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, Raghav Sundar, Ting-Ting Wang, Thian-C Ng, Bo Zhang, Sing-Huang Tan, Thomas I P Soh, Angela S L Pang, Chee-Seng Tan, Samuel G W Ow, Lingzhi Wang, Jannet Mogro, Jingshan Ho, Anand D Jeyasekharan, Yiqing Huang, Choon-Hua Thng, Ching-Wan Chan, Mikael Hartman, Philip Iau, Shaik A Buhari, Boon-Cher Goh, Soo-Chin Lee, Andrea L A Wong, Raghav Sundar, Ting-Ting Wang, Thian-C Ng, Bo Zhang, Sing-Huang Tan, Thomas I P Soh, Angela S L Pang, Chee-Seng Tan, Samuel G W Ow, Lingzhi Wang, Jannet Mogro, Jingshan Ho, Anand D Jeyasekharan, Yiqing Huang, Choon-Hua Thng, Ching-Wan Chan, Mikael Hartman, Philip Iau, Shaik A Buhari, Boon-Cher Goh, Soo-Chin Lee

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 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.

Keywords: anti-angiogenic therapy; breast cancer; neoadjuvant chemotherapy; sunitinib; vascular normalization.

Conflict of interest statement

CONFLICTS OF INTEREST

All authors express no conflicts of interest in contributing to this work. This work has previously been presented in part [J Clin Oncol 30; 2012 (suppl, abstr 1064) and J Clin Oncol 32: 5s, 2014 (suppl, abstr 1060)].

Figures

Figure 1. CONSORT diagram: trial profile
Figure 1. CONSORT diagram: trial profile
Figure 2. Immunohistochemistry staining was performed at…
Figure 2. Immunohistochemistry staining was performed at baseline and after one cycle of chemotherapy plus sunitinib in a representative patient (200x magnification)
Compared with immunoreactivity levels in baseline tumors a. and c., chemotherapy plus sunitinib led to increased vascular normalization index [ratio of α-SMA(brown)/CD31(red)] b. and decreased lymphatic vessel density as determined by D2-40 d.

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