The oestrogen-dependent biology of breast cancer. Sensitivity and resistance to aromatase inhibitors revisited: a molecular perspective.

Endocrine treatment of breast cancer was the first molecular targeted anti-cancer therapy to reach clinical practice. Among the several options that share the common denomination of hormonal treatment, aromatase inhibitors (AIs) in the postmenopausal setting show the highest efficacy rates. These drugs have become the standard of care both in the advanced and adjuvant scenarios. Nevertheless resistance to AIs either upfront or after initial clinical response is almost a universal feature whenever tumour excision is not possible. Multiple reports have established the role of alternative pro-growth signalling pathways in the acquisition of resistance to the oestradiol deprivation that AIs produce. However the first clinical trials addressing the double blockade of both the oestrogen and other growing factor pathways raise some concerns on the efficacy of this approach. This review presents the evidence on the molecular events underpinning the response and resistance to AIs and suggests some key issues to consider when designing clinical research projects in this context.