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

• Published in: Oncotarget Vol. 7; no. 39; pp. 64089 - 64099
• Main Authors: Wong, Andrea L.A., Sundar, Raghav, Wang, Ting-Ting, Ng, Thian-C, Zhang, Bo, Tan, Sing-Huang, Soh, Thomas I.P., Pang, Angela S.L., Tan, Chee-Seng, Ow, Samuel G.W., Wang, Lingzhi, Mogro, Jannet, Ho, Jingshan, Jeyasekharan, Anand D., Huang, Yiqing, Thng, Choon-Hua, Chan, Ching-Wan, Hartman, Mikael, Iau, Philip, Buhari, Shaik A., Goh, Boon-Cher, Lee, Soo-Chin
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 27.09.2016
• Subjects: Adult; Aged; Anthracyclines - administration & dosage; Antineoplastic Agents - administration & dosage; Biomarkers, Tumor; Breast Neoplasms - drug therapy; Contrast Media; Cyclophosphamide - administration & dosage; Disease-Free Survival; Doxorubicin - administration & dosage; Drug Administration Schedule; Female; Humans; Immunohistochemistry; Indoles - administration & dosage; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Preoperative Period; Pyrroles - administration & dosage; Research Paper; Treatment Outcome; sunitinib; anti-angiogenic therapy; neoadjuvant chemotherapy; vascular normalization; breast cancer
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11596

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 efficacy. 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 identified. 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. 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 significantly 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 (Ktrans: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 significantly altered by chemotherapy alone. Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.