 3-fold change) with time to sacrifice, tumor volume, or ascitic fluid production. SOCS1 gene expression, which is known to down-regulate proangiogenic molecules, was up-regulated in IFN treated animals (3-fold increase) but not control animals or animals receiving IL-2. Conclusions: IFNα-2b up-regulates SOCS1 expression in our in vivo mouse model. Cytokine-stimulated cellular immune therapy produces an anti-tumor effect in vivo. This data strongly supports development of cellular therapy (autologous or allogeneic) and is a potentially useful therapeutic strategy for the treatment of OC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3518. doi:1538-7445.AM2012-3518

Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients

Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients

Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients

A major challenge in advanced-stage epithelial ovarian cancer (EOC) is prediction of chemoresistant relapse. Our aim was to identify a microRNA (miRNA) signature associated with early relapse in advanced-stage EOC patients. miRNA expression was assessed by microarray profiling in training (n = 55) and test (n = 30) sets selected on the basis of time to relapse (TTR), followed by internal quantitative reverse transcriptase-PCR validation on a set of 45 consecutive cases unselected for clinical response and external in silico validation on publicly available datasets. Thirty-two differentially expressed miRNAs in early vs. late relapsing patients were identified in the training set. In the test set, 8 of these, belonging to a cluster located on chrXq27.3, were down-modulated in early relapsing patients. Hierarchical clustering of the internal validation set according to chrXq27.3 miRNA expression associated low miRNA expression with shorter TTR (log-rank P=0.00074, HR 2.44). The cluster was an independent prognostic factor in both internal and external validation sets. Forced expression of chrXq27.3-cluster selected miRNAs in human EOC cellular models was associated to reduction of cell proliferation and increased sensitivity to cisplatin. The role of down-modulation of the chrXq27.3 miRNA cluster in early relapse of advanced-stage EOC patients and its association to a reduced sensitivity to chemotherapeutic treatments warrant further investigation.

Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile

Epithelial mesenchymal transition (EMT) and cancer stem cells (CSC) have been associated with resistance to chemotherapy. Eighty percent of ovarian cancer patients initially respond to platinum-based combination therapy but most return with recurrence and ultimate demise. To better understand such chemoresistance we have assessed the potential role of EMT in tumor cells collected from advanced-stage ovarian cancer patients and the ovarian cancer cell line OVCA 433 in response to cisplatin in vitro. We demonstrate that cisplatin-induced transition from epithelial to mesenchymal morphology in residual cancer cells correlated with reduced E-cadherin, and increased N-cadherin and vimentin expression. The mRNA expression of Snail, Slug, Twist, and MMP-2 were significantly enhanced in response to cisplatin and correlated with increased migration. This coincided with increased cell surface expression of CSC-like markers such as CD44, α2 integrin subunit, CD117, CD133, EpCAM, and the expression of stem cell factors Nanog and Oct-4. EMT and CSC-like changes in response to cisplatin correlated with enhanced activation of extracellular signal-regulated kinase (ERK)1/2. The selective MEK inhibitor U0126 inhibited ERK2 activation and partially suppressed cisplatin-induced EMT and CSC markers. In vivo xenotransplantation of cisplatin-treated OVCA 433 cells in zebrafish embryos demonstrated significantly enhanced migration of cells compared to control untreated cells. U0126 inhibited cisplatin-induced migration of cells in vivo, suggesting that ERK2 signaling is critical to cisplatin-induced EMT and CSC phenotypes, and that targeting ERK2 in the presence of cisplatin may reduce the burden of residual tumor, the ultimate cause of recurrence in ovarian cancer patients.

Expression profiles in matched primary and recurrent serous ovarian carcinomas.

5058 Background: Little is known about the molecular characteristics of tumors present at relapse in advanced stage ovarian cancer patients following treatment with standard chemotherapy. Such know...

Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations

ObjectivesPrevious studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for “survival bias” by minimizing lead time that may exist between diagnosis and genetic testing. MethodsPatients with stage III/IV ovarian cancer and a non-AJ BRCA mutation, seen between January 1996 and July 2007, were identified from eight institutions. Patients with sporadic ovarian cancer were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. Progression-free (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Fisher's exact test and chi-square were also used for analysis. ResultsNinety-five advanced stage ovarian cancer patients with non-AJ BRCA mutations and 183 sporadic controls were analyzed. Compared to sporadic ovarian cancer patients, non-AJ BRCA patients had longer PFS (27.9 months vs. 17.9 months, HR 0.61 [95% CI 0.43–0.86]) and OS (101.7 months vs. 54.3 months, HR 0.43 [95% CI 0.27–0.68]). BRCA status was an independent predictor of PFS and OS. ConclusionsThis multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the “survival bias” that coincides with genetic testing.

Abstract 3072: Promoter hypermethylation of FBXO32, a novel TGF-β/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer

Abstract Refractory to TGF-β is frequently observed in ovarian cancer, and disrupted TGF-β/SMAD4 signaling results in aberrant expression of downstream target genes in the disease. We hypothesized that aberrant expression of TGF-β/SMAD4 targets are mediated through epigenetic mechanism and also contribute to resistance to TGF-β meditated growth inhibition. Our previous report using chromatin immunoprecipitation microarray (ChIP-chip) identified FBXO32 as one of SMAD4 targets in immortalized ovarian surface epithelial cell (IOSE) (Qin et al., BMC Syst Biol, 17: 73, 2009). In the present study, we investigated the mechanism conferring FBXO32 down-regulation, its clinical significance, and its function in ovarian cancer. Our result showed that expression of FBXO32 was observed in normal ovarian surface epithelium but not in ovarian cancer cell lines (HeyC2, SKOV3, CP70, A2708, MCP2, MCP3) using real time RT-PCR. Promoter methylation of FBXO32 was seen in ovarian cancer cell lines, HeyC2 and SKOV3, that display constitutive TGF-β/SMAD4 signaling. Moreover, our finding that epigenetic drug treatment restored FBXO32 expression in ovarian cancer cell lines regardless of FBXO32 methylation status, suggested that epigenetic regulation of FBXO32 in ovarian cancer may be a common event. Re-expression of FBXO32 markedly impeded proliferation of a platinum-resistant ovarian cancer cell lines, HeyC2 and CP70 (colony number: HeyC2: 19.33 ± 3.06 vs 1 ± 0, P< 0.005; CP70: 46.5 ± 6.36 vs 1.5 ± 0.7, P< 0.001) by using colony formation assay, due to increased apoptosis of the cells (CP70; apoptotic cell%, control: 2.55 ± 0.17; FBXO32: 10.72 ± 1.07, P<0.05), and resensitized the cells to cisplatin (P < 0.05). Surprisingly, elevated apoptosis was not observed in HeyC2 cells which have much higher drug-resistance than CP70 cells (IC50, HeyC2: 5.6ug/ml, CP70: 2.2ug/ml). However, an increase in the G1 cell population was observed in FBXO32-transfected HeyC2 cells. In in vivo study, the FBXO32-transfecte CP70 showed smaller tumor size compared to vector control after day14 (P < 0.05) of tumor injection. In advanced stage ovarian cancer patients, significant methylation frequency (29.3%; P<0.05) of FBXO32 was observed by real-time qMSP and such an outcome further correlated with the protein expressed level of FBXO32 by IHC stain. Importantly, FBXO32 methylation was significantly associated with shorter progression-free survival, as determined by both Kaplan-Meier analysis (P<0.05) and multivariate Cox regression analysis (hazard ratio 1.003, P<0.05). In conclusion, the novel tumor suppressor FBXO32 is epigenetically silenced in ovarian cancer cell lines with disrupted TGF-β/SMAD4 signaling, and FBXO32 methylation status predicts survival in ovarian cancer patients. Future regimen of treating ovarian cancer by ectopic expression of FBXO32 can be considered. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3072.

