Erin K. Crane

Differential platelet levels affect response to taxane-based therapy in ovarian cancer

Purpose: We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy. Experimental Design: The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro coculture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel. Results: Thrombocytosis at the diagnosis of ovarian cancer was correlated with decreased interval to progression (P = 0.05) and median overall survival (P = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet coculture protected against apoptosis (P < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (P < 0.05). Compared with mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (P = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (P < 0.05), blocked the effect of docetaxel on tumor growth (P = 0.55) and decreased tumor cell apoptosis. Pretransfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion. Conclusions: Platelet-driven effects of chemotherapy response may explain clinical observations. Clin Cancer Res; 21(3); 602–10. ©2014 AACR.

Molecular Biomarkers of Residual Disease after Surgical Debulking of High-Grade Serous Ovarian Cancer

Purpose: Residual disease following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of residual disease has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease. Methods: We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with residual disease and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using quantitative RT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for residual disease. Predictive success was evaluated using a one-sided Fisher exact test. Results: Forty-seven probe sets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold and had high expression levels associated with increased incidence of residual disease. In the validation cohort (n = 139), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a prespecified threshold, we found 30 of 35 cases of residual disease in the predicted high-risk group (positive predictive value = 86%) and 54 of 104 among the remaining patients (P = 0.0002; OR, 5.5). Conclusion: High FABP4 and ADH1B expression is associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy. Clin Cancer Res; 20(12); 3280–8. ©2014 AACR.

The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer.

OBJECTIVES We sought to determine the benefit of secondary cytoreductive surgery (SCRS) in patients with low-grade serous ovarian or peritoneal carcinoma, and whether cytoreduction to no gross residual disease affects survival. METHODS A single institution retrospective chart review was conducted in patients with recurrent low-grade serous carcinoma who underwent SCRS between 1995 and 2012. Data including demographics, survival, chemotherapy, disease characteristics at the time of surgery, residual disease, and operative complications were collected. Overall survival (OS) and progression-free survival (PFS) were calculated. Kaplan-Meier and log-rank tests were used to examine survival outcomes. RESULTS Forty-one patients met inclusion criteria. The median time between primary tumor debulking and SCRS was 33.2 months. Of 41 eligible patients who underwent SCRS, 32 (78%) had gross residual disease at the completion of secondary surgery. The median PFS for patients with no gross residual disease after SCRS was 60.3 months, compared to 10.7 months for patients with gross residual disease (p = 0.008). Median OS from diagnosis for patients with no gross residual disease after SCRS was 167.5 months compared to 88.9 months (p = 0.10). Median OS from the time of SCRS for patients with no gross residual disease was 93.6 months compared to 45.8 months (p = 0.04). Complications occurred in 61% of patients after SCRS; there were no deaths directly attributable to surgery. CONCLUSION Our results suggest a benefit to SCRS in patients with recurrent low-grade serous carcinoma. Efforts to maximally cytoreduce patients should be made as patients with no gross residual disease had a better PFS and a trend toward better OS.

Nutlin-3a: A potential therapeutic opportunity for TP53 wild-type ovarian carcinomas

Epithelial ovarian cancer is a diverse molecular and clinical disease, yet standard treatment is the same for all subtypes. TP53 mutations represent a node of divergence in epithelial ovarian cancer histologic subtypes and may represent a therapeutic opportunity in subtypes expressing wild type, including most low-grade ovarian serous carcinomas, ovarian clear cell carcinomas and ovarian endometrioid carcinomas, which represent approximately 25% of all epithelial ovarian cancer. We therefore sought to investigate Nutlin-3a—a therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis—as a therapeutic compound for TP53 wild-type ovarian carcinomas. Fifteen epithelial ovarian cancer cell lines of varying histologic subtypes were treated with Nutlin-3a with determination of IC50 values. Western Blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analyses quantified MDM2, p53, and p21 expression after Nutlin-3a treatment. DNA from 15 cell lines was then sequenced for TP53 mutations in exons 2-11 including intron-exon boundaries. Responses to Nutlin-3a were dependent upon TP53 mutation status. By qRT-PCR and WB, levels of MDM2 and p21 were upregulated in wild-type TP53 sensitive cell lines, and p21 induction was reduced or absent in mutant cell lines. Annexin V assays demonstrated apoptosis in sensitive cell lines treated with Nutlin-3a. Thus, Nutlin-3a could be a potential therapeutic agent for ovarian carcinomas expressing wild-type TP53 and warrants further investigation.

