Abstract OT2-3-05: AVASTEM: a phase II randomized trial evaluating anti-cancer stem cell activity of pre-operative bevacizumab and chemotherapy in breast cancer
Authors: Gonçalves A , Pierga J-Y , Brain E , Tarpin C , Cure H , Esterni B , Boyer-Chammard A , Bertucci F , Jalaguier A , Houvenaeghel G , Viens P , Charaffe-Jauffret E , Extra J-M 
Published: August 2014

Abstract
Background: Bevacizumab (BEV) in combination with chemotherapy (CT) improved response rate and progression-free survival without detectable impact on overall survival (OS) in metastatic breast cancer (BC). BC contains population of cells that display stem-cell properties. These cancer stem cells (CSC) are known to be relatively insensitive to cytotoxic chemotherapies and might play a major role in treatment resistance and relapse. Complex interactions exist between CSC and angiogenesis: whereas CSC may secrete VEGF and pro-angiogenic factors and may stay in VEGF-dependant vascular niche, recent preclinical data indicate that antiangiogenics may increase breast CSC population via hypoxia. CSC proportion may be monitored in human BC using IHC staining of ALDH1. AVASTEM trial was designed to evaluate whether the addition of BEV to conventional CT alters the proportion of CSC in BC patients receiving neo-adjuvant (NA) CT.
Trial design: In this open-label phase II randomized study, patients are stratified by HER2 status and randomized 1:2 to receive NACT: – arm A (experimental): FEC100 (5FU 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) + BEV (15 mg/kg, 3-weekly) × 4 followed by Docetaxel (100 mg/m2) + BEV +/− trastuzumab (T, 8 mg/kg and then 6 mg/kg, 3-weekly) if HER2-positive, × 4– arm B (control): FEC100 × 4 followed by Docetaxel 100 +/− T if HER2-positive, × 4.
Tumor biopsies are required at baseline and after the first 4 cycles of FEC. After NACT, appropriate surgery and radiation therapy are performed, followed by adjuvant T and hormonal therapy, if indicated.
Eligibility criteria: - Primary HER2-positive or -negative BC candidate to NACT (inflammatory breast cancer and synchronous metastatic disease are eligible) – Primary BC accessible to initial biopsy– Left ventricular ejection fraction ≥ 55%– Appropriate haematological, liver, renal and coagulation functions
Specific aims: – Primary endpoint: to measure the variations of CSC proportion (by measuring the amount of IHC ALDH1-positive cells) in tumor biopsies obtained before C1 and after C4 in patients treated with BEV-based NACT or with NACT alone.– Secondary endpoints: tolerance, pCR, disease-free survival, recurrence-free survival and OS; ancillary studies (CSC characterization by CD44/CD24 IHC staining and evaluation of tumor-initiating properties of fresh tumor cells; CTC counts; contrast-based breast ultra-sonography; transcriptomics and proteomics)
Statistical design: The difference between percentage of ALDH1-positive cells after 4 cycles of BEV-based NACT and before treatment will be calculated. In the experimental arm, an equivalence test will be used to validate the hypothesis that the cell percentage does not increase more than 5% during treatment (under the following hypothesis: no difference of expression, difference variability σ = 13, significance level of 0.05, power of 0.8). With the assumption of approximately 20% of missing data, 50 patients will be included in the tested arm. The control arm (n = 25) is needed to confirm CSC increase during conventional CT.
Present and target accrual: By May June 2012, 69 patients have been included. A total of 75 patients are to be enrolled. Funded by INCA-PHRC 2009.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-05.