Andrew J. Li

Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

CONTEXT Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE Five-year overall mortality. RESULTS The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer

PURPOSE Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. PATIENTS AND METHODS Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. RESULTS Sixty-five patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. CONCLUSION The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.

Effect of obesity on survival in epithelial ovarian cancer

Epidemiologic studies suggest that obese women are more likely to die of ovarian cancer than those of ideal body weight, but it is not known whether increased incidence, comorbidities common to obese women, or altered tumor biology is responsible for this difference. The current study attempted to determine the influence of excess body weight on ovarian cancer survival, disease progression, and clinicopathologic factors.

Impact of beta blockers on epithelial ovarian cancer survival

OBJECTIVE Stress may promote ovarian cancer progression through mechanisms including autonomic nervous system mediators such as norepinephrine and epinephrine. Beta blockers, used to treat hypertension, block production of these adrenergic hormones, and have been associated with prolonged survival in several malignancies. We sought to determine the association between beta blocker use and epithelial ovarian cancer (EOC) disease progression and survival. METHODS We performed an institutional retrospective review of patients with EOC treated between 1996 and 2006. Patients underwent cytoreductive surgery followed by platinum-based chemotherapy. Women were considered beta blocker users if these medications were documented on at least two records more than 6 months apart. Statistical tests included Fishers exact, Kaplan-Meier, and Cox regression analyses. RESULTS 248 met inclusion criteria. 68 patients used antihypertensives, and 23 used beta blockers. Median progression-free survival for beta blocker users was 27 months, compared with 17 months for non-users (p=0.05). Similarly, overall disease-specific survival was longer for beta blocker users (56 months) compared with non-users (48 months, p=0.02, hazard ratio=0.56). Multivariate analysis identified beta blocker use as an independent positive prognostic factor, after controlling for age, stage, grade, and cytoreduction status (p=0.03). Overall survival remained longer for beta blocker users (56 months) when compared with hypertensive patients on other medications (34 months) and patients without hypertension (51 months) (p=0.007). CONCLUSIONS In this cohort of patients with EOC, beta blocker use was associated with a 54% reduced chance of death compared with that of non-users.

Ovarian preservation in stage I low-grade endometrial stromal sarcomas.

OBJECTIVE: To examine the impact of ovarian preservation in a case-control study of women with stage I low-grade endometrial stromal sarcomas. METHODS: Patients with low-grade endometrial stromal sarcomas were identified at 5 institutions from 1976 to 2002. Cases were defined as patients who retained ovarian function; each case was matched to 2 control patients who underwent bilateral salpingo-oophorectomy (BSO). Immunostaining for estrogen and progesterone receptors was performed. Data were examined with Student t, &khgr;2, Cox regression, and Kaplan-Meier analyses. RESULTS: Twelve premenopausal patients with low-grade endometrial stromal sarcomas who did not undergo BSO were matched to 24 controls. Of the 36 patients in the entire cohort, disease recurred in 14 (39%). Recurrences were identified in the pelvis, abdomen, lung, or lymphatics in both cases and controls. Disease recurred in 4/12 (33%) case patients, compared with 10/24 (42%) control patients (P = .63). When case patients were compared with controls, no differences in progression-free (91.3 months versus 68.6 months, P = .44) or overall survival (median survival not yet reached versus 406 months, P = .82) were identified. This study had 13% power to detect the observed difference in median disease-free survival. After controlling for use of adjuvant therapy and BSO, older age remained the only independent poor prognostic factor for progression-free survival (P = .008). Twenty-two available tumors demonstrated positivity for both estrogen and progesterone receptors. CONCLUSION: Bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas. LEVEL OF EVIDENCE: II-2

Hormone receptor expression in uterine sarcomas: Prognostic and therapeutic roles

OBJECTIVES.: The utility of hormone therapy in the management of uterine sarcomas is poorly defined. We hypothesize that estrogen receptor (ER) expression is common in uterine sarcomas, and carries prognostic significance. Further, we hypothesize that ER-positive uterine sarcomas respond to hormone therapy. METHODS.: We retrospectively reviewed charts of patients with uterine sarcomas. Stepwise Cox proportional hazards regression model was used to evaluate variables related to the risk of death: age, histology, stage, use of pelvic radiotherapy, and ER expression. In addition, we examined clinical outcomes in patients treated with aromatase inhibitors, megestrol acetate, depot medroxyprogesterone acetate, and tamoxifen. RESULTS.: Fifty-four patients underwent immunohistochemical staining, and 34 (63%) were ER-positive. Kaplan-Meier survival analysis and log-rank test indicated that patients with ER-positive sarcomas demonstrated improved overall survival when compared with ER-negative patients (median OS 36 vs. 16 months, p=0.004). Upon multivariate analysis, ER positivity retained significance as an independent predictor of survival (HR=0.32, CI 0.12-0.89, p=0.03). Four patients received hormonal treatment in the adjuvant setting and remained in remission (range of follow up: 18-68 months). Eighteen patients received hormone therapy in the setting of recurrent or progressive disease: fourteen (78%) demonstrated stable disease or complete or partial response (range of follow up: 6-124 months). CONCLUSIONS.: ER expression is common and is associated with improved overall survival in uterine sarcomas. Conducting immunohistochemical staining to ascertain ER status may aid with prognostication in this disease. Hormone therapy should be considered in patients with primary and recurrent ER-positive uterine sarcomas.

Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: A phase III trial of the AGO OVAR, COGI, GINECO, and GEICO-the MIMOSA study

PURPOSE To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. PATIENTS AND METHODS Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. RESULTS Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35 U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti-anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. CONCLUSION Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.

Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated by oxidized low density lipoprotein

OBJECTIVES We previously observed an association between ovarian cancer outcome and statin use and hypothesized lipoproteins have direct effects on ovarian cancer proliferation. Here we investigate the direct effects of low density lipoprotein (LDL) and oxidized LDL (oxLDL) on proliferation and the inhibitory effects of fluvastatin and a liver X receptor (LXR) agonist. METHODS The effects of LDL, oxLDL, the LXR agonist TO901317, fluvastatin and cisplatin on cellular proliferation were determined using MTT assays. LXR pathway proteins were assayed by immunoblotting. Cytokine expression was determined by antibody array. RESULTS Concentrations of oxLDL as small as 0.1 microg/ml stimulated CAOV3 and SKOV3 proliferation, while LDL had no effect. TO901317 inhibited the proliferation of CAOV3, OVCAR3 and SKOV3 cells stimulated by oxLDL. Fluvastatin inhibited oxLDL mediated proliferation of CAOV3 and SKOV3. Cardiotrophin 1 (CT-1) was mitogenic to CAOV3 and SKOV3, was induced by oxLDL, and was reversed by TO901317. OxLDL increased cisplatin IC50s by 3.8 microM and > 60 microM for CAOV3 and SKOV3 cells, respectively. The LXR pathway proteins CD36, LXR, and ABCA1 were expressed in eight ovarian carcinoma cell lines (A2780, CAOV3, CP70, CSOC882, ES2, OVCAR3, SKOV3). CONCLUSIONS OxLDL reduced ovarian carcinoma cell chemosensitivity and stimulated proliferation. These effects were reversed by LXR agonist or fluvastatin. The LXR agonist also inhibited expression of the ovarian cancer mitogen CT-1. These observations suggest a biologic mechanism for our clinical finding that ovarian cancer survival is associated with statin use. Targeting LXR and statin use may have a therapeutic role in ovarian cancer.

Obesity-associated adipokines correlate with survival in epithelial ovarian cancer

OBJECTIVES Obesity impacts outcome in women with epithelial ovarian cancer (EOC), although its exact role and the molecular mechanisms remain poorly defined. Adipocytes secrete leptin and adiponectin, and the leptin to adiponectin (L:A) ratio is correlated with poor survival in other malignancies. We hypothesized that the L:A ratio is associated with survival in women with EOC. METHODS We queried the institutional tumor registry for patients with advanced stage EOC and identified a cohort of 161 women with banked fasting prediagnostic serum samples. Patients underwent cytoredutive surgery followed by platinum-based chemotherapy. Sera were assayed for leptin and adiponectin, and clinico-pathologic data were abstracted. Standard statistical tests were performed. RESULTS 161 patients met inclusion criteria. We identified a significant correlation between BMI and leptin and the L:A ratio, but not adiponectin, in this cohort (r=0.46, 0.46, and -0.13, respectively; p=0.001, 0.001, and 0.106). Women with low L:A ratios demonstrated statistically longer disease-specific survival (57 months) compared to those with median or high levels (49 and 37 months, respectively; p=0.02). On multivariate analysis, we determined that BMI and age, but not L:A ratio, retained significance as independent prognostic factors for survival (p=0.04, 0.004, and 0.895, respectively). CONCLUSIONS In this cohort, the L:A ratio correlated statistically with clinical outcome, but did not independently predict survival. Obesity remains a modifiable risk factor in women with EOC. Further studies are needed to determine if leptin and/or adiponectin may be potential therapeutic targets in obese women with EOC.

Stimulation of bone regeneration following the controlled release of water-insoluble oxysterol from biodegradable hydrogel

Recently bone graft substitutes using bone morphogenetic proteins (BMPs) have been heralded as potential alternatives to traditional bone reconstruction procedures. BMP-based products, however, are associated with significant and potentially life-threatening side effects when used in the head and neck region and furthermore, are exorbitantly priced. Oxysterols, products of cholesterol oxidation, represent a class of molecules that are favorable alternatives or adjuncts to BMP therapy due to their low side effect profile and cost. In order to establish the optimal clinical utility of oxysterol, an optimal scaffold must be developed, one that allows the release of oxysterol in a sustained and efficient manner. In this study, we prepare a clinically applicable bone graft substitute engineered for the optimal release of oxysterol. We first solubilized oxysterol in water by making use of polymeric micelles using l-lactic acid oligomer (LAo) grafted gelatin. Then, the water-solubilized oxysterol was incorporated into a biodegradable hydrogel that was enzymatically degraded intracorporeally. In this manner, oxysterol could be released from the hydrogel in a degradation-driven manner. The water-solubilized oxysterol incorporated biodegradable hydrogel was implanted into rat calvarial defects and induced successful bone regeneration. The innovative significance of this study lies in the development of a bone graft substitute that couples the osteogenic activity of oxysterol with a scaffold designed for optimized oxysterol release kinetics, all of which lead to better repair of bone defects.