Efficacy and safety of niraparib in patients aged 65 years and older with advanced ovarian cancer: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD). RESULTS: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups. CONCLUSION: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age.

Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. RESULTS: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. CONCLUSIONS: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

Optimizing disease progression assessment using blinded central independent review and comparing it with investigator assessment in the PRIMA/ENGOT-ov26/GOG-3012 trial: challenges and solutions.

OBJECTIVE: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy. METHODS: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention. RESULTS: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups. CONCLUSION: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.

Lymphovascular space invasion in uterine corpus cancer: What is its prognostic significance in the absence of lymph node metastases?

OBJECTIVE: Lymphovascular space invasion (LVSI) is a poor prognostic indicator in uterine cancer, primarily due to its association with lymph node metastases. We sought to determine if LVSI provides any prognostic information for uterine cancer subjects in the absence of nodal disease. METHODS: A retrospective review was performed using a database of women treated for uterine cancer at MUSC from 2005 to 2012. Subjects with negative nodes after complete staging were identified. Multiple regression modeling was used to adjust for demographic and histopathologic covariates. The C-index was calculated for models of survival that included LVSI and those that did not. Competing risks analysis was conducted to examine factors associated with time to recurrence. RESULTS: Two hundred and five subjects were completely staged and had negative nodes, 24 with LVSI and 181 without. Factors significantly associated with survival included age, race, stage, grade, histology, and LVSI. Regression models for recurrence-free survival (RFS) and overall survival (OS) had similar C-indices regardless of whether LVSI was included. Competing risks analysis confirmed no significant difference in time to recurrence for subjects with LVSI compared to those without, after adjusting for other prognostic factors (P=0.53). CONCLUSIONS: LVSI is associated with shorter recurrence-free and overall survival in uterine cancer subjects with negative lymph nodes. However, after adjusting for other prognostic factors, LVSI status does not provide additional prognostic information. This finding suggests that recurrence-free and overall survival for uterine cancer patients with negative lymph nodes can be estimated without factoring in LVSI.

Vintafolide: a novel targeted agent for epithelial ovarian cancer.

Vintafolide (EC145) is a novel folate-conjugated vinca alkaloid (desacetylvinblastine hydrazide; DAVBLH) that binds with high affinity to the folate receptor (FR), expressed in a majority of epithelial ovarian cancers. In preclinical studies, vintafolide had significant antiproliferative activity and tolerability. Phase I studies demonstrated an acceptable safety profile, with constipation being the dose-limiting toxicity. A Phase II study of vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with platinum-resistant ovarian cancer showed a statistically significant improvement in progression-free survival with combination therapy. (99m)Tc-etarfolatide, a diagnostic radiopharmaceutical, determines FR status, which allows determination of those patients most likely to benefit from treatment with vintafolide. A Phase III study evaluating vintafolide plus PLD versus PLD alone in patients with platinum-resistant ovarian cancer is currently underway.

Vaginal cancer: the experience from 2 large academic centers during a 15-year period.

OBJECTIVE: Limited data regarding the natural history, management, and prognosis of vaginal cancer exist owing to the relative disease rarity. MATERIALS AND METHODS: A retrospective chart review was performed at 2 institutions to identify women receiving treatment for vaginal cancer between 1990 and 2004. Demographics, risk factors, histology, International Federation of Gynecology and Obstetrics stage, treatment, and treatment-related complications were recorded. Statistical Analysis Software (SAS) version 9.2 was used. RESULTS: A total of 110 patients were identified in the 2 university databases. Median age was 63 years (range = 36-93 years), and 84% were white; 73% had squamous cell carcinoma, 40% were ever users of tobacco, and 64% had no abnormal Pap smear results. Of the patients, 83% had early-stage (I or II) disease. Treatment varied by stage with increasing use of radiation with advancing stage. Recurrence was 24%, 32%, and 53% for stage I, II, and III/IV disease, respectively. After a median follow-up of 21 months, progression-free survival was 59, 35, and 23 months for stage I, II, and III/IV disease, respectively. Overall survival was 106, 58, and 34 months for stage I, II, and III/IV disease, respectively. Age greater than 60 years (p = .0339; hazard ratio [HR] = 2.162), advanced stage (p = .0004; HR = 2.475), and tobacco use (p = .0004; HR = 1.02) were negatively associated with survival. Thirty percent developed a significant complication (fistula, stricture, cystitis, or proctitis), and 21% developed a vesicovaginal and/or rectovaginal fistula. There was no association of fistula development with age, stage, tobacco use, histological finding, or treatment history (including radiation therapy). CONCLUSIONS: Age, stage, and tobacco abuse seem to be negatively associated with survival in vaginal cancer. However, no risk factors were associated with fistula development.

