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
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Andrea L.A. Wong1,2,3, Raghav Sundar1,2, Ting-Ting Wang3, Thian-C Ng4, Bo Zhang4, Sing-Huang Tan1,2, Thomas I.P. Soh1,2, Angela S.L. Pang1,2, Chee-Seng Tan1,2, Samuel G.W. Ow1,2, Lingzhi Wang3,5, Jannet Mogro2, Jingshan Ho1,2, Anand D. Jeyasekharan1,2,3, Yiqing Huang1,2, Choon-Hua Thng6, Ching-Wan Chan7, Mikael Hartman7, Philip Iau7, Shaik A. Buhari7, Boon-Cher Goh1,2,3,5, Soo-Chin Lee1,2,3
1Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore
2Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore
3Cancer Science Institute, National University of Singapore, Singapore
4Clinical Imaging Research Centre, National University of Singapore, Singapore
5Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore
6Department of Diagnostic Imaging, National Cancer Centre, Singapore
7Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore
Soo-Chin Lee, email: [email protected]
Keywords: vascular normalization, anti-angiogenic therapy, sunitinib, neoadjuvant chemotherapy, breast cancer
Received: January 31, 2016 Accepted: August 08, 2016 Published: August 25, 2016
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 efficacy.
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 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.
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 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.
Conclusion: 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.
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