Wong AL1,2,3, Sundar R1,2, Wang TT3, Ng TC4, Zhang B4, Tan SH1,2, Soh TI1,2, Pang AS1,2, Tan CS1,2, Ow SG1,2, Wang L3,5, Mogro J2, Ho J1,2, Jeyasekharan AD1,2,3, Huang Y1,2, Thng CH6, Chan CW7, Hartman M7, Iau P7, Buhari SA7, Goh BC1,2,3,5, Lee SC1,2,3
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.
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 wererandomized 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.
KEYWORDS: anti-angiogenic therapy; breast cancer; neoadjuvant chemotherapy; sunitinib; vascular normalization
- PMID: 27577069