Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer.

Manuel Feisst,Markus Wallwiener,Chiara Fischer,Marc Sutterlin,Klaus Pantel,Andreas D. Hartkopf,Fabian Riedel,Sara Y. Brucker,Christoph Domschke,Thomas M. Deutsch,Andreas Schneeweiss,Stefan Stefanovic,Carlo Fremd

doi:10.3390/cancers12041055

Abstract

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.

Highlights

Significant strides have been made in recent years, but metastatic breast cancer (MBC) is still associated with a poor prognosis [1,2,3]
107 patients were excluded from the analysis due to missing circulating tumor cells (CTC) enumeration at baseline, 229 patients due to missing CTC enumeration after one cycle of systemic therapy, 132 patients due to missing follow-up data, missing clinical data, false or double inclusions, or withdrawal of patients consents for further participation
108 patients were included in the analysis with a median of 41.0 days (inter quartile range (IQR: 29.0–58.5) between CTC enumeration at baseline and after one cycle of systemic therapy. 64 (59.3%) patients showed stable disease or partial response (SD) and 44 (40.7%) experienced disease progression (PD) at three months (Table 1)

Summary

Introduction

Significant strides have been made in recent years, but metastatic breast cancer (MBC) is still associated with a poor prognosis [1,2,3]. The presence of circulating tumor cells (CTCs) in the peripheral blood prior to treatment was found to be an independent poor prognostic factor in MBC patients [4,5,6,7,8,9]. CTCs can guide the therapy approach by distinguishing between aggressive and indolent metastatic disease [10]. They can be used to monitor treatment response [11,12,13] and have even shown greater prognostic utility than imaging in a single study [14]. The phenotypic characteristics of CTCs are different from those of the primary tumor and may be predictive for the metastatic tumor phenotype [15,16]

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