Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial

SIMPLE SUMMARY: We recently published the results of the AVASTEM study, in which we explored the impact of the addition of an angiogenesis inhibitor (bevacizumab) to standard pre-operative chemotherapy for breast cancer. In this work, we aimed to identify biological parameters correlated to prognosis and treatment efficacy. To do so we explored if circulating tumor cells (CTCs), that are cells released by the tumor and that can be detected in the bloodstream of a patient; can predict the outcome of the women treated in this study. We also analyzed if bevacizumab concentration in the blood during treatment was associated with outcome, i.e., response to treatment and survival. We observed that CTCs detection before treatment initiation is associated with survival but was not correlated to local response to treatment. We moreover found that CTC status after three weeks of chemotherapy was not correlated to outcome as well as bevacizumab levels before and during treatment. However, bevacizumab concentration tended to be associated with an increase of hematological toxicities during the study. We thus show in this work that CTCs detection at baseline is prognostic for patients with breast cancer receiving a pre-operative chemotherapy-bevacizumab combination, and that this prognostic value was independent of tumor response. ABSTRACT: The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75–22.06), p = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17–10.52), p = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR (p = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19–12.67); p = 0.68 for OS and HR = 2.76; 95%CI (0.60–12.61); p = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.