Longitudinal enumeration and cluster evaluation of circulating tumor cells improve prognostication for patients with newly diagnosed metastatic breast cancer in a prospective observational trial

Abstract

Background: Circulating tumor cells (CTCs) carry independent prognostic information in patients with metastatic breast cancer (MBC) on different lines of therapy. Moreover, CTC clusters are suggested to add prognostic information to CTC enumeration alone but their significance is unknown in patients with newly diagnosed MBC. We aimed to evaluate whether longitudinal enumeration of circulating tumor cells (CTCs) and CTC clusters could improve prognostication and monitoring of patients with metastatic breast cancer (MBC) starting first-line therapy.

Methods: This prospective study included 156 women with newly diagnosed MBC. CTCs and CTC clusters were detected using CellSearch technology at baseline (BL) and after 1, 3, and 6 months of systemic therapy. The primary end point was progression-free survival (PFS) and the secondary end point overall survival (OS). Median follow-up time was 25 (7-69) months.

Results: There were 79 (52%) and 30 (20%) patients with ≥ 5 CTCs and ≥ 1 CTC cluster at baseline, respectively; both factors were significantly associated with impaired survival. Landmark analyses based on follow-up measurements revealed increasing prognostic hazard ratios for ≥ 5 CTCs and CTC clusters during treatment, predicting worse PFS and OS. Both factors added value to a prognostic model based on clinicopathological variables at all time points and ≥ 5 CTCs and presence of CTC clusters enhanced the model's C-index to > 0.80 at 1, 3, and 6 months. Importantly, changes in CTCs during treatment were significantly correlated with survival and patients with a decline from ≥ 5 CTCs at BL to < 5 CTCs at 1 month had a similar odds ratio for progression to patients with < 5 CTCs at BL and 1 month. Stratification of patients based on CTC count and CTC clusters into four groups (0 CTCs, 1-4 CTCs, ≥ 5 CTCs, and ≥ 1 CTC + CTC clusters) demonstrated that patients with CTC clusters had significantly worse survival compared to patients without clusters.

Conclusions: Longitudinal evaluation of CTC and CTC clusters improves prognostication and monitoring in patients with MBC starting first-line systemic therapy. The prognostic value increases over time, suggesting that changes in CTC count are clinically relevant. The presence of CTC clusters adds significant prognostic value to CTC enumeration alone.

Trial registration: NCT01322893 . Registered on 25 March 2011.

Keywords: Circulating tumor cells (CTCs); Cluster; Enumeration; Metastatic breast cancer; Prognosis.

Conflict of interest statement

Ethics approval

The study was approved by the Ethics Committee at Lund University, Lund, Sweden (LU 2010/135).

Consent for publication

All included patients provided written informed consent for publication.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Flowchart of study cohort and time points for circulating tumor cell (CTC) analysis

Fig. 2

Progression-free survival (PFS) and overall survival (OS) by circulating tumor cell (CTC) count. Kaplan-Meier curves displaying PFS and OS by baseline (BL) CTC count (≥ 5 CTCs) (a-b), by CTC count at BL and 1 month (c-d), by CTC count at BL and 3 months (e-f) and by CTC count at BL and 6 months (g-h) during the first 6 months of systemic therapy for MBC. Analyses at 1, 3, and 6 months were performed using landmark analysis, in which the follow-up time was recalculated with a new starting date from the 1, 3, and 6-month sample, respectively

Fig. 3

Progression-free survival (PFS) and overall survival (OS) by circulating tumor cell (CTC) count and CTC cluster detection. Kaplan-Meier curves displaying PFS and OS by four groups including CTC count and CTC cluster detection at baseline (a-b) at 1 month (c-d), 3 months (e-f) and 6 months (g-h). The four groups were patients with no CTCs, patients with 1–4 CTCs and no clusters, patients with ≥ 5 CTCs and no clusters, and patients with > 1 CTC and clusters. Analyses at 1, 3, and 6 months were performed with landmark analysis where the follow-up time was recalculated with a new starting date from the 1, 3, and 6-month samples, respectively