Abstract 2162: Gene expression profile for predicting survival in ovarian cancer across two independent datasets

Abstract Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. To identify a progression-free survival (PFS) related profile for predicting survival, advanced-stage serous ovarian cancer tissues from 110 patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We first selected 88 PFS-related genes by a univariate Cox model (p < 0.01). To avoid overfitting our dataset, we then adjusted regression coefficients of the genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index for each patient based on the 88-gene expression profile with the estimated coefficients was significantly correlated with PFS time as a continuous variable. In multivariate analysis, the prognostic index was independently associated with PFS time compared to other clinical factors [hazard ratio (HR), 4.84; 95% confidence interval (CI), 3.50-6.55; p < 0.001]. This prognostic ability was validated using an external validation dataset (n = 87) and proven by multivariate analysis (HR, 1.25; 95% CI, 1.08-1.45; p = 0.0032). The correlation between the prognostic index and overall survival time was confirmed in the two independent datasets. Furthermore, biological characterization of 88 PFS-related genes mainly highlighted several oncogenic signaling pathways. This PFS-related profile is the first step toward clinical practice for optimizing clinical management for advanced-stage serous ovarian cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2162.

Gene Expression Profile for Predicting Survival in Advanced-Stage Serous Ovarian Cancer Across Two Independent Datasets

BackgroundAdvanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer.Methodology/Principal FindingsAdvanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66–5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20–1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008).Conclusions/SignificanceThe prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

Quality of care in advanced ovarian cancer: The importance of provider specialty

Background One of the cornerstones of ovarian cancer therapy is cytoreductive surgery, which can be performed by surgeons with different specialty training. We examined whether surgeon specialty impacts quality of life (as proxied by presence of ostomy) and overall survival for women with advanced ovarian cancer. Methods Stage IIIC/IV ovarian cancer patients were identified using 4 state cancer registries: California, Washington, New York, and Florida and linked records to the corresponding inpatient-hospital discharge file, AMA Masterfile, and 2000 U.S. Census SF4 File. Predictors of receipt of care by a general surgeon and creation of fecal ostomy were analyzed. Multivariate modeling was performed to assess the association of hospital volume (low volume (LV) [0–4 cases], middle volume (MV) [5–9], high volume (HV) [10–19], and very high volume (VHV) [20+]) and surgeon specialty training (gynecologic oncologists/gynecologists, general surgeons, and other specialty) on survival. Results We identified 31,897 Stage IIIC/IV patients; mean age was 64 years. Treatment of patients by a general surgeon was predicted by LV, rural patient residence, poverty, and high level of comorbidity. Patients had lower hazard of death when treated in higher volume hospitals as compared to LV [VHV hazard ratio (HR) = 0.79, P < .0001; HV HR = 0.89, P < 0.001]. Patients treated by a general surgeon had higher likelihood of an ostomy (OR = 4.46, P < .0001) and hazard of death (HR = 1.63, P < .0001) compared to gynecologic oncologist/gynecologist. Conclusions Advanced stage ovarian cancer patients have better survival when treated by gynecologic oncology/gynecology trained surgeons. Data suggest that referral to these specialists may optimize surgical debulking and minimize the creation of a fecal ostomy.

