Breast cancer complexity: implications of intratumoral heterogeneity in clinical management.

Generation of intratumoral phenotypic and genetic heterogeneity has been attributed to clonal evolution and cancer stem cells that together give rise to a tumor with complex ecosystems. Each ecosystem contains various tumor cell subpopulations and stromal entities, which, depending upon their composition, can influence survival, therapy responses, and global growth of the tumor. Despite recent advances in breast cancer management, the disease has not been completely eradicated as tumors recur despite initial response to treatment. In this review, using data from clinically relevant breast cancer models, we show that the fates of tumor stem cells/progenitor cells in the individual tumor ecosystems comprising a tumor are predetermined to follow a limited (unipotent) and/or unlimited (multipotent) path of differentiation which create conditions for active generation and maintenance of heterogeneity. The resultant dynamic systems respond differently to treatments, thus disrupting the delicate stability maintained in the heterogeneous tumor. This raises the question whether it is better then to preserve stability by preventing takeover by otherwise dormant ecosystems in the tumor following therapy. The ultimate strategy for personalized therapy would require serial assessments of the patient's tumor for biomarker validation during the entire course of treatment that is combined with their three-dimensional mapping to the tumor architecture and landscape.