Intratumoral heterogeneity and subclonal diversification of early breast cancer.

Heterogeneity has long been recognized as a feature of some primary breast cancers manifesting as mixed histopathological subtypes or variable expression of the therapeutic targets ER, PgR and HER2. The recent emergence of next generation sequencing (NGS) technologies has revolutionized our understanding of the extent and nature of subclonal diversification. Careful examination of primary breast cancers often reveals multiple genomically distinct subclones that may contain driver alterations that follow spatial patterns of segregation. Subclonality is of clinical relevance as it forms the substrate of selection and can give rise to aggressive clinical features such as invasiveness, metastasis and treatment resistance. However, spatial and temporal intra-tumoral heterogeneity pose fundamental challenges to representative sampling and consequently the feasibility of a personalized medicine approach. Fundamental clinical and biological questions are starting to be addressed by applying NGS to the study of intra-tumoral heterogeneity and the insights that it provides should be used to better inform the prospective design of clinico-genomics trials.