Gonzalez, Sergio E.

5077 Background: A standard of care (SOC) for the adjuvant treatment of ovarian and primary peritoneal cancer is a platinum-based intravenous (IV) chemotherapy doublet. Intraperitoneal (IP) chemotherapy is also a SOC, but the high incidence of grade 3/4 adverse events has limited its acceptance among clinicians. To identify genetic markers for completion of IP chemotherapy, we analyzed SNPs in four genes known to play a role in metabolism of platinum or taxane drugs. Methods: Patients diagnosed with primary or recurrent stage III or IV epithelial ovarian or primary peritoneal cancer who had primary or secondary debulking surgery at Mayo Clinic (Rochester, MN) between January 2007 and February 2009 followed by IP chemotherapy were included in this study. A cycle was defined as IV paclitaxel (135mg/m2) on day one, IP cisplatin (100mg/ m2) on day two, and IP paclitaxel (60mg/ m2) on day eight. With prior consent from the patient, peripheral blood was obtained before treatment for extraction of germline DNA. Using a custom Illumina BeadXpress 96-plex panel, SNPs in GSTM1 (N=7), ABCB1 (N=57), CYP3A4 (N=7), and CYP2C8 (N=25) were genotyped. The association between SNPs in these subsets of genes and completion of IP chemotherapy was analyzed using linear regression. Results: Thirty-seven patients were included in this study and 16 (43.2%) completed IP chemotherapy. Twenty-two out of the fifty-seven ABCB1 SNP’s were associated with the number of cycles (p<0.15). There were no significant associations for GSTM1, CYP3A4 and CYP2C8 SNP’s. The minor A allele at missense SNP rs2229109 in the ABCB1 gene was present in five (31.2%) who completed treatment and only one (4.8%) who did not (p<0.007). However, the later was due to catheter complication. There was no association between rs2229109 and overall or progression-free survival. Conclusions: Our findings suggest that SNP rs2229109 in ABCB1 gene is associated with completion of IP chemotherapy, and potentially, less toxicity from chemotherapy. Thus, these patients may be optimal candidates for IP chemotherapy. Further studies in a larger population are needed.

Abstract Despite advances in chemotherapeutic options over the last four decades, ovarian cancer remains the most lethal gynecologic malignancy with a cure rate that is essentially unchanged. A major barrier is lack of treatment-naïve, clinically- relevant in vivo models of epithelial ovarian cancer (EOC). To target this problem, we have developed low-passage in vivo models of EOC derived from patient primary debulking procedures at Mayo Clinic (Rochester, MN). Tumors were obtained from consented patients with suspected ovarian cancer, minced and injected into severe combined immunodeficiency (SCID) mice intraperitoneally for model establishment. To the date, we have heterotransplanted 129 EOC or ovarian malignant mixed mullerian (MMMT) tumors. The most common histologic subtype is serous (70.5%), followed by endometrioid (12.4%), clear cell (6.9%), and others (9.9%). The tumors were injected intraperitoneally into severe combined immunodeficiency (SCID) mice and the average time to moribund (TTM) was 174 +/− 83 days. In general, tumors grew faster with serial passages, TTM for epithelial tumors was 87 +/− 15 days and 19.5 +/− 3 days for MMMT. De novo ascites developed in 17 models and 24 models developed bowel metastasis, two clinically-relevant complications in late-stage ovarian cancer patients. Tumorgrafts were histologically similar to their source patient tumors and were positive for expression epithelial markers (pan-cytokeratin). The engraftment rate was 72.4% (n=87) after ≤ 6 months of lead-time, which is the average time to tumorgraft harvest. Passage of well-established tumorgrafts in SCID mice was successful in 88.6 % (n= 70) of all mice but only 56% (n=16) of athymic nude mice, consistent with prior studies demonstrating improved engraftment rates in more immunodeficient mice. Molecular characterization of tumorgrafts by array comparative genomic hybridization revealed similar gains and losses between the patient, early-passage, and later-passage tumorgraft tissues, indicating the tumorgrafts were genetically similar to their primary tumor. Analysis of tumorgrafts using the Affymetrix Human Plus 2.0 arrays revealed a predominance of previously described molecular subtypes C3, C4, and C5. Current investigations with both standard chemotherapy and novel targeted therapies are ongoing. Taken together, these models are as diverse as the patient population from which they are derived, produce clinically-relevant complications of EOC, maintain genetic fidelity in SCID mice, and are useful preclinical models for testing and development of novel therapeutics for ovarian cancer. High rates of engraftment are feasible. These tumorgrafts may help define predictors of response and eventually, lead to better treatments for patients. This work is funded by the Mayo Ovarian SPORE (CA136393) and the Minnesota Ovarian Cancer Alliance. 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 3274. doi:1538-7445.AM2012-3274

Abstract Purpose: To improve the significance of insulin-like growth factor–binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer. Experimental Design: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts. Results: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS. Conclusion: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting. Clin Cancer Res; 18(6); 1808–17. ©2012 AACR.