Oncotarget 64089 www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 39 Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer Andrea L.A. Wong 1,2,3 , Raghav Sundar 1,2 , Ting-Ting Wang 3 , Thian-C Ng 4 , Bo Zhang 4 , Sing-Huang Tan 1,2 , Thomas I.P. Soh 1,2 , Angela S.L. Pang 1,2 , Chee-Seng Tan 1,2 , Samuel G.W. Ow 1,2 , Lingzhi Wang 3,5 , Jannet Mogro 2 , Jingshan Ho 1,2 , Anand D. Jeyasekharan 1,2,3 , Yiqing Huang 1,2 , Choon-Hua Thng 6 , Ching-Wan Chan 7 , Mikael Hartman 7 , Philip Iau 7 , Shaik A. Buhari 7 , Boon-Cher Goh 1,2,3,5 , Soo-Chin Lee 1,2,3 1 Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore 2 Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore 3 Cancer Science Institute, National University of Singapore, Singapore 4 Clinical Imaging Research Centre, National University of Singapore, Singapore 5 Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 6 Department of Diagnostic Imaging, National Cancer Centre, Singapore 7 Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore Correspondence to: Soo-Chin Lee, email: csilsc@nus.edu.sg Keywords: vascular normalization, anti-angiogenic therapy, sunitinib, neoadjuvant chemotherapy, breast cancer Received: January 31, 2016 Accepted: August 08, 2016 Published: August 25, 2016 ABSTRACT Background: Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy effcacy. Patients and Methods: In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identifed. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. Results: In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy signifcantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (K trans :12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not signifcantly altered by chemotherapy alone. Research Paper