AVASTEM - Stem cells inhibition by bevacizumab in combination with neoadjuvant chemotherapy for locally advanced breast cancers: A prospective proof of concept randomized phase II trial
CANCER RESEARCH(2019)
Abstract
Abstract Background. Preclinical works have suggested that conventional cytotoxic chemotherapies may increase the number of cancer stem cells. Angiogenesis inhibition has been described in vitro to have an impact on stem cells proliferation. We developed a proof of concept clinical trial to explore Bevacizumab-chemotherapy activity on breast cancer stem cells for patients treated in the neoadjuvant setting. Patients and Methods. Breast cancer patients requiring preoperative chemotherapy were included in this open-label, randomized, prospective, multicentre phase II trial. All received FEC-docetaxel combination for a maximum of 8 cycles, and patients randomized in the experimental arm received concomitant Bevacizumab (15 mg/kg Q3W). The primary endpoint was to describe aldehyde dehydrogenase (ALDH1, identified by immunohistochemistry) positive tumour cells rate before treatment and after the 4th cycle. Secondary objectives included safety, pathological complete response (pCR) rate, disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). Results. Seventy-five patients were included from March 2010 to July 2012, including 50 in the experimental arm. More than 80% of patients received all planned chemotherapy cycles. ALDH1 expression could be assessed both before treatment and after the fourth cycle of chemotherapy for 32 patients. The absence of a significant increase (> 5%) in ALDH1+ cells rate after chemotherapy was demonstrated in the Bevacizumab arm (n=19, Median=-0.125, one-sided 95%CI=[-∞-0], p=0.001).Yet, the same was observed in the control arm (n=13, Median=-0.25, one-sided 95%CI=[-∞-0],, p=0.006). Grade 3 or 4 adverse events, including haematological, digestive, and cutaneous disorders, were observed for 94% of the patients in the experimental arm and 88% in the control arm. A non-significant increase in pCR was observed in the Bevacizumab arm (OR=2.24, 95CI [0.77-6.54], p=0.14), but survival was not improved (OS: p=0.89 for the whole cohort; DFS: p=0.45; and RFS: p=0.68 for non-metastatic cases) . ALDH1 status at inclusion was not correlated to efficacy. Conclusions. We observed that the rate of ALDH1+ tumour cells did not increase after Bevacizumab-based chemotherapy. However, as similar results were observed with chemotherapy only, Bevacizumab impact on breast cancer stem cells cannot be confirmed. Citation Format: Sabatier R, Charafe-Jauffret E, Pierga J-Y, Curé H, Lambaudie E, Houvenaeghel G, Ginestier C, Sfumato P, Extra J-M, Gonçalves A. AVASTEM – Stem cells inhibition by bevacizumab in combination with neoadjuvant chemotherapy for locally advanced breast cancers: A prospective proof of concept randomized phase II trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-10-02.
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Key words
advanced breast cancers,bevacizumab,neoadjuvant chemotherapy,avastem cells inhibition
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