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Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools ( n  = 45) appeared less aberrant than the corresponding primary tumors (PT,  n  = 16).  PIK3CA  mutations were detected in 26% of DTC pools ( n  = 53), none of them were shared with matched PTs. Expression profiling of DTC pools ( n  = 30) confirmed the upregulation of  EPCAM  expression and certain oncogenes (e.g.,  MYC  and  CCNE1 ), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high  ESR1  and  VIM/CAV1  expression), and (2) basal-like with proliferative/stem cell-like phenotype (low  ESR1  and high  MKI67/ALDH1A1  expression). We observed high discordance between  ESR1  (40%) and  ERRB2  (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example,  ALDH1A1 ,  CAV1 , and  VIM  were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.

Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer