Abstract 4645: Plasma cytokine and angiogenic factor (CAF) profiling for identification of markers associated with clinical benefit from bevacizumab (BEV) and with primary tumor presence in a phase II presurgical study of metastatic renal cell carcinoma (mRCC) patients
Authors: Yetil Alper , Jonasch Eric , Wang Xuemei , Wood Christopher , Matin Surena , Tran Hai T. , Tannir Nizar M. , Heymach John V. , Zurita Amado J. 
Published: August 2014

Purpose: The main objectives of this exploratory analysis were to identify biomarkers in blood associated with clinical benefit from bevacizumab, and to assess CAF changes related to nephrectomy (Nx) in mRCC.

Methods: Plasma samples were obtained from 44 pts participating in a frontline presurgical study of bevacizumab in clear cell mRCC (22 pts treated with BEV and&#x2028; 22 pts with BEV and erlotinib) (Jonasch et al. J Clin Oncol 2009), before treatment (BL), after 8 weeks of therapy/pre-nephrectomy (Nx), after 16 weeks of therapy/postNx, and every 4 weeks thereafter. Multiplex bead suspension arrays and ELISA were used to measure concentrations of 58 CAFs including VEGF, VEGF-C, placental growth factor (PlGF), soluble CAIX (sCA9), hepatocyte growth factor (HGF), osteopontin (OPN), matrix metalloproteinase-9 (MMP9), transforming growth factor (TGF)b1, endoglin, type IV collagen (ColIV), and multiple chemokines and interleukins (IL). CAFs were correlated with progression-free survival (PFS), overall survival (OS), and best response in primary and metastatic disease (% relative to BL).

Results: Of 58 CAFs available at BL, high (above median) concentrations of TRAIL and ColIV were associated with longer PFS (7.6 v 2.8 and 8.1 v 2.9 months [mos], respectively; both P=0.001) and OS (27.9 v 13.2 and 32.8 v 14.3 mos, respectively; P=0.023 and P=0.025). In addition to high TRAIL, low levels of VEGF and PlGF also showed a significant association with enhanced response both in primary disease and metastases (all P&lt;0.05). The combination BEV+erlotinib resulted in differential modulation of several CAFs relative to BEV from BL to preNx, including E-selectin, TRAIL and stem cell factor (SCF). Multiple CAFs, most prominently sCA9, endoglin, OPN, VEGF, HGF, and E-selectin, significantly decreased postNx, while TRAIL, SCF, and CTACK increased (relative to BL and also preNx; all P&lt;0.05).

Conclusions: We identified TRAIL, ColIV, VEGF and PlGF as candidate CAFs associated with clinical benefit from BEV in clear cell mRCC. The combination of BEV with erlotinib resulted in distinct on treatment CAF changes. The integration of these data with CAF profiling studies in pts with non-metastatic RCC could help define CAF sets useful to assist in risk stratification of RCC pts and provide insights into the biology of RCC progression.

Citation Format: Alper Yetil, Eric Jonasch, Xuemei Wang, Christopher Wood, Surena Matin, Hai T. Tran, Nizar M. Tannir, John V. Heymach, Amado J. Zurita. Plasma cytokine and angiogenic factor (CAF) profiling for identification of markers associated with clinical benefit from bevacizumab (BEV) and with primary tumor presence in a phase II presurgical study of metastatic renal cell carcinoma (mRCC) patients [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4645. doi:10.1158/1538-7445.AM2013-4645