Clinical management of breast cancer heterogeneity.

Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. Results of high-throughput molecular profiling studies have subsequently revealed the true extent of this heterogeneity. Further complicating this scenario, the heterogeneous expression of the oestrogen receptor (ER), progesterone receptor (PR), and HER2 has been reported in different areas of the same tumour. Furthermore, discordance, in terms of ER, PR and HER2 expression, has also been reported between primary tumours and their matched metastatic lesions. High-throughput molecular profiling studies have confirmed that spatial and temporal intratumour heterogeneity of breast cancers exist at a level beyond common expectations. We describe the different levels of tumour heterogeneity, and discuss the strategies that can be adopted by clinicians to tackle treatment response and resistance issues associated with such heterogeneity, including a rationally selected combination of agents that target driver mutations, the targeting of deleterious passenger mutations, identifying and eradicating the 'lethal' clone, targeting the tumour microenvironment, or using adaptive treatments and immunotherapy. The identification of the most-appropriate strategies and their implementation in the clinic will prove highly challenging and necessitate the adoption of radically new practices for the optimal clinical management of breast malignancies.