Circulating tumor cells in metastatic breast cancer: the need for a standardized approach

Abstract

Gradilone et al. [1.Gradilone A. Naso G. Raimondi C. et al.Circulating tumor cells (CTCs) in metastatic breast cancer (MBC): prognosis, drug resistance and phenotypic characterization.Ann Oncol. 2011; 22: 86-92Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] recently published a study addressing the prognostic and predictive value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) and its relation to drug resistance molecular profile and stemness markers. We know that CTCs are highly relevant to the study of the biology of the metastatic process. The detection and enumeration of CTCs has been shown to be a useful tool in predicting response and clinical outcome of the treatment of MBC patients. Current evidence suggests that patients with elevated CTCs levels (5 CTCs/7.5 ml of blood) have shorter progression-free survival (PFS) and overall survival [2.Cristofanilli M. Budd G.T. Ellis M.J. et al.Circulating tumor cells, disease progression, and survival in metastatic breast cancer.N Engl J Med. 2004; 351: 781-791Crossref PubMed Scopus (3521) Google Scholar, 3.Hayes D.F. Cristofanilli M. Budd G.T. et al.Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival.Clin Cancer Res. 2006; 12: 4218-4224Crossref PubMed Scopus (809) Google Scholar]. Moreover, it has been shown that elevated CTC values any time in the clinical course of MBC patients is indicative of impending disease and hence CTCs monitoring is proposed as a possibly better prognostic tool compared with functional imaging [3.Hayes D.F. Cristofanilli M. Budd G.T. et al.Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival.Clin Cancer Res. 2006; 12: 4218-4224Crossref PubMed Scopus (809) Google Scholar, 4.De Giorgi U. Valero V. Rohren E. et al.Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer.J Clin Oncol. 2009; 27: 3303-3311Crossref PubMed Scopus (128) Google Scholar]. In the present study, the authors defined patients with positive CTCs as those having at least one EpCAM-positive cell isolated by CELLection Dynabeads (CD45-, CK8+, CK20+) [1.Gradilone A. Naso G. Raimondi C. et al.Circulating tumor cells (CTCs) in metastatic breast cancer (MBC): prognosis, drug resistance and phenotypic characterization.Ann Oncol. 2011; 22: 86-92Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], differing from previous studies that count and dichotomized CTCs levels (<5 or ≥5) [2.Cristofanilli M. Budd G.T. Ellis M.J. et al.Circulating tumor cells, disease progression, and survival in metastatic breast cancer.N Engl J Med. 2004; 351: 781-791Crossref PubMed Scopus (3521) Google Scholar, 3.Hayes D.F. Cristofanilli M. Budd G.T. et al.Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival.Clin Cancer Res. 2006; 12: 4218-4224Crossref PubMed Scopus (809) Google Scholar, 4.De Giorgi U. Valero V. Rohren E. et al.Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer.J Clin Oncol. 2009; 27: 3303-3311Crossref PubMed Scopus (128) Google Scholar]. While Gradilone et al. demonstrated a shorter PFS for patients with positive CTCs expression, they added some controversy on the exact definition of CTC positivity. Although the drug resistance profile predicted a poor response to chemotherapy, the results were obtained in a population treated with different regimens. It would have been of value to know details of the chemotherapy used, whether single agent or combination. Furthermore, ∼50% of patients were known to be HER2 positive but were not offered anti-HER2-targeted therapy. It also would have been interesting to provide information regarding the breast cancer molecular classification, considering that it has recently been shown to correlate with CTCs dissemination [5.Lang J.E. Mosalpuria K. Cristofanilli M. et al.HER2 status predicts the presence of circulating tumor cells in patients with operable breast cancer.Breast Cancer Res Treat. 2009; 113: 501-507Crossref PubMed Scopus (66) Google Scholar]. All these factors along with the small sample size and lack of a control group should be taken into consideration when interpreting these data. Currently, the Southwest Oncology Group (SWOG) is addressing, in a prospective randomized trial, the issue of treatment decision based on CTCs blood levels. This study will determine, among women with MBC and elevated CTCs, the value of an immediate change of therapy versus waiting until classic clinic–radiological evidence of progressive disease. Both SWOG and the present study are interesting steps toward therapy individualization. However, one important issue remains open: what treatment should be chosen when CTCs levels rise, and how could this molecular chemosensitivity profile be used? Hence, we could interrogate ourselves regarding the real importance of learning about the CTCs biocharacteristics, molecular portrait of the most relevant signaling pathways and their drug resistance profiles. It would, indeed, help us to overcome the aggressiveness of metastatic disease in the era of personalized medicine. The authors have declared no conflicts of interest.