Circulating Endothelial Cells (CEC) as an Early Surrogate Marker and Circulating Tumor Cells (CTC) as a Prognostic Factor in Metastatic Breast Cancer (MBC) Patients Treated First-Line with Bevacizumab (Bv) and Chemotherapy (CT): A French Sub-Study of the Phase IIIb International Multicentre MO19391 Trial.
Authors: F. Bidard, C. Mathiot, A. Degeorges, P. Formento, M. Francoual, M. Coulon-Sfairi, M. Espié, P. De Cremoux, C. Levaché, F. Dalenc, L. Bobadilla, G. Milano, J. Pierga
Journal: Cancer Research (2009)

Abstract Background: Detection of circulating tumor cells (CTC) is an independent prognostic factor in MBC. A decrease of CTC during treatment is associated with a better outcome (Cristofanilli, NEJM 2004). The antiangiogenic agent Bv, in combination with CT, (i) improves progression free survival (PFS) of first line treatments, (ii) may modify tumor cell intravasation and CTC count, and (iii) may change CEC levels. We therefore investigated whether CTC and CEC counts could be early surrogate markers of time to progression (TTP) in MBC patients receiving a highly active anti-tumor treatment (HAATT) comprising taxanes combined with Bv.Methods: Eligible patients received Bv (10mg/kg q2w or 15mg/kg q3w) combined with a taxane–based CT or non-anthracycline CT, until disease progression, unacceptable toxicity or withdrawal. For patients participating in the sub-study, CTC and CEC were measured in 7.5ml of blood at baseline and after cycle 2 or 3 of treatment. Analysis was performed using the CellSearch™ System, combining EpCAM immunomagnetic selection (IMS) followed by anti-cytokeratin (A45B/B3) staining for CTC and CD146 IMS and CD105 staining for CEC. VEGF-A constitutional polymorphisms from blood (2578C&amp;gt;A, -1498T&amp;gt;C, -634G&amp;gt;C, 936C&amp;gt;T) were also analyzed in the same patients. CTC and CEC counts at baseline and changes during treatment were correlated with TTP.Results: Sixty-seven patients were included. There was no correlation between CTC, CEC levels and VEGF-A polymorphisms. At baseline, using the threshold of 5 CTC/7.5 ml which was previously defined with standard CT: (i) CTC positivity (54% of patients) was associated with elevated LDH (p=0.04), elevated CA15.3 (p&amp;lt;0.001) and high tumor burden (&amp;gt;3 metastatic sites) (p=0.03); (ii) CTC was a significant prognostic marker for TTP at a threshold of 3 CTC/7.5 ml (p&amp;lt;0.05) and not at 5 CTC/7.5 ml (p=0.09). Baseline CEC levels (median:17, range [1-769]) were associated with age ≥45y (p=0.01), with elevated LDH (p&amp;lt;0.01) and not with TTP at any threshold. In our series, changes of CTC count during treatment was not a surrogate for TTP, with any of the model tested (threshold-based or relative decrease in %). However, changes of CEC count during treatment was significantly associated with TTP, at the threshold of 20 (p&amp;lt;0.001).Conclusion: Our study is the first to monitor both CTC and CEC levels in the era of HAATT comprising an antiangiogenic agent combined with standard CT. We observed that previously reported CTC thresholds may be modified by antiangiogenic therapy, whereas changes in CEC levels are a promising early surrogate marker for TTP under HAATT. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6087.