Factors associated with hospice use in ovarian cancer

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155 Elevated serum adiponectin levels correlate with survival in epithelial ovarian cancers E. Diaz, I. Chen, N. Liburd, B. Karlan, C. Walsh, I. Cass, A. Li Cedars–Sinai Medical Center, Los Angeles, CA Objective: The adipocyte-secreted hormone adiponectin influences the regulation of inflammation and angiogenesis, and serum concentrations are determined not only by adiposity but also by genetic factors and nutrition. Translational studies indicate adiponectin may exert antiproliferative effects in cancer biology, but data in pancreatic cancer suggest elevated levels promote carcinogenesis. We sought to examine the correlation between serum adiponectin and clinical outcome in a cohort of women with epithelial ovarian cancers. After institutional review board approval we queried the institutional tumor registry for consecutive patients with ovarian cancer with available banked fasting prediagnostic serum. All patients underwent cytoreductive surgery with histologically confirmed epithelial ovarian or primary peritoneal cancer, followed by platinum-based chemotherapy. We assayed frozen serum for adiponectin using ELISA (R&D, Inc.) and abstracted clinicopathologic data from medical records. Adiponectin levels were considered elevated if greater than 10.0 μg/mL. Statistical tests included rank correlation, Kaplan–Meier, and Cox regression analyses. Results: We examined serum and clinical data from 95 patients. Adiponectin concentrations ranged from 2.7 to 28.4 μg/mL (mean = 11.2); body mass index (BMI) ranged from 16.9 to 39.9 kg/ m2 (mean = 24.7). We did not determine a significant correlation between BMI and adiponectin (r = –0.21). Women with elevated adiponectin levels demonstrated statistically shorter diseasespecific survival (44 months) compared with those with normal levels (67 months) (P = 0.03). When examining the cohort in three strata (low, moderate, and high levels of adiponectin), we identified a significant trend of decreasing survival with increasing adiponectin concentration (median survival = 125, 58, and 44 months, respectively) (P = 0.02). On multivariate analysis, after controlling for BMI, age, stage, and grade, we determined that adiponectin and cytoreductive status retained significance as independent prognostic factors for overall survival (P = 0.02 and 0.004, respectively). Conclusions: These data suggest adiponectin concentration, independent of adiposity, is negatively associated with clinical outcome in this cohort. Translational studies and prospective trials are indicated to determine the role of adiponectin as a potential therapeutic target in women with ovarian cancer.

doi:10.1016/j.ygyno.2010.12.162

156 Evaluation of the risk of ovarian malignancy algorithm in women with a pelvic mass presenting to general gynecologists R. Moore1, C. Miller2, P. DiSilvestro1, L. Landrum3, W. Gajewski4, P. Renneisen5, S. Skates6 1 Women & Infants Hospital/Brown University, Providence, RI, 2Statistical Consultant, Quakertown, PA, 3University of Oklahoma, Oklahoma City, OK, 4New Hanover Regional Medical Center, Wilmington, NC, 5Fujirebio Diagnostics, Malvern, PA, 6Massachusetts General Hospital/Harvard University, Boston, MA Objective: Women with epithelial ovarian cancer (EOC) have improved outcomes when surgically managed by gynecologic

