Synchronous detection of circulating tumor cells in blood and disseminated tumor cells in bone marrow predict adverse outcome in early breast cancer

Purpose: We examined the prognostic impact of circulating tumor cells(CTCs) and disseminated tumor cells (DTCs) detected at the time of surgeryin 742 untreated early breast cancer patients. Experimental Design: DTCs in bone marrow were enumerated using the EPCAM-based immunomagnetic enrichment and flow cytometry (IE/FC) assay. CTCs in blood were enumerated either by IE/FC or CellSearch. Median follow-up was 7.1 years for distant recurrence-free survival (DRFS) and 9.1 years for breast cancer-specific survival (BCSS) and overall survival (OS). Cox regressions were used to estimate hazard ratios for DRFS, BCSS and OS in all patients as well as in hormone receptor-positive (HR-positive, 87%) and HR-negative (13%) subsets. Results: In multivariate models, CTC-positivity by IE/FC was significantly associated with reduced BCSSin both all (n=288, p=0.0138) and HR-positive patients (n=249, p=0.0454). CTC-positivity by CellSearch was significantly associated with reduced DRFS in both all (n=380, p=0.0067) and HR-positive patients (n=328, p=0.0002). DTC status, by itself, was not prognostic; however, when combined with CTC status by IE/FC (n=273), double positivity (CTC+/DTC+, 8%) was significantly associated with reduced DRFS (p=0.0270), BCSS (p=0.0205), and OS (p=0.0168). In HR-positive patients, double positivity (9% of 235) was significantly associated with reduced DRFS (p=0.0285), BCSS (p=0.0357), and OS (p=0.0092). Conclusions: Detection of CTCs in HR-positive early breast cancer patients was an independent prognostic factor for DRFS (using CellSearch) and BCSS (using IE/FC). Simultaneous detection of DTCs provided additional prognostic power for outcome, including OS.