Surgical versus non-surgical management for patients with malignant bowel obstruction (S1316): a pragmatic comparative effectiveness trial.

BACKGROUND: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction. METHODS: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450. FINDINGS: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group). INTERPRETATION: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction. FUNDING: Agency for Healthcare Research and Quality and the National Cancer Institute. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Impact of smoking on perioperative pulmonary and upper respiratory complications after laparoscopic gynecologic surgery.

OBJECTIVE: To determine the impact of smoking on the rate of pulmonary and upper respiratory complications following laparoscopic gynecologic surgery. METHODS: We retrospectively identified all patients who underwent laparoscopic gynecologic surgery at one institution between January 2000 and January 2009. Pulmonary and upper respiratory complications were defined as atelectasis, pneumonia, upper respiratory infection, acute respiratory failure, hypoxemia, pneumothorax, or pneumomediastinum occurring within 30 days after surgery RESULTS: Nine hundred three patients underwent attempt at laparoscopic surgery. Fifty-four were excluded because of conversion to laparotomy and 31 because of insufficient data. Of the 818 patients included, 356 (43%) had cancer. A total of 576 (70%) patients were never smokers, 156 (19%) were past smokers, and 86 (10%) were current smokers (smoked within 6 weeks before surgery). These three groups were similar with regard to median body mass index, operative time, and length of hospital stay. Compared to never and past smokers, current smokers were more likely to undergo high-complexity laparoscopic procedures (10.4%, 15.4%, and 19.8%, respectively; p=0.015) and had younger median age 49 years, 51 years, and 46 years, respectively; p=0.035. Nineteen (2.3%) patients experienced pulmonary complications - symptomatic atelectasis (n=9), pneumonia (n=5), acute respiratory failure (n=2), hypoxemia (n=1), pneumomediastinum (n=1), and pneumothorax (n=2). The rate of pulmonary complications was 2.1% (12 of 564 patients) in never smokers, 4.5% (7 of 156 patients) in past smokers, and zero in current smokers. CONCLUSION: In this cohort, smoking history did not appear to impact postoperative pulmonary and upper respiratory complications. In smokers scheduled for operative procedures, laparoscopy should be considered when feasible.

Racial disparities in treatment and survival from ovarian cancer.

BACKGROUND: Black women with ovarian cancer in the U.S. have lower survival than whites. We aimed to identify factors associated with racial differences in ovarian cancer treatment and overall survival (OS). METHODS: We examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center Cancer Registry in Charleston, S.C. between 2000 and 2015. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between race and receipt of surgery and chemotherapy, and Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs between race and OS. Model variables included diagnosis center, stage, histology, insurance status, smoking, age-adjusted Charlson comorbidity index (AACI) and residual disease. Interactions between race and AACI were assessed using -2 log likelihood tests. RESULTS: Blacks vs. whites were over two-fold less likely to receive a surgery-chemotherapy sequence (multivariable-adjusted OR 2.46, 95% CI 1.43-4.21), particularly if they had a higher AACI (interaction p = 0.008). In multivariable-adjusted Cox models, black women were at higher risk of death (HR 1.81, 95% CI 1.35-2.43) than whites, even when restricted to patients who received a surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10-2.89) and particularly for those with higher AACI (HR 4.70, 95% CI 2.00 - 11.02, interaction p = 0.01). CONCLUSIONS: Among blacks, higher comorbidity associates with less chance of receiving guideline-based treatment and also modifies OS. Differences in receipt of guideline-based care do not completely explain survival differences between blacks and whites with ovarian cancer. These results highlight opportunities for further research.

Morbidity and mortality of vulvar and vaginal cancers: Impact of 2-, 4-, and 9-valent HPV vaccines.

Vaginal and vulvar cancers do not account for a large proportion of gynecologic malignancies but their impact is significant. Both vaginal and vulvar lesions have precursors and display levels of dysplasia before progression to invasive disease. Human Papillomavirus (HPV) is a known causative agent of such dysplasia and can be detected now more readily than ever with adequate recognition techniques and provider awareness. Although HPV vaccination is still lagging compared to other recommended childhood vaccinations, the impact on lower genital tract neoplasia is promising. The bivalent and quadrivalent vaccines have been shown to be efficacious and the newest nonavalent vaccine should add even more of impact on coverage of cancer-causing HPV types. Although it is still early to show true clinical and population-based disease reduction due to low disease incidence and relatively short time of vaccine availability, the potential is noteworthy.

Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer.

PURPOSE: Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FRα, in ovarian cancer models. EXPERIMENTAL DESIGN: We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003-induced cell death. RESULTS: MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation, but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In addition, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cancer. CONCLUSIONS: MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.

Detection and monitoring of ovarian cancer.

Ovarian cancer is the fifth leading cause of death among women in the United States and remains the most common cause of death from a gynecologic malignancy. Most ovarian cancers are diagnosed at an advanced stage in which 5-year survival rate is approximately 30%. Given that the 5-year survival rate is greater than 90% for women diagnosed at an early stage, early detection in women presenting with vague symptoms is crucial to improve outcome. Diagnosis of ovarian cancer is largely based on symptoms, imaging, and laboratory biomarkers. Overall, more than 200 potential biomarkers differentially expressed in ovarian cancer have been identified (Lokshin, 2012). However, no single marker has been found useful for the diagnosis of ovarian cancer. Increased sensitivity and specificity for the diagnosis of ovarian cancer are observed when multiple markers are used in combination. The Food and Drug Administration (FDA) recently cleared two algorithms to evaluate the risk of ovarian cancer for women who present with pelvic mass. In this review, we will summarize the most recent serum biomarkers and clinical applications of biomarkers for the early detection and treatment monitoring of ovarian cancers. We will also discuss the algorithms for predicting the risk of ovarian cancers.

Small bowel perforation 17 months after robotic surgery for endometrial cancer: A case report.

► Robotic surgery offers several advantages in the management of endometrial cancer. ► No long-term data exist regarding recurrence in patients undergoing robotic surgery. ► Metastasis or recurrence may result in bowel obstruction post surgery.

Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death.

BACKGROUND: We investigated the clinical and biological significance of p130cas, an important cell signaling molecule, in ovarian carcinoma. METHODS: Expression of p130cas in ovarian tumors, as assessed by immunohistochemistry, was associated with tumor characteristics and patient survival. The effects of p130cas gene silencing with small interfering RNAs incorporated into neutral nanoliposomes (siRNA-DOPC), alone and in combination with docetaxel, on in vivo tumor growth and on tumor cell proliferation (proliferating cell nuclear antigen) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were examined in mice bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) or taxane-resistant (HeyA8-MDR) ovarian tumors (n = 10 per group). To determine the specific mechanisms by which p130cas gene silencing abrogates tumor growth, we measured cell viability (MTT assay), apoptosis (fluorescence-activated cell sorting), autophagy (immunoblotting, fluorescence, and transmission electron microscopy), and cell signaling (immunoblotting) in vitro. All statistical tests were two-sided. RESULTS: Of 91 ovarian cancer specimens, 70 (76%) had high p130cas expression; and 21 (24%) had low p130cas expression. High p130cas expression was associated with advanced tumor stage (P < .001) and higher residual disease (>1 cm) following primary cytoreduction surgery (P = .007) and inversely associated with overall survival and progression-free survival (median overall survival: high p130cas expression vs low expression, 2.14 vs 9.1 years, difference = 6.96 years, 95% confidence interval = 1.69 to 9.48 years, P < .001; median progression-free survival: high p130cas expression vs low expression, 1.04 vs 2.13 years, difference = 1.09 years, 95% confidence interval = 0.47 to 2.60 years, P = .01). In mice bearing orthotopically implanted HeyA8 or SKOV3ip1 ovarian tumors, treatment with p130cas siRNA-DOPC in combination with docetaxel chemotherapy resulted in the greatest reduction in tumor growth compared with control siRNA therapy (92%-95% reduction in tumor growth; P < .001 for all). Compared with control siRNA therapy, p130cas siRNA-DOPC reduced SKOV3ip1 cell proliferation (31% reduction, P < .001) and increased apoptosis (143% increase, P < .001) in vivo. Increased tumor cell apoptosis may have persisted despite pan-caspase inhibition by the induction of autophagy and related signaling pathways. CONCLUSIONS: Increased p130cas expression is associated with poor clinical outcome in human ovarian carcinoma, and p130cas gene silencing decreases tumor growth through stimulation of apoptotic and autophagic cell death.