title: 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.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.|Cancer Science Institute, National University of Singapore, Singapore.
authors: Andrea L A
authors: AL
authors: Wong
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Raghav
authors: R
authors: Sundar
authors: Cancer Science Institute, National University of Singapore, Singapore.
authors: Ting-Ting
authors: TT
authors: Wang
authors: Clinical Imaging Research Centre, National University of Singapore, Singapore.
authors: Thian-C
authors: TC
authors: Ng
authors: Clinical Imaging Research Centre, National University of Singapore, Singapore.
authors: Bo
authors: B
authors: Zhang
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Sing-Huang
authors: SH
authors: Tan
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Thomas I P
authors: TI
authors: Soh
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Angela S L
authors: AS
authors: Pang
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Chee-Seng
authors: CS
authors: Tan
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Samuel G W
authors: SG
authors: Ow
authors: Cancer Science Institute, National University of Singapore, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors: Lingzhi
authors: L
authors: Wang
authors: Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Jannet
authors: J
authors: Mogro
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Jingshan
authors: J
authors: Ho
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.|Cancer Science Institute, National University of Singapore, Singapore.
authors: Anand D
authors: AD
authors: Jeyasekharan
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.
authors: Yiqing
authors: Y
authors: Huang
authors: Department of Diagnostic Imaging, National Cancer Centre, Singapore.
authors: Choon-Hua
authors: CH
authors: Thng
authors: Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore.
authors: Ching-Wan
authors: CW
authors: Chan
authors: Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore.
authors: Mikael
authors: M
authors: Hartman
authors: Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore.
authors: Philip
authors: P
authors: Iau
authors: Department of Surgical Oncology, National University Cancer Institute, National University Health System, Singapore.
authors: Shaik A
authors: SA
authors: Buhari
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.|Cancer Science Institute, National University of Singapore, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors: Boon-Cher
authors: BC
authors: Goh
authors: Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.|Haematology Oncology Research Group, National University Cancer Institute, National University Health System, Singapore.|Cancer Science Institute, National University of Singapore, Singapore.
authors: Soo-Chin
authors: SC
authors: Lee
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy*; D003287:Contrast Media; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D057234:Preoperative Period; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003287:Contrast Media; D007211:Indoles; D011758:Pyrroles; D004317:Doxorubicin; D003520:Cyclophosphamide; D000077210:Sunitinib
keywords: anti-angiogenic therapy; breast cancer; neoadjuvant chemotherapy; sunitinib; vascular normalization