Abstract S6-6: High Independent Prognostic and Predictive Value of Circulating Tumor Cells in a Large Prospective Multicenter Trial Including Serum Tumor Markers in First Line Chemotherapy Metastatic Breast Patients
Authors: Pierga J-Y , Bachelot T , Delaloge S , Brain E , Campone M , Asselain B , Mathiot C , Hajage D , Bidard F-C. 
Published: April 2011

Abstract
Background: Circulating tumor cells (CTCs) in peripheral blood and decrease during treatment has been reported as an independent prognostic factor in metastatic breast cancer (MBC) (Cristofanilli M., NEJM 2004). Data comparing CTC with circulating tumor markers are limited. We conducted a multicenter prospective study to validate these markers in a large series of patients receiving specifically first line chemotherapy (CT) for MBC including assessment of CA15.3, CEA and LDH. Methods: CTC were measured in 7.5ml of whole blood at baseline, before cycle 2, at clinical and/or radiological evaluation (C3-C4) and at tumor progression. Analysis was performed using the CellSearch™ System, combining EpCAM immunomagnetic selection (IMS) followed by anti-cytokeratin (A45B/B3). Double labeling for HER2 was performed in a subgroup of patients. Tumor markers were assessed locally with ELISA kit and high if above normal.
Results: From 06/07 to 9/09, 267 patients with measurable or evaluable disease starting first line CT for MBC were included in five French Cancer Centers. Median follow-up was 16 months, 57 deaths and 160 progressions were observed. Median age was 57 years, 39 patients (15%) had HER2+ tumor and received trastuzumab, 55 (21%) had triple negative tumor, 125 received bevacizumab associated with CT, 260 were evaluable for CTC levels at baseline, 170 (65%) had ≥1CTC and 115 (44%) ≥5CTC. CTC HER2 status was assessed in 113 patients at baseline and was positive in 64% of the cases in at least one cell. CA15.3 was high in159/247 (64%), CEA in 109/212 (51%) and LDH in 99/220 (45%). CTC were highly correlated with tumor markers, tumor burden, performans status (PS), number of metastatic sites, liver metastasis) but were independent of tumor biology (HER2 status, Triple Negative BC (TNBC), grade). At first evaluation (C3-C4), 110/225 patients (49%) had objective response. At univariate analysis, high CTC level with a threshold of 1 or 5 at base line, before C2 (3-4w) and at radiological evaluation (C3-C4, 9-12w) was predictive of poor progression-free survival (PFS) and overall survival (OS) (p&lt;10-5). Baseline CA15.3, CEA and LDH were prognostic for PFS and LDH only for OS. At multivariate analysis, TNBC, PS ≥2, CTC ≥5, and high CEA were prognostic for PFS and TNBC, high LDH, CTC ≥5 and PS ≥2 for OS. Multivariate analyses including CTC and tumor markers variations during treatment are ongoing.
Conclusions: This is the largest prospective series validating the prognostic value of CTC in first line chemotherapy MBC independently from serum tumor marker for PFS and OS. Persistence of a high level of CTC before second cycle of chemotherapy is a strong and early predictive marker of poor PFS, before radiological evaluation. A prospective multicenter randomized trial (CIRCE01) to assess the use of CTC to modify treatment after second line chemotherapy is ongoing.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S6-6.