oncologists. It is often difficult to distinguish a benign pelvic mass from a malignancy, and tools to help referring physicians are needed. The objective of this trial was to validate the Risk of Ovarian Malignancy Algorithm (ROMA) in a population of women presenting to a gynecologist with a pelvic mass. This was an institutional review board-approved multicenter blinded prospective trial. All women had a pelvic mass and surgical intervention. Serum levels of HE4 and CA-125 were determined preoperatively. An initial clinical assessment (ICA) was performed by a gynecologist. A ROMA risk was calculated for each patient. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values were calculated for ROMA, ICA, and ROMA plus ICA. Results: Thirteen sites enrolled 512 women with 468 evaluable patients, of whom 255 were premenopausal and 213 were postmenopausal. There were 48 cases of EOC (8 stage I, 4 stage II, 32 stage III, two stage IV, and two unstaged), 18 low-malignantpotential (LMP) tumors, 21 cases of nonepithelial ovarian cancer, and 381 benign cases. In evaluation of premenopausal women with benign tumors (n = 235) versus EOC (n = 8), ROMA had a sensitivity of 100% (95% CI = 63.1–100%) and a specificity of 74.5% (95% CI = 68.4–79.9%). In postmenopausal women with benign tumors (n = 146) versus EOC (n = 40), ROMA had a sensitivity of 92.5% (95% CI = 79.6–98.4%) and a specificity of 76.0% (95% CI = 68.3–82.7%). In all women with benign tumors (n = 381) versus EOC (n = 48), ROMA had a sensitivity of 93.8% (95% CI = 82.8–98.7%), a specificity of 75.1% (95% CI = 70.4–79.3%), a PPV of 32.1% (95% CI = 24.5– 40.6%), and a NPV of 99.0% (95% CI = 97.0–99.8%). In contrast, the ICA had a sensitivity of 83.3% (95% CI = 69.8–92.5%), a specificity of 84.5% (95% CI = 80.5–88.0%), a PPV of 40.4% (95% CI = 30.7–50.7%), and a NPV of 97.6% (95% CI = 95.3–98.9%). In analysis of benign versus EOC and LMP tumors, ROMA had a sensitivity of 87.9% (95% CI = 77.5–94.6%) and a specificity of 75.1% (95% CI = 70.4–79.3%), whereas the ICA had a sensitivity of 75.8% (95% CI = 63.6–85.5%) and a specificity of 84.5% (95% CI = 80.5–88.0%). In analysis with the combination of ICA and ROMA in benign versus EOC and LMP tumors, the two methods together had a sensitivity of 90.9% (95% CI = 81.3– 96.6%) and a specificity of 66.9% (95% CI = 62.0–71.6%). Of the 8 cases of EOC the ICA missed, ROMA detected 5 (3 stage I or II and 2 stage III or IV). Conclusions: ROMA has a high sensitivity for evaluating women with a pelvic mass for EOC. ROMA should be used in conjunction with ICA to aid in the triage of women to gynecologic oncologists.

doi:10.1016/j.ygyno.2010.12.163

157 Factors associated with hospice use in ovarian cancer C. Casey, H. Deshmukh, A. Sherman, L. Chen, J. Chan UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA Objective: The purpose of this study was to determine the factors and trends in hospice use in patients with ovarian cancer in the Medicare population. All women aged 65 and older who were diagnosed and died of ovarian cancer between 1991 and 2002 were identified from the Medicare–SEER database. χ2 analyses were used to examine hospice use and length of stay in hospice. Results: Among 8740 patients, the overall rate of hospice use was 30.5% (n = 2667). Of these patients, 29.8% were white and 41.3% were black. The proportions of patients aged 65–70, 71–75, 76–80, and >80 years were 30.4, 32.3, 30, and 29.7%, respectively. The median

ABSTRACTS / Gynecologic Oncology 120 (2011) S2–S133

length of stay was constant (approximately 30 days) across all age groups. Hospice was used by 28% of married women versus 33% of widowed and/or single women. There was an association between higher income (<$30,000, $30,000–$75,000, and >$75,000) and decreased hospice use (35.4, 21.6, and 19%). Over the periods 1991– 1994, 1995–1998, and 1999–2002, hospice use varied from 35.17% to 36.7% to 22.7%, while the average length of stay remained constant (32.2 days vs 32.09 days vs 31.9 days). Conclusions: In this patient cohort, race and income level are factors associated with hospice use. Factors associated with hospice use can help guide the development of palliative care programs to improve the quality of care given to patients with ovarian cancer.

doi:10.1016/j.ygyno.2010.12.164

158 Genes functionally regulated by methylation in ovarian cancer are involved in cell proliferation, development and morphogenesis K. Yamaguchi1, T. Baba2, I. Konishi2, N. Matsumura2, S. Murphy1, Z. Huang1, A. Berchuck1 1 Duke University Medical Center, Durham, NC, 2Kyoto University, Kyoto, Japan Objective: Gene promoter methylation leads to transcriptional repression, but genomewide relationships between methylation and expression in ovarian cancer (OVCA) have not been reported. We sought to elucidate genes directly regulated by methylation using genomic approaches and determine the biologic functions targeted by this epigenetic modification. Illumina HumanMethylation27 BeadChip (HM27) data and Affymetrix HT HG-U133A (Affy) expression data (generated following culture ± DNMT inhibitor decitabine) for the same 32 OVCA cell lines were analyzed. HM27 and Affy data for 508 TCGA OVCAs were also analyzed. Pearson correlation analysis identified "Genes Functionally Regulated by Methylation" (GFRM) showing: (1) positive correlation between methylation and expression induction by decitabine, and (2) inverse correlation between methylation and expression in mock-treated cells. Methylation status was confirmed using MS-PCR. Gene functions were analyzed using Web-based GATHER software. GSE6008 (OVCAs) and GSE5846 (NCI60 cell lines) were used for validation. Results: We identified 225 genes as GFRM. MS-PCR showed that six of 6 GFRM (DAPK1, IER3, IGFBP3, KLK10, KRT7 and VEGFC) exhibit methylation; mRNA expression also differed between methylated and unmethylated groups (P < 0.05). GFRM included Gene Ontology annotations of "Cell Proliferation" (P = 0.0002), "Development" (P = 0.00006), and "Morphogenesis" (P = 0.00016). Hierarchical clustering of 51 OVCA cell lines by GFRM identified two major clusters with different population doubling times (P < 0.0001). Hierarchical clustering of GSE6008 and GSE5846 generated histology-based clusters. Two GSE5846 clusters also showed different population doubling times (P = 0.008). Conclusions: Using genomic approaches, we have identified 225 GFRM in OVCA that are involved in regulating cell proliferation and morphologic development. Distinct patterns of methylation based on growth characteristics and histologic type may be useful toward development of disease biomarkers.