Notch 1 signaling is active in ovarian cancer

Objective. Despite advances in chemotherapy and radical surgery, most advanced stage ovarian cancer patients die from their disease, highlighting the need for the development of novel treatment strategies. The Notch signaling pathway plays an important role in cellular differentiation, proliferation and apoptosis. We hypothesized that the active form of Notch 1, the Notch 1 intracellular domain (NICD), would be overexpressed in ovarian cancer cells and that depletion of NICD would lead to growth reduction. Methods. Following institutional review board approval, NICD expression was analyzed in human ovarian cancer specimens as well as the ovarian cancer cell lines OVCAR3, SKOV3, and CaOV3. In addition, the effects of Notch 1 depletion on ovarian cancer cell growth were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) growth assay for 6 days following transfection with siRNA against Notch 1. Results. Western blot analysis revealed abundant NICD expression in all 3 ovarian cancer cell lines, as well as in 16 of 21 (76%) human ovarian cancer samples. Following treatment with Notch 1 siRNA, expression of NICD was greatly reduced in all three cell lines. Furthermore, this depletion of NICD was associated with significant growth inhibition of all three ovarian cancer cell lines. Conclusions. NICD was frequently expressed in ovarian cancer cell lines and human ovarian cancer specimens. Importantly, depletion of Notch 1 led to growth inhibition of ovarian cancer cells. These findings support the hypothesis that Notch 1 plays a role in ovarian cancer proliferation, encouraging the investigation of this pathway as a therapeutic target.

Neuronal transcription factor Brn-3a(l) is over expressed in high-grade ovarian carcinomas and tumor cells from ascites of patients with advanced-stage ovarian cancer

ObjectivesIn view of the recent association of Brn-3 transcription factors with neuroblastomas, cervical, breast, and prostate cancers we examined the expression of Brn-3a(l) in normal ovaries and in different histological grades of ovarian tumors. The expression of Brn-3a(l) was also evaluated in normal ovarian and cancer cell lines and tumor cells isolated from the ascites of advanced-stage ovarian cancer patients.MethodsNormal ovaries, benign, borderline, grades 1, 2 and 3 ovarian tumors were analyzed by immunohistochemistry for Brn-3a(l) expression. A total of 46 ovarian specimens were included in the study. Immunofluorescence was used to investigate the expression of Brn-3a in normal ovarian and cancer cell lines. Brn-3a(l) expression was also evaluated by Western blot in tumor cells isolated from ascites of advanced-stage ovarian cancer patients and also in ovarian cancer cell lines.ResultsNearly 12% of normal and benign ovarian tissues and 57% of borderline ovarian tumors were positive for epithelial Brn-3a(l) expression. Stromal staining was higher and it constituted 40% of normal non-cancerous ovaries compared to 50 and 86% in benign and borderline tumors. On the other hand, 85-100% of grades 1, 2 & 3 ovarian tumors demonstrated nuclear and cytoplasmic Brn-3a(l) staining in the epithelium. Stromal staining in grades1, 2 and 3 tumors constituted 71-88% of total staining. Overall, immunoreactive Brn-3a was present in all grades of ovarian tumors. The extent of epithelial and stromal Brn-3a staining was significantly different between the normal and histological grades of tumors (epithelial-χ2 = 41.01, df = 20, P = 0.004, stromal-χ2 = 24.66. df = 15, P = 0.05). The extent of epithelial staining was significantly higher in grades 1 and 2 ovarian tumors compared to normal ovaries and benign ovarian tumors (p < 0.05). In parallel, stromal staining was significantly higher in grade 3 tumors compared to normal ovaries (p < 0.05). In addition, cytoplasmic and nuclear Brn-3a expression was evident in ovarian cancer cell lines while no such expression was observed in SV40 antigen immortalized normal ovarian cell lines.ConclusionThese data suggest that like other cancers, Brn-3a(l) expression is enhanced in ovarian tumors and its expression is consistent with its known role in inhibiting apoptosis and enhancing tumorigenesis. Specific targeting of Brn-3a may provide a useful strategy for regulating multiple tumor related genes involved with ovarian carcinomas.

