Abstract LB-76: Tissue biomarkers and interstitial fluid pressure in a phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC)
Authors: Boucher Yves , Martin John D. , Tolaney Sara M. , Seano Giogio , Goel Shom , Ancukiewicz Marek , Isakoff Steven J. , Winer Eric P. , Krop Ian E. , Jain Rakesh K. 
Published: August 2014

Purpose: Recent studies evaluating the efficacy of bev in BC have shown conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive biomarkers and their relationship to the pharmacodynamic effects of bev would facilitate the identification of BC patients (pts) most likely to benefit from bev. To examine this, we conducted a unique preop phase II trial with a run-in of single agent bev followed by dose-dense AC-T with bev in two cohorts, one with HR+HER2- BC pts, and a smaller triple negative (TN) BC pts.

Methods: Pts with HR+, HER2- or TNBC were eligible. Treatment consisted of a single dose of bev 10 mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, followed by T 175 mg/m2 x1. Core biopsies and interstitial fluid pressure (IFP) were assessed pre- and post- bev alone. Pathologic response was confirmed centrally and Miller-Payne (MP) was assessed.

Results: The study enrolled 84 pts with HR+ and 20 pts with TN BC. Amongst HR+ pts, 79 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. Amongst TN BC pts, 19 pts had tissue centrally reviewed and 9 (47%) had a pCR. Grade was found to predict MP response in both HR+ and TN pts (p=0.001). Tissue biomarkers and IFP were evaluated as predictors of response to bev. Single-agent bev reduced the mean IFP in the overall cohort and HR+ patients by 20 (p=0.020) and 24.5% (p=0.001), respectively. The IFP decreased &gt; 50% in 24/65 pts and did not change in others. Bev reduced the mean vascular density (MVD) by 33.0% (p&lt;0.05) in TN BC pts, but did not affect the vessel area fraction covered by perivascular cells (PCs). Bev did not modify the fraction of tumor tissue positive for the hypoxia marker CAIX. In TN BC pts, pre- and post-bev, the MVD was inversely correlated with the CAIX fraction (p&lt;0.01). In addition, a drop in MVD associated with increased CAIX+ fraction post-BEV (p=0.05). MP score was more favorable for TN BC pts with lower CAIX+ fraction at baseline (p=0.058) and post-BEV (p&lt;0.05), and higher MVD at baseline (p&lt;0.05) and post-BEV (p&lt;0.05). In contrast, in HR+ BC, BEV reduced MVD non-significantly by 15% (p=0.25) and increased the vessel area fraction covered by PCs (p&lt;0.05). There was no significant correlation between MVD and CAIX+ fraction in HR+ BCs. In contrast to TN BC, in HR+ BCs the fraction of CAIX+ tumor was directly correlated with MP score (p&lt;0.01).

Discussion: Collectively, these results indicate that vascular pruning post-BEV may reduce vascular function and increase hypoxia, which is associated with less favorable pathologic response after BEV with chemotherapy in TN BC. In conclusion, our exploratory study suggests that elevated hypoxia and reduced MVD in TN BC reduces the effectiveness of chemotherapy.

Citation Format: Yves Boucher, John D. Martin, Sara M. Tolaney, Giogio Seano, Shom Goel, Marek Ancukiewicz, Steven J. Isakoff, Eric P. Winer, Ian E. Krop, Rakesh K. Jain. Tissue biomarkers and interstitial fluid pressure in a phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC) [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-76. doi:10.1158/1538-7445.AM2013-LB-76