Abstract 2273: Mechanistic and functional implications of FABP4 in ovarian cancer metastasis

Purpose:The purpose of this study was to identify molecular predictors of residual disease (RD) in high grade serous ovarian cancer (HGSC) and further understand their role in promoting cancer metastasis. Method:The current study analyzed Affymetrix gene expression data of 504 HGSC cases from The Cancer Genome Atlas (TCGA) data to identify differentially expressed genes in tumors from patients with no gross residual disease after surgery (NRD) or presence of RD following initial debulking surgery. It was followed by qRT-PCR analysis of tumor samples for validation purposes. RPPA data of 354 patients from TCGA were analyzed. Immunohistochemical analysis was performed on the patient samples to determine the expression at the protein level (cancer versus stromal cells). Gene array was carried out after overexpressing the selected gene in ovarian cancer cells and the data was analyzed by Ingenuity Pathway Analysis (IPA). In vitro (migration and invasion) and in vivo (orthotopic mouse models) assays were used to determine the biological roles of gene(s) identified from the above analyses. Results: In TCGA data set, 97/107 (90.6%) of the patients with high expression of FABP4 gene had residual disease. In the validation cohort, among the 35 patients predicted to be at high risk for residual disease, 30 (86%) did have residual disease. In contrast, only 54 of the 104 patients with FABP4 values below the decision threshold (52%) had incomplete resection (p = 0.0002). RPPA analysis indicated that expression of FABP4 was positively correlated (Spearman correlation analysis) with expression of several other proteins known to increase tumor cell infiltration and metastasis such as JNK2 (p = 0.194), transglutaminase (p = 0.199), c-kit (p = 0.173), fibronectin (p = 0.364), PKC-A (p = 0.178), collagen-6 (p = 0.197) and paxillin (p = 0.239). It was negatively correlated with E-cadherin (p = -0.246) and claudin-7 (p = -0.201) expression. Immunohistochemical analysis confirmed that apart from endothelial cells and adipocytes, cancer cells also express significant amount of FABP4. In vitro assays showed significant reduction in invasion and migration after silencing FABP4 in HGSC cell lines (p Conclusion:These findings provide a new understanding of ovarian cancer metastasis and identify a potentially important target for therapeutic intervention. Citation Format: Kshipra M. Gharpure, Susan L. Tucker, Shelley M. Herbrich, Anna K. Unruh, Alpa M. Nick, Erin K. Crane, Robert L. Coleman, Jamie Guenthoer, Heather J. Dalton, Sherry Y. Wu, Rajesha Rupaimoole, Gabriel Lopez-Berestein, Bulent Ozpolat, Cristina Ivan, Wei Hu, Keith Baggerly, Anil Sood. Mechanistic and functional implications of FABP4 in ovarian cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2015-2273

Successful Laparoscopic Removal of Adnexal Mass in a Patient With a Large Ventral Hernia

After a fall, an 80-year-old woman was incidentally found to have an 11-cm cystic ovarian mass when computed tomography was performed. CA125 was within normal range. Family history was negative for any breast or ovarian cancers. The patient’s medical history was significant for a large asymptomatic ventral hernia, hypertension, dementia, hypothyroidism, history of deep vein thrombosis with permanent inferior vena cava filter, thrombocytopenia (baseline platelet count, 90 to 100), and irregular heartbeat requiring pacemaker placement. Her surgical history included a hysterectomy with left salpingo-oopherectomy to treat menorrhagia. The patient consented to undergo diagnostic laparoscopy, pelvic washings, and removal of the adenxal mass. Because of the asymptomatic nature of the patient’s hernia and her medical comorbidities, it was decided that primary repair of the ventral hernia would not be pursued. A left upper quadrant port site was used to enter the abdominal cavity. Insufflation of the abdomen with CO2 to

When less is more: Minimally invasive surgery compared to laparotomy for interval debulking after neoadjuvant chemotherapy in women with advanced ovarian cancer

STUDY OBJECTIVE To compare outcomes of advanced ovarian cancer patients who had minimally invasive surgery (MIS) with outcomes of advanced ovarian cancer patients who had laparotomy for interval cytoreduction after neoadjuvant chemotherapy (NACT). DESIGN Retrospective cohort study (Canadian Task Force classification II-2). SETTING One large teaching hospital with a tertiary referral function for gynecologic oncology and MIS. PATIENTS All consecutive patients with stages III to IV epithelial ovarian, tubal, or peritoneal cancer who underwent MIS or laparotomy for interval cytoreduction after at least 1 NACT cycle from 2006 to 2017 at 1 institution. INTERVENTIONS Patients underwent either MIS or laparotomy for interval cytoreduction after at least 1 cycle of NACT. MEASUREMENTS AND MAIN RESULTS Medical records were reviewed and data abstracted and analyzed. Survival was estimated by the Kaplan-Meier method, and outcomes were compared with Fishers exact test, Students t test, Wilcoxon rank sum test, and the log-rank test. In total, 157 assessable patients underwent interval cytoreductive surgery through MIS (n = 53) or laparotomy (n = 104). MIS was completed without conversion in 44 of 53 patients (83%), of whom 20 required a hand port and/or mini-laparotomy. R-zero and optimal resections were achieved in 60.4% and 96.3% of MIS patients respectively, compared with 42.3% and 82.7% of laparotomy patients (p = .02). MIS patients had lower estimated blood loss (EBL; 156 vs 278 mL, p <.001), fewer intraoperative transfusions (2% vs 17%, p = .006), and shorter hospital stay (3.0 vs 5.7 days, p < .001). Operative time was longer (171 vs 150 minutes, p = .007), but complications, intensive care unit stay, readmission, median progression-free survival (27 vs 29 months, p = .45), and median overall survival (37 vs 35 months, p = .74) were similar. CONCLUSION MIS is feasible and effective for interval cytoreduction after NACT in advanced ovarian cancer patients. MIS is associated with less EBL, lower transfusion rate, and shorter length of hospital stay with no difference in patient outcomes.