Background: The prognostic significance of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTCs after adjuvant therapy increases the risk of subsequent relapse and death.Patients and Methods: Individual patient data from 676 women with primary diagnosis of early breast cancer stages I-III from 3 follow-up studies were pooled. During clinical follow-up, patients underwent BM aspiration (BMA) to determine the presence of DTC. Tumor cells were detected by the standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS).Results: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for DFS, distant DFS (DDFS), cancer-specific survival, and OS during the first 5 years following cancer diagnosis (log-rank test P < 0.001 values for all investigated endpoints).Conclusion: Among breast cancer patients, persistent DTCs during follow-up significantly predicted the increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials. Clin Cancer Res; 17(9); 2967-76. Ó2011 AACR.

Published by Elsevier B.V. All rights reserved. IntroductionGenome-wide expression profiling has demonstrated great power in deciphering molecular portraits of human breast tumors and has identified gene signatures that can be correlated to many different aspects of breast cancer such as tumor progression, prediction of outcome and sensitivity to therapy (Ayers et al., 2004;Chang et al., 2005Chang et al., , 2003Dai et al., 2005;Ma et al., 2003;Sorlie et al., 2001;van't Veer et al., 2002;Wang et al., 2004). Distinct subtypes that are associated with significant differences in overall and disease-free survival have been identified and validated in different patient cohorts (Bertucci et al., 2005;Sorlie et al., 2003;Sotiriou et al., 2003;Yu et al., 2004). Molecular profiling by microarray technologies will improve our understanding of primary tumor biology and the mechanisms behind tumorigenesis, and also provide