Original Articles Circulating tumor cell thresholds and survival scores in advanced metastatic breast cancer: The observational step of the CirCe01 phase III trial C. Helissey a , F. Berger b,c , P. Cottu a , V. Diéras a,b , L. Mignot a , V. Servois d , C. Bouleuc e , B. Asselain b , S. Pelissier b , I. Vaucher e , J.Y. Pierga a,f,g, *, F.C. Bidard a,f a Department of Medical Oncology, Institut Curie, Paris, France b Department of Clinical Research, Institut Curie, Paris, France c INSERM U900, Paris, France d Department of Radiology, Institut Curie, Paris, France e Department of Supportive Care, Institut Curie, Paris, France f Circulating Tumor Biomarkers Laboratory, SIRIC, Institut Curie, Paris, France g University Paris Descartes, Paris, France ARTICLE INFO Article history: Received 22 December 2014 Received in revised form 5 February 2015 Accepted 7 February 2015 Keywords: Circulating tumor cells Metastatic breast cancer CirCe01 A B ST R AC T The clinical validity of circulating tumor cell (CTC) count changes during chemotherapy in metastatic breast cancer patients has been validated, but its clinical utility remains to be demonstrated. We report here the non-randomized run-in phase of the CirCe01 trial which was designed to evaluate CTC changes and thresholds to other palliative prognostic scores and establish CTC thresholds to be used in the ran- domized part of the study. CTC count (CellSearch®) and other prognostic parameters (serum albumin level, lymphocyte level, LDH level, prognostic inflammatory and nutritional index (PINI) and Barbot’s score) were assessed in 56 metastatic breast cancer patients before the first cycle of third line chemotherapy. Early changes of CTC count were correlated with treatment outcome. Independent prognostic markers in multivariate analysis were: low serum albumin (HR = 11.1), poor performance status (HR = 3.8), ≥5 CTC/ 7.5 ml (HR = 3.8) and triple negative subtype (HER2+ and hormone positive vs triple negative: both HR = 0.2). Among patients with ≥5 CTC/7.5 ml at baseline, a composite criteria (<5 CTC/7.5 ml or relative decrease ≥-70% of the baseline CTC count) showed better prognostication for PFS (p = 0.002). © 2015 Elsevier Ireland Ltd. All rights reserved. Introduction In 2004, using the CellSearch® system, circulating tumor cell (CTC) count has been reported to be a prognostic biomarker for progression-free (PFS) and overall (OS) survival in metastatic breast cancer patients [1]. Hazard ratios for different thresholds at base- line were not reported initially but are available online for progression-free survival (PFS; as of February 2015, https:// www.cellsearchctc.com/clinical-applications/interpretation-of- results): the hazard ratio curve appears flat between 2 and 10 CTC/ 7.5 ml but, as 5 was the median number of CTC detected, the p-value for difference was maximized with the ≥5 CTC/7.5 ml threshold. Using this threshold, changes in CTC count after one cycle of che- motherapy were also associated with PFS and OS [2]. Indeed, among patients with high CTC count (≥5 CTC/7.5 ml) before the first cycle (C1) of chemotherapy, those with ≥5 CTC/7.5 ml before the second cycle (C2) were shown to be at high risk of short PFS. Insufficient “early CTC response” therefore appeared as a promising biomarker for early detection of resistance to treatment in metastatic-breast cancer. However the real clinical utility of the CTC test had to be demonstrated in randomized trials. In 2006, the SWOG 0500 phase III trial (NCT00382018) was ini- tiated in the United States. This trial screened 600 metastatic breast cancer patients receiving first line chemotherapy for patients with no “early CTC response” [3]. For the sake of internal coherence, this trial was designed based on the thresholds that were previously used for FDA approval: patients with no CTC response were defined as having ≥5 CTC/7.5 ml at both days 1 and 21 – the second cycle of chemotherapy being postponed to day 28. One hundred and twenty patients were randomized between early switch to second line che- motherapy or the continuation of the first line chemotherapy until radiological progression. As disclosed on December 2013 and discussed beyond, this trial failed to reach both OS and PFS endpoints [4]. * Corresponding author. Tel.: +33 1 44 32 40 00; fax: +33 1 56 24 40 41. E-mail address: jean-yves.pierga@curie.fr (J.Y. Pierga). http://dx.doi.org/10.1016/j.canlet.2015.02.010 0304-3835/© 2015 Elsevier Ireland Ltd. All rights reserved. Cancer Letters 360 (2015) 213–218 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet