Abstract LB-81: A study of circulating biomarkers of angiogenesis and inflammation in ER+ breast cancer (BC) versus triple-negative breast cancer (TNBC) patients enrolled in a phase II study of preoperative treatment with 1 cycle of Bevacizumab followed by standard chemo
Authors: Duda Dan G. , Tolaney Sara M. , Ancukiewicz Marek , Winer Eric P. , Krop Ian E. , Jain Rakesh K. 
Published: August 2014

Abstract
VEGF is one of the most potent pro-angiogenic factors. However, the benefit of blocking VEGF in patients with BC — despite its confirmed activity in many studies — remains unclear. The lack of improvement in overall survival seen with the anti-VEGF antibody bevacizumab with chemotherapy may reflect that its benefit is limited to an unknown subset of BC patients. We previously showed that high plasma concentration of the endogenous VEGF inhibitor sVEGFR1 (sFLT1) may be a biomarker of inherent tumor resistance to anti-VEGF agents in cancer patients. Moreover, we found that bevacizumab as well as 5 other anti-VEGF agents induce “pharmacodynamic” increases in circulating PlGF in cancer patients after treatment. Finally, we showed that resistance to treatment with anti-VEGF agents is often associated with elevation of plasma SDF1α levels.
Here, we measured circulating biomarkers in BC patients enrolled in a phase II study of bevacizumab alone (10mg/kg, 1 cycle) followed by bevacizumab with standard dose-dense Doxorubicin/Cyclophosphamide/Paclitaxel (ddACT) chemotherapy (NCT00546156). We evaluated 14 biomarkers of angiogenesis and inflammation in ER+ BC (n=84) and TNBC (n=20) pts. The primary endpoint was pathologic response, measured by the Miller-Payne (MP) score.
Only 6/74 centrally reviewed ER+ BC patients (9%) had a pathologic complete response (pCR). However, 8/18 TNBC patients (44%) who had tissue centrally reviewed had a pCR. This supports the hypothesis that the activity of bevacizumab may depend on BC subtype. Treatment was associated with predictable “pharmacodynamic” changes in the biomarkers evaluated (e.g., increase in PlGF) in all patients. However, we detected differential correlations between biomarkers and response. In the TNBC patients, we found that more favorable MP scores were directly associated with lower plasma sVEGFR1 and greater increase in plasma PlGF at day 14 and inversely associated with increase in plasma SDF1α at day 14 (ie, after bevacizumab alone). On the other hand, plasma IGF-1 increased during combination treatment (day 70) only in ER+ BC patients; plasma IGF-1 level at day 70 was associated with unfavorable MP scores.
In conclusion, the addition of bevacizumab to neoadjuvant ddACT chemotherapy showed promising pCR rates only in TNBC patients in this phase II study. Correlative data support further evaluation of plasma sVEGFR1, PlGF and SDF1α as response biomarkers for bevacizumab in TNBC. In addition, we detected the potential resistance biomarker value of increased plasma IGF-1 during ddACT chemotherapy.
Citation Format: Dan G. Duda, Sara M. Tolaney, Marek Ancukiewicz, Eric P. Winer, Ian E. Krop, Rakesh K. Jain. A study of circulating biomarkers of angiogenesis and inflammation in ER+ breast cancer (BC) versus triple-negative breast cancer (TNBC) patients enrolled in a phase II study of preoperative treatment with 1 cycle of Bevacizumab followed by standard chemo [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 LB-81. doi:10.1158/1538-7445.AM2013-LB-81