Abstract
Preclinical works have suggested cytotoxic chemotherapies may increase the number of cancer stem cells (CSC) whereas angiogenesis inhibition may decrease CSC proliferation. We developed a proof of concept clinical trial to explore bevacizumab activity on breast CSC. Breast cancer patients requiring preoperative chemotherapy were included in this open-label, randomized, prospective, multicenter phase II trial. All received FEC-docetaxel combination, and patients randomized in the experimental arm received concomitant bevacizumab. The primary endpoint was to describe ALDH1 (Aldehyde dehydrogenase 1) positive tumor cells rate before treatment and after the fourth cycle. Secondary objectives included safety, pathological complete response (pCR) rate, disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). Seventy-five patients were included. ALDH1+ cells rate increase was below the predefined 5% threshold in both arms for the 32 patients with two time points available. Grade 3 or 4 adverse events rates were similar in both arms. A non-significant increase in pCR was observed in the bevacizumab arm (42.6% vs. 18.2%, p = 0.06), but survival was not improved (OS: p = 0.89; DFS: p = 0.45; and RFS: p = 0.68). The increase of ALDH1+ tumor cells rate after bevacizumab-based chemotherapy was less than 5%. However, as similar results were observed with chemotherapy alone, bevacizumab impact on breast CSC cells cannot be confirmed.
Highlights
Breast cancer remains the first cancer in women in western countries [1]
We proposed to assess cancer stem cells (CSC) inhibition by a chemotherapy–bevacizumab combination compared to chemotherapy alone for breast cancer patients treated in the neoadjuvant setting
There was a trend in higher rates of lymph node involvement for non-metastatic patients included in arm B (N1: 52.4% vs. 77.3%; N2: 16.7% vs. 4.5%; N3: 2.4% vs. 9.1%; p = 0.06)
Summary
Breast cancer remains the first cancer in women in western countries [1]. Breast tumors can benefit from neoadjuvant chemotherapy to enhance the rate of conservative surgery [2,3,4,5]. VEGF proteins are released by tumor cells, bind to their receptors (mainly VEGFR1 and VEGFR2), and are involved in cell division, endothelial cell migration, extracellular matrix modifications, vessels permeability, and vessels survival [18,19,20]. A combination of chemotherapy and an anti-VEGF monoclonal antibody (bevacizumab) has been shown to improve progression-free survival in first-line metastatic breast cancer [21,22,23] as well as pathological response rates after neoadjuvant treatment [24,25] but failed to improve overall survival in both early and advanced settings. Similar results have been obtained with other types of advanced cancer with improvements of progression-free survival with small or no clinical impact on overall survival [26,27,28,29]
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