Outcome in Advanced Ovarian Cancer following an Appropriate and Comprehensive Effort at Upfront Cytoreduction: A Twenty-Year Experience in a Single Cancer Institute

Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patients was to compare outcome with published findings from other centers and to discuss future options for the management of advanced ovarian carcinoma patients. Methods. A retrospective series of 340 patients with a mean age of 58 years (range: 17–88) treated for FIGO stage III and IV ovarian cancer between January 1985 and January 2005 was reviewed. All patients had primary cytoreductive surgery, without extensive bowel, peritoneal, or systematic lymph node resection, thereby allowing initiation of chemotherapy without delay. Chemotherapy consisted of cisplatin-based chemotherapy in combination with alkylating agents before 2000, whereas carboplatin and paclitaxel regimes were generally used after 1999-2000. Overall survival and disease-free survival were analyzed by the Kaplan-Meier method and the log-rank test. Results. With a mean followup of 101 months (range: 5 to 203), 280 events (recurrence or death) were observed and 245 patients (72%) had died. The mortality and morbidity related to surgery were low. The main prognostic factor for overall survival was postoperative residual disease (P < .0002), while the main prognostic factor for disease-free survival was histological tumor type (P < .0007). Multivariate analysis identified three significant risk factors: optimal surgery (RR = 2.2 for suboptimal surgery), menopausal status (RR = 1.47 for postmenopausal women), and presence of a taxane in the chemotherapy combination (RR = 0.72). Conclusion. These results confirm that optimal surgery defined by an appropriate and comprehensive effort at upfront cytoreduction limits morbidity related to the surgical procedure and allows initiation of chemotherapy without any negative impact on survival. The impact of neoadjuvant chemotherapy to improve resectability while lowering the morbidity of the surgical procedure is discussed.

Completion of intraperitoneal chemotherapy in advanced ovarian cancer and catheter-related complications

Objective Combination intravenous/intraperitoneal (IV/IP) chemotherapy has been shown in three randomized trials to be superior to IV therapy alone in the treatment of advanced ovarian cancer with respect to overall survival (OS). We sought to evaluate the effect of dose modification of IP therapy on completion rates. Methods From November 1999 until August 2008, all optimally debulked, advanced stage ovarian cancer patients who received adjuvant IP chemotherapy at a single institution were reviewed. The primary endpoint was completion of 6 cycles of IP chemotherapy. This rate was compared to published results from GOG 172. A secondary analysis evaluated completion of chemotherapy based on IP catheter type. Statistical analysis was performed with a chi square test with a significance level of p < 0.05. Results One hundred and three patients received IP chemotherapy during this period. Seventy-five patients received the modified IV/IP chemotherapy regimen. Sixty-two patients (83%) completed all 6 cycles in our cohort compared to 119 patients (42%) reported in GOG 172 ( p = 0.0001). Fifty-five patients had a fenestrated catheter (F) and 48 had a non-fenestrated (NF) catheter. Eight patients in each cohort discontinued treatment, for a completion rate of 85.5% in NF and 82.3% in F ( p = 0.79). Conclusions The dose modifications utilized in this study allowed for completion of 6 cycles of adjuvant IP chemotherapy in 83% of patients. Choice of catheter type did not affect completion rates. Continued monitoring of outcomes is planned to compare PFS and OS. The high completion rate may increase acceptance of IP chemotherapy in the community setting.

Interleukin‐6 and leptin as markers of energy metabolicchanges in advanced ovarian cancer patients

