Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination

Abstract

Introduction: Traditional factors currently used for prognostic stratification do not always adequately predict treatment response and disease evolution in advanced breast cancer patients. Therefore, the use of blood-based markers, such as circulating tumor cells (CTCs), represents a promising complementary strategy for disease monitoring. In this retrospective study, we explored the role of CTC counts as predictors of disease evolution in breast cancer patients with limited metastatic dissemination.

Methods: A total of 492 advanced breast cancer patients who had a CTC count assessed by CellSearch prior to starting a new line of systemic therapy were eligible for this analysis. Using the threshold of 5 CTCs/7.5 ml of blood, pretreatment CTC counts were correlated in the overall population with metastatic site distribution, evaluated at baseline and at the time of treatment failure, using Fisher's exact test. Time to visceral progression and time to the development of new metastatic lesions and sites were estimated in patients with nonvisceral metastases and with single-site metastatic disease, respectively, by the Kaplan-Meier method. Survival times were compared between groups according to pretreatment CTC count by logrank test.

Results: In the overall population, a pretreatment level ≥5 CTCs/7.5 ml was associated with an increased baseline number of metastatic sites compared with <5 CTCs/7.5 ml (P = 0.0077). At the time of treatment failure, patients with ≥5 CTCs/7.5 ml more frequently developed new metastatic lesions and sites compared with those with <5 CTCs/7.5 ml (development of new lesions: P = 0.0002; development of new sites: P = 0.0031). Among patients with disease originally confined to nonvisceral sites, ≥5 CTCs/7.5 ml was associated with remarkably shorter time to visceral metastases (P = 0.0021) and overall survival (P = 0.0006) compared with <5 CTCs/7.5 ml. In patients with single-site metastatic disease, ≥5 CTCs/7.5 ml was associated with a significant reduction of the time to development of new metastatic sites (P = 0.0051) and new lesions (P = 0.0002) and with worse overall survival (P = 0.0101).

Conclusion: Our results suggest that baseline CTC counts can be used as an early predictor of metastatic potential in breast cancer patients with limited metastatic dissemination.

Figure 1

Association of baseline circulating tumor cell counts with metastatic spread in the overall population. (A) and (B) Rates of development of new metastatic sites (A) and new lesions (B) refer to the first progression of disease (PD) after baseline in the overall population (N = 492), stratified by circulating tumor cell (CTC) count. (C) Number of new metastatic sites that had developed by the first PD after baseline in patients whose disease had progressed in new sites (n = 121), stratified by CTC count.

Figure 2

Association of baseline circulating tumor cell counts with visceral disease spread. (A) Types of the first progression of disease (PD) occurring after baseline in 149 patients with disease initially confined to nonvisceral organs, stratified by circulating tumor cell (CTC) count. Thirty-seven (19.9%) of the total of one hundred eighty-six patients without baseline visceral metastases had not developed PD before the last follow-up visit. (B) and (C) Time to visceral disease (B) and overall survival (C) in the 186 patients without visceral metastases, stratified by CTC count.

Figure 3

Association of baseline circulating tumor cell counts with metastatic spread in patients with single-site disease. (A) Type of the first progression of disease (PD) occurring after baseline in 112 patients with single metastatic site disease, stratified by circulating tumor cell (CTC) count. Thirty-four (23.3%) of the total one hundred forty-six patients with single-site disease had not developed PD before the last follow-up visit. (B), (C) and (D) Time to new metastatic sites (B), time to new metastatic lesions (C) and overall survival (D) in the 146 patients with single metastatic site disease, stratified by CTC count.