Implementing circulating tumor cells in routine practice of breast cancer management: overview of the interventional trials

In 2004, circulating tumor cells (CTC) enumeration by the CellSearch® technique at baseline and during treatment was reported to be associated with prognosis in metastatic breast cancer patients. In 2008, the first evidence of the impact of CTC detection by this technique on survival of cM0(i+) patients were reported. These findings were confirmed by other noninterventional studies, whereas CTC were also investigated as a surrogate for tumor biology, mainly for HER2 expression/amplification. The aim of this report is to present the current prospective large interventional studies that have been specifically designed to demonstrate that CTC enumeration/characterization may improve the management of breast cancer patients: STIC CTC METABREAST (France) and Endocrine Therapy Index (USA) assess the CTC-guided hormone therapy vs chemotherapy decision in M1 patients; SWOG0500 (USA) and CirCe01 (France) assess the CTC count changes during treatment in metastatic patients; DETECT III (M1 patients, Germany) and Treat-CTC (cM0(i+) patients, EORTC/BIG) assess the use of anti-HER2 treatments in HER2-negative breast cancer patients selected on the basis of CTC detection/characterization. These trials have different designs in various patient populations, but are expected to be the pivotal trials for CTC implementation in the routine management of breast cancer patients. in se rm -0 07 49 45 0, v er si on 2 27 N ov 2 01 2 Introduction – Background 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. 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/7.5ml 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/7.5ml 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 has suggested an adverse prognostic value of CTC detection in non metastatic 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 in se rm -0 07 49 45 0, v er si on 2 27 N ov 2 01 2 prognostic markers in the STIC CTC METABREAST trial and 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. in se rm -0 07 49 45 0, v er si on 2 27 N ov 2 01 2 STIC CTC METABREAST (France) Rationale: As stated above, baseline CTC count has unambiguously demonstrated its very good performance as an independent prognostic marker. Multivariate analyses performed in both the pooled analysis and in the IC 2006-04 study showed that the other independent prognostic factors were the performance status and hormone-receptor (HR) status. Oppositely, the other criteria that are frequently used to choose between hormone therapy and chemotherapy for the treatment of first line metastatic HR+ breast cancer patients (e.g. metastatic sites, metastasis-free interval.) were not independent prognostic factors. It has been then proposed that CTC count may be a better criterion for this important choice than the currently used empiric criteria, which have a low level of evidence (expert consensus). Design: In the STIC CTC METABREAST trial (NCT awaited), about 1000 HR+ M+ breast cancer patients will be randomized between the clinician choice and CTC count-driven choice (Figure 1). In the CTC arm, patients with ≥5 CTC/7.5ml will receive chemotherapy whereas patients with <5 CTC/7.5ml will receive endocrine therapy as first line treatment. Within each treatment category (hormone or chemotherapy), the treatment type will be the clinician choice, targeted therapy being allowed. The only difference between CTC and standard arms will be the rates of hormone therapy vs chemotherapy-based treatment. As every patient will receive a treatment, this pivotal trial has been designed to show a noninferiority of the CTC arm for PFS (primary clinical endpoint) and a superiority of the CTC arm for the medico-economics study (co-primary endpoint). This trial began in February 2012. Several secondary endpoints are pre-planned (subgroups analyses). Funding: The STIC CTC METABREAST trial has been funded by the French Ministry of Health (STIC program, #50%) and Veridex (#50%). The promoter is the Institut Curie (Paris). in se rm -0 07 49 45 0, v er si on 2 27 N ov 2 01 2