Abstract 4457: In Search of a novel EPO receptor: The clinical significance of the Eph connection
Authors: Nick Alpa M. , Stone Rebecca L. , Chang Bin , Liu Jinsong , Urbauer Diana , Mora Edna , Pecot Chad , Mangala Lingegowda , Han Hee-Dong , Vivas-Mejias Pablo , Sung Bokyung , Nishimura Masato , Matsuo Koji , Kannan Sankar , Zweidler-McKay Patrick , Alicea Rene N. , Armaiz-Pena Guillermo N. , Shahzad Mian , Haghpeykar Shyon , Hu Wei , Aggarwal Bharat , Lopez-Berestein Gabriel , Stein Martin , Brock Stephan , Jackson David , Sood Anil K. 
Published: June 2012

Abstract
Background: Treatment of chemotherapy-induced anemia with recombinant human erythropoietin (Epo) has been shown to reduce transfusion requirements and improve quality of life among patients with solid malignancies. Recent reports of negative outcomes among cancer patients receiving Epo raises the concern that Epo may promote tumor growth. Given the uncertain relevance of the erythropoietin receptor (EpoR) in mediating the tumor growth stimulatory effects of Epo, we identified Ephrin B4 (EphB4) as a novel alternate receptor for Epo. The current work tests if the clinical impact of Epo administration on prognosis was receptor-dependent in patients with epithelial ovarian cancer.
Methods: Immunohistochemistry was used to characterize receptor expression in 175 invasive epithelial ovarian cancers. An H-score characterizing EpoR and EphB4 expression was calculated for each clinical sample. Slides were scored by a gynecologic pathologist blinded to the clinical outcome. Clinical data was extracted and 5 year disease specific survival was calculated and correlated with degree of receptor expression as well as Epo administration.
Results: The mean age of patients was 58.2 (range 20-92). Eighty-five percent of patients had serous histology and 91% had high grade tumors. Ninety-six percent of patients had stage II-IV disease and 67% underwent optimal cytoreduction (defined as &lt;1cm residual disease). EpoR overexpression was noted in 79% of tumors and EphB4 overexpression was seen in 39%. Multivariate analysis revealed EphB4, but not EpoR overexpression to be an independent predictor of poor survival (HR 4.53 [95% CI 2.87-7.16], p&lt;0.001 vs. HR 1.21 [95% CI 0.72-2.02], p=0.47). Kaplan-Meier analyses indicate that high EphB4 was related to high mortality rate (3 years vs. 6.69 years, p&lt;0.0001), but EpoR overexpression was not (4.78 years vs. 5.88 years, p=0.64). Additionally, Epo treatment was related to higher mortality among patients with EphB4 overexpressing tumors (2.18 years vs. 4.52 years, p=0.0004), but not patients with high tumoral levels of EpoR (4.38 years vs. 5.28 years, p=0.19).
Conclusions: We identify EphB4 as a novel Epo receptor. Tumor overexpression of EphB4, and not EpoR, is associated with poor survival among patients with epithelial ovarian cancer. Epo treatment among patients with EphB4 overexpressing tumors results in decreased disease-specific patient survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4457. doi:10.1158/1538-7445.AM2011-4457