Abstract POSTER-TECH-1107: Primary platinum sensitivity in ovarian cancer and serum antibodies recognizing hypoxia-inducible factor 1-alpha and p53
Authors: Dao M. D. , Ovenell K. J. , Agnew K. J. , Swisher E. M. , Goff B. A. , Disis M. L. , Liao J. B. 
Published: August 2015

Objective: Overexpression of hypoxia inducible factor 1-alpha (HIF-1α), a protein associated with apoptosis resistance, angiogenesis and metastasis, correlates with aberrant p53 protein accumulation in ovarian cancer. Humoral immunity to tumor-associated antigens in ovarian cancer has been associated with prognosis. We hypothesize that serum IgG antibodies recognizing HIF-1α and p53 in ovarian cancer patients could predict primary platinum response in ovarian cancer.

Methods: Serum samples collected from ovarian cancer patients (n = 171) at the time of their initial surgery were analyzed by enzyme-linked immunosorbent assay for IgG antibodies to human recombinant HIF-1α and p53 proteins. The positive cut-off for each IgG antibody was derived at a serum level yielding highest hazard ratio of overall survival. Age, stage, grade, histology, neo-adjuvant therapy, surgical outcome, primary platinum response, and overall survival (OS) were correlated with serum IgG antibody levels.

Results: Ovarian cancer patients were mostly stage III/IV (94%) with serous histology (85%), and the majority were optimally debulked (74%). Primary platinum sensitive patients (n = 116) had significantly higher IgG antibody levels than primary platinum resistant patients (n = 55) (median 0.83 µg/mL vs. 0.0 µg/mL, p = 0.001 for HIF-1α and median 6.37 µg/mL vs. 2.69 µg/mL, p =0.001 for p53). Humoral immune competence among cancer patients was not significantly different between primary platinum sensitive and resistant groups. Multivariate analysis of overall survival associated age and advanced stage with adverse survival, while elevated levels of serum HIF-1α IgG(≥ 0.32 µg/mL, HR = 0.57, p = 0.012) and p53 IgG (≥ 2.8 µg/mL, HR = 0.58, p = 0.024) were favorable prognostic factors. Multivariate logistic regression revealed HIF-1α and p53 -specific IgG antibody levels to be independent predictors of primary platinum sensitivity (OR=3.28, 95% CI 1.55 – 6.94, p = 0.002 for HIF-1α and OR = 4.61, 95% CI 2.11 – 10.1, p &lt; 0.001 for p53). A model predicting sensitivity to adjuvant platinum-based treatment that includes only 2 factors, HIF-1α and p53 IgG antibody levels, yields an AUC = 0.710 and bests one containing 6 clinical variables (age, stage, histology, grade, surgical outcome, neoadjuvant treatment) which reaches AUC = 0.688. Our selected model of 4 factors: HIF-1α and p53 IgG antibody levels, stage, and neoadjuvant treatment, achieves comparable discrimination (AUC = 0.797) with a comprehensive model of 2 serum biomarkers and 6 clinical factors (AUC = 0.802).

Conclusion: Viable strategies for the primary treatment of ovarian cancer have expanded beyond intravenous carboplatin and paclitaxel every 3 weeks after primary cytoreductive surgery to include alternate dosing, neoadjuvant chemotherapy, intraperitoneal administration, and the addition of novel biologic agents such as bevacizumab, yet there are no biomarkers to guide which patients derive the most benefit from these treatments, despite significant differences in their toxicities, cost, and associated quality of life. The ability of serum antibodies recognizing tumor associated antigens at time of diagnosis to identify patients most likely to achieve a durable response to platinum based chemotherapy may allow the selection of primary treatment to be optimized and improve response rates.

Citation Format: M. D. Dao, K. J. Ovenell, K. J. Agnew, E. M. Swisher, B. A. Goff, M. L. Disis, J. B. Liao. Primary platinum sensitivity in ovarian cancer and serum antibodies recognizing hypoxia-inducible factor 1-alpha and p53 [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1107.