Abstract 896: Serum-vascular endothelial growth factors (sVEGF) A and C have a potential as predictive tests for neoadjuvant bevacizumab in primary breast cancer
Authors: Linderholm Barbro K. , Minckwitz Gϋnter von , Caramuta Stefano , André Fabrice , Sotiriou Christos , Cerone Maria A. , Schwenkglenks Matthias , Blank Patricia , Denkert Carsten , Gade Stephan , Loibl Sibylle 
Published: May 2015

Abstract
Background: Vascular endothelial growth factor (VEGF) is the major angiogenic factor in human cancer; VEGF-A is the most studied cytokine; VEGF-C is also involved in lymphatic development and both can act through binding to VEGFR2. Bevacizumab (Bev) is a humanized antibody directed towards VEGF with a modest effect in unselected HER2-negative breast cancer (BC). Patients & Methods: These VEGFs were determined in the randomized GeparQuinto trial investigating Bev as neoadjuvant treatment for HER2-negative BC (von Minckwitz et al N Eng J Med 2012). Patients were randomized to neoadjuvant chemotherapy with ECx4 and docetaxelx4 with or without concomitant Bev. VEGF-A, VEGF-C and VEGFR2 (VEGFs) were determined in serum samples prior to any treatment by use of commercial enzyme-linked immuno assays (Quantikine, R & D Systems, Minneapolis, USA). Serum levels of VEGF-A; -C and R2 were analyzed as dichotomized variables and correlated with pathological complete response (pCR, ypT0 ypN0) at surgery. Results: The VEGFs were determined in 830 (43%) trial participants of which 289 had triple negative (TN) and 541 hormone receptor positive (HR+) BC. The median age was 48 years (range 42-56), 81% had a ductal cancer and 44% were grade III. Median levels were 295.0 range 160-497 pg/mL for VEGF-A; 2102 range 1576-2588 pg/mL for VEGF-C; and 2328 range 1887-2913 pg/mL for VEGFR2, respectively.
STEPP (subpopulation treatment effect pattern plot) analyses revealed a potential predictive value for all 3 VEGF's. In dichotomized analyses, TNBC patients with high VEGF-C had a higher chance of pCR with Bev in univariate analysis [interaction OR=4.4; p= 0.010] and multivariate analysis (interaction OR=6.5; p= 0.005) adjusted for age (≥ 50y vs. &lt; 50y), histological type (ductal vs. lobular vs. others), grade (III vs. I-II), tumor stage (stage 4 vs. 1-3) and nodal status (node-negative vs. node positive). High VEGFR2 was correlated with pCR in univariate analysis [interaction OR=7.9; p= 0.017] whilst no effect was seen in multivariate analysis. HR+BC patients with high VEGF-A had an increased chance of pCR in univariate analysis [interaction OR=25.7; p&lt; 0.001] and multivariate analysis [OR=29.4; p&lt; 0.001].
A total 37.7% of the TNBC were classified as having high VEGFC and 31.2% obtained a pCR; 44.8% with Bev vs. 15.7% without Bev. A total of 89.3% of the TN patients were classified as “high VEGFR2” with a pCR rate of 31.4%; 39.5% with Bev vs. 23.9% without Bev. In the HR+ group, 41.6% were classified as having high VEGFA with a pCR rate of 6.7%; 11% with Bev vs. 2.6% without Bev.
Conclusions: Results from the prospective GeparQuinto study demonstrate that VEGFs determined in serum can function as predictive tests for chemotherapy+/-Bev in the neoadjuvant setting. Prominent findings were a predictive value for bevacizumab for VEGF-C in TNBC and for VEGF-A in HR+BC.
Citation Format: Barbro K. Linderholm, Gϋnter von Minckwitz, Stefano Caramuta, Fabrice André, Christos Sotiriou, Maria A. Cerone, Matthias Schwenkglenks, Patricia Blank, Carsten Denkert, Stephan Gade, Sibylle Loibl, on behalf of the GBG neoadjuvant board and the RESPONSIFY consortium. Serum-vascular endothelial growth factors (sVEGF) A and C have a potential as predictive tests for neoadjuvant bevacizumab in primary breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 896. doi:10.1158/1538-7445.AM2014-896