Circulating tumor cells (CTC) designate cancer cells that are detected in the blood of cancer patients. Their detection, quantification, and characterization represent a new window on cancer dissemination and have opened major perspectives for both biological and clinical research on the metastatic process. Commonly accepted endpoints in clinical research for both nonmetastatic and metastatic breast cancer patients are detailed in Box 1. Technically, as most carcinomas do not have specific and recurrent DNA mutation or fusion transcripts, CTC isolation methods rely on the detection of cells that express epithelial-related markers in blood. Since the normal components of human whole blood are mesenchymally derived, they are not identified using this strategy; this principle is similar to the detection of isolated breast tumor cells in axillary lymph node in pN0(i+) breast cancer patients. In 2012, the standard for CTC detection remains the CellSearch® system (Veridex), which is still the only system that has been approved by the FDA for
in vitro diagnosis purposes. In 2004, a seminal study with this technique showed that CTC count was an independent prognostic factor for both progression-free (PFS) and overall (OS) survival in metastatic (M1) breast cancer patients [
1]. In this report, the threshold of ≥5 CTC/7.5 ml to define the poor prognosis group was “learned” from a training group (
n = 102 patients) and validated in another group of patients (
n = 75 patients). This prognostic value for PFS and OS has been repeatedly validated in smaller following studies [
2‐
4]. Unsurprisingly, a pooled analysis confirmed these results in multivariate analysis [
5]. A prospective study “IC 2006-04,” specifically designed and powered to assess the prognostic value of CTC count changes in patients treated by first-line chemotherapy (with or without targeted therapy), had the same conclusions in multivariate analysis and supported the use of the ≥5 CTC/7.5 ml threshold [
6]. Serum markers have been also prospectively assessed [
7] and were not prognostic markers in multivariate analysis. The only issue appeared with the use of targeted therapy, namely trastuzumab and bevacizumab, which decrease profoundly the CTC count: some reports suggested that this decrease might impact its prognostic value [
8,
9]. Moreover, recent data have suggested an adverse prognostic value of CTC detection in nonmetastatic breast cancer [
10‐
12]. At the same time, HER2 expression on CTCs using the CellSearch® system was studied in the neoadjuvant setting [
13] and across all breast cancer stages from preinvasive lesions to overt metastatic disease [
14].
With these numerous non-interventional studies published, interventional controlled “phase III” trials were needed to demonstrate that the use of CTC enumeration and monitoring could improve the outcome of breast cancer patients and/or lower the medical costs paid by the patient or its insurer. The aim of this article is to report and discuss the different interventional trials currently ongoing or on the edge of starting that have been set up by different CTC research groups in the world. Basically, CTCs are investigated as prognostic markers in the STIC CTC METABREAST trial and Endocrine Therapy Index (ETI) study, as early surrogate of chemotherapy efficacy in the SWOG0500 and in the CirCe01 trials, and finally as an indicator of tumor biology in the Treat CTC, DETECT III, and CirCe XXX1 trials.