doi:10.1016/j.ygyno.2010.12.165

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159 Horm-A domain-containing protein 1 (HORMAD1) and outcomes in patients with ovarian cancer M. Shahzad1, K. Matsuo2, Y. Shin3, R. Stone4, J. Bottsford-Miller4, C. Lu4, H. Han4, A. Rajkovic3, A. Sood4 1 University of Wisconsin School of Medicine and Public Health, Madison, WI, 2University of Southern California, Los Angeles, CA, 3University of Pittsburgh Medical Center, Pittsburgh, PA, 4University of Texas M.D. Anderson Cancer Center, Houston, TX Objective: HORMAD proteins are recognized for their role in cell cycle regulation and meiosis. Recent data indicate a potentially oncogenic role for HORMAD1 in breast carcinoma. However, the clinical and biologic significance of HORMAD1 in ovarian carcinoma is not known. In vitro effects of HORMAD1 silencing on 2774 ovarian cancer cell viability, invasion, and migration were determined. In vivo targeting of HORMAD1 using siRNA incorporated into DOPC nanoliposomes was done in a well-characterized orthotopic mouse model of ovarian carcinoma (2774). Additionally, we evaluated HORMAD1 mRNA levels using quantitative RT-PCR from 92 human epithelial ovarian tumors and looked for potential correlations with clinical outcome. Results: Compared with normal cells, ovarian cancer cells had high expression of HORMAD1. In vitro HORMAD1 siRNA treatment in 2774 ovarian cancer cells resulted in a >80% reduction (P < 0.05) in the IC50 of docetaxel. Hormad1 siRNA and docetaxel treatment increased apoptosis by 53% compared with docetaxel treatment alone (P < 0.05). HORMAD1 siRNA reduced 2774 ovarian cancer cell invasion and migration by 65 and 42% (both P < 0.05), respectively. In therapy experiments (2774 ovarian cancer model), HORMAD1 siRNA-DOPC or cisplatin treatment resulted in 45 and 81% (P < 0.05, both) reductions in tumor weight. Combination treatment resulted in a 94% reduction in tumor weight compared with control treatment (P < 0.01) and a further 72% reduction in tumor weight compared with cisplatin monotherapy (P < 0.05). Similar results were noted with tumor nodules and ascites formation. HORMAD1 siRNA-DOPC or cisplatin treatment alone resulted in 38 and 62% reductions in microvessel density (MVD) (P < 0.05), respectively compared with control siRNA-DOPC treatment. Combination treatment resulted in a 75% (P < 0.05) reduction in MVD compared with control siRNA-DOPC and a further 20% reduction in MVD compared with cisplatin alone. Levels of HORMAD1 mRNA were increased in 76.1% of ovarian cancer specimens (fold change >1). Median fold change of HORMAD1 expression was 5.6-fold higher (range: 0.23–1297.5) than that of the normal ovarian epithelium. FIGO stage and preoperative CA-125 values were associated with therapy response (P < 0.01). Patient age, preoperative CA-125 level and chemotherapy response significantly affected overall survival. High levels of HORMAD1 were significantly associated with the presence of ascites (P = 0.01). Conclusions: HORAMD1 expression is frequently increased in ovarian carcinoma. Our data indicate that HOMRAD1 may be an important therapeutic target.

doi:10.1016/j.ygyno.2010.12.166

160 Human epididymis protein 4 increases specificity for the detection of invasiive epithelial ovarian cancer in premenopausal women presenting with an adnexal mass K. Holcomb1, C. Miller2, Z. Vucetic2, R. Knapp3 1 Weill Medical College of Cornell University, New York, NY, 2Fujirebio Diagnostics, Inc., Malverne, PA, 3Harvard Medical School, Boston, MA