Abstract
BackgroundCirculating 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.MethodsThis 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.ResultsThere 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.ConclusionsLongitudinal 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 registrationNCT01322893. Registered on 25 March 2011.
Highlights
Circulating tumor cells (CTCs) carry independent prognostic information in patients with metastatic breast cancer (MBC) on different lines of therapy
The prognostic value increases over time, suggesting that changes in CTC count are clinically relevant
Several studies have been published in support of these results [2,3,4,5,6,7,8,9,10,11,12,13,14] and in 2014 a pooled analysis of data from 1944 patients confirmed that a CTC count of ≥ 5 cells per 7.5 mL blood is an independent predictor of worse progression-free survival (PFS) and overall survival (OS) in patients with MBC [15]
Summary
Circulating tumor cells (CTCs) carry independent prognostic information in patients with metastatic breast cancer (MBC) on different lines of therapy. 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. Most individual studies evaluating CTC count in MBC included patients regardless of prior lines of systemic therapy and baseline CTC was measured in a heterogeneous population of patients on different lines of treatment. The focus of these studies has primarily been on CTC evaluation before starting a new line of treatment or at the first post-treatment evaluation, but no studies have conclusively evaluated long-term monitoring of CTC dynamics. Recent studies have shown that detection of CTC clusters in patients with MBC adds prognostic value to CTC enumeration alone [12, 13, 17], but limited data are available on the prognostic value of CTC clusters in previously untreated patients with MBC before and during treatment [18]
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