The progression of the neoplastic disease is characterized by specific alterations of energy metabolism and by symptoms like fatigue, anorexia, nausea, anaemia, immunodepression and poor performance status (PS). The main cause of these symptoms and metabolic abnormalities is the chronic action of proinflammatory cytokines released both by tumour and immune cells. The present study aimed to assess the relationship between markers of inflammation (C-Reactive Protein, Fibrinogen, proinflammatory cytokines) and energy metabolic status (BMI, leptin, oxidative stress) according to clinical parameters in 104 ovarian cancer patients at different stage and, moreover, to evaluate prospectively the changes of these parameters in accordance to tumour response in a subgroup of 70 advanced stage ovarian cancer patients. Advanced stage and poor PS were associated to high-grade inflammation and impaired energy metabolism. Among inflammatory mediators, interleukin (IL)-6 had a central role as predictive factor of leptin, reactive oxygen species and glutathione peroxidase. In turn, leptin considered the key marker of the nutritional status and energy metabolism, was independently determined from stage and IL-6, not only from BMI. Moreover, the evaluation of the changes of these parameters during the course of the neoplastic disease in the subgroup of advanced ovarian cancer patients clearly unveils the central role of IL-6 and leptin as early markers of the metabolic alterations and symptoms associated to disease progression in advanced stage ovarian cancer. Their assessment should be included in monitoring disease outcome, especially when cancer is no longer curable and quality of life becomes the primary endpoint.

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

This study compares Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) expression as predictive markers and evaluates the in vitro enhancement of platinum sensitivity using targeted agents in sporadic ovarian cancer (OC). A retrospective study was performed of advanced stage OC patients receiving platinum-based chemotherapy. BRCA1 and ERCC1 mRNA expression was determined from frozen tissue of 51 patients. Median overall survival (OS) was longer for patients with lower BRCA1 vs. higher BRCA1 (46 vs.33 months, p = 0.03). High BRCA1 was predictive of poorer OS specifically in patients with residual disease (RD) <2 cm (p = 0.03). There was a non-significant association for patients with lower ERCC1 and RD <2 cm in favor of improved OS and time to progression. Patients who expressed higher levels of both BRCA1 and ERCC1 mRNA had a shorter OS compared to patients with lower levels of either or both transcript (33 vs.46 months, p = 0.04). When Cox proportional modeling was used by representing BRCA1 and ERCC1 mRNA expression as a continuous variable, both emerge as potential predictors of survival. OC cell lines were exposed to chemotherapy in combination with DNA repair pathway inhibitors and cell viability was assessed. In vitro histone deacetylase (HDAC) inhibition increased the sensitivity of A2780s/cp cells to cisplatin and carboplatin but not to taxol, coincident with a significant decrease in BRCA1 and ERCC1 expression, suggesting that this compound directly targets DNA repair. In summary, this study shows that low BRCA1 and ERCC1 expression correlate with improved survival in advanced OC and HDAC inhibition induces synergistic cytotoxicity with platinum in vitro.

Interleukin-6, Cortisol, and Depressive Symptoms in Ovarian Cancer Patients

Inflammatory processes have been implicated in the pathogenesis of both depression and cancer. Links between depressive symptoms, interleukin-6 (IL-6), and cortisol dysregulation have been demonstrated in cancer patients, but vegetative versus affective components of depression have been minimally examined. The objective of the current study was to examine associations between IL-6, diurnal cortisol rhythms, and facets of depression in epithelial ovarian cancer patients. Patients awaiting surgery for a pelvic mass suspected for ovarian cancer completed questionnaires, collected salivary samples for 3 days presurgery, and gave a presurgical blood sample. Ascites was obtained during surgery. IL-6 was measured by enzyme-linked immunosorbent assay and cortisol by a chemiluminescence immunoassay. The final sample included 112 invasive ovarian cancer patients (86 advanced stage, 26 early stage) and 25 patients with tumors of low malignant potential (LMP). Advanced-stage ovarian cancer patients demonstrated elevations in vegetative and affective depressive symptoms, plasma IL-6, and the cortisol area under the curve (AUC) compared with patients with LMP tumors (all P < .05). Among invasive ovarian cancer patients, greater vegetative depression was related to elevated IL-6 in plasma (P = .008) and ascites (P = .024), but affective depression was unrelated to IL-6. Elevations in total depression (P = .026) and vegetative depression (P = .005) were also related to higher evening cortisol levels. Plasma IL-6 was related to greater afternoon and evening cortisol and cortisol AUC (all P values < .005). These results demonstrate significant relationships between IL-6, cortisol, and vegetative depression, and may have implications for treatment of depression in ovarian cancer patients.

Are Three Additional Cycles of Chemotherapy Useful in Patients with Advanced-stage Epithelial Ovarian Cancer After a Complete Response to Six Cycles of Intravenous Adjuvant Paclitaxel and Carboplatin?

BackgroundTo evaluate the efficacy of three additional cycles of chemotherapy in patients with the International Federation of Gynecology and Obstetrics Stage III or IV, who achieved a complete response after six cycles of intravenous adjuvant paclitaxel/carboplatin after surgery.MethodsThe clinical data of 94 patients with complete response after six cycles of adjuvant paclitaxel/carboplatin after surgery between January 1997 and March 2007 were reviewed retrospectively. Three additional cycles using the same chemotherapy were administered to 57 patients as consolidation chemotherapy (Group 1). Thirty-seven patients without the additional cycles served as controls (Group 2). Disease-free survival (DFS) and overall survival (OS) were evaluated using the Kaplan–Meier method with the log-rank test. The importance of consolidation chemotherapy as a prognostic factor affecting survival was examined using the Cox's proportional hazard analysis. The incidence of chemotherapy-induced hematological toxicities was compared between the two groups using chi-square test.ResultsMedian DFS and mean OS were not significantly different between the two groups (15 versus 22 months, P = 0.703; 69 versus 73 months, P = 0.891, respectively). Consolidation chemotherapy was not a prognostic factor of survival although optimal debulking surgery and lower value of serum CA-125 levels after six cycles of the chemotherapy were prognostic factors improving DFS (P < 0.01). Grade 3 or 4 leukopenia was more common in patients treated with consolidation chemotherapy than in those not treated (50.9 versus 21.6%, P = 0.004).ConclusionConsolidation chemotherapy using paclitaxel/carboplatin may be inefficient and relatively toxic to advanced-stage epithelial ovarian cancer patients with complete response to six cycles of the same chemotherapy after surgery.

Subcellular Localization of Activated Leukocyte Cell Adhesion Molecule Is a Molecular Predictor of Survival in Ovarian Carcinoma Patients

Currently available clinicopathologic prognostic factors are imperfect predictors of clinical course in advanced-stage epithelial ovarian cancer patients. New molecular predictors are needed to identify patients with higher risk of relapse or death from disease. In a retrospective study, we investigated the prognostic impact of activated leukocyte cell adhesion molecule (ALCAM) expression in epithelial ovarian cancer. We analyzed the effect of cell-anchorage loss on ALCAM cellular localization in vitro and assessed ALCAM expression by immunohistochemistry in a series of 109 well-characterized epithelial ovarian cancer patient samples. Chi-square test, Kaplan-Meier method, and Cox proportional hazard analyses were used to relate ALCAM cellular localization to clinical-pathologic parameters and to overall survival (OS) rate. Loss of epithelial ovarian cancer cell anchorage was associated both in vitro and in vivo with decreased ALCAM membrane expression. In vivo, ALCAM was localized to cell membrane in normal surface ovarian epithelium, whereas in 67% of the epithelial ovarian cancer samples, membrane localization was decreased or even lost, and the molecule was mainly expressed in cytoplasm. Median OS in this group of patients was 58 months, whereas a median OS was not yet reached in patients with ALCAM membrane localization (P = 0.036, hazard ratio [HR] = 2.0, 95% confidence interval [CI] 1.1 to 3.5). In a multivariate Cox regression model including all the available clinicopathologic variables, loss of ALCAM membrane expression was an independent factor of unfavorable prognosis (P = 0.042, HR = 2.15, 95% CI: 1.0 to 4.5). Decreased/lost ALCAM membrane expression is a marker of poorer outcome in epithelial ovarian cancer patients and might help to identify patients who could benefit from more frequent follow-up or alternative therapeutic modalities.