Unlike the great advances that have been made in reducing breast cancer mortality through the multidisciplinary treatment of primary disease, much less is understood about the natural history of metastatic disease, despite this being the single most significant predictor of poor outcome for patients. Currently, much of treatment decision-making concerning a patient with metastatic disease is based on the biological characteristics of their primary tumour. There is a growing appreciation, however, that metastases arise from clonal subpopulations of cells from a primary tumour that may be genetically and phenotypically heterogeneous. The metastases may also undergo successive rounds of clonal expansion and adaptation in response to selective pressures endured in the foreign microenvironment of new tissues and treatment. In fact, cancer progression and colonisation is likely to be underpinned by a collective cooperation between cellular, genomic and microenvironmental factors that generate diversity to facilitate treatment resistance and metastatic capability. The extent and overall clinical significance of this diversity in metastatic progression is still unclear, owing to the scarcity of samples of metastases that are available for molecular analysis.
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