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When tackling endocrine resistance in breast cancer, the current strategies are focused around combining hormonal agents with drugs targeting several escape pathways, as outlined in the mechanisms of endocrine resistance section. The aim is to block all the tumour survival escapes.

The main approach in overcoming endocrine resistance in those breast cancers that are both ER+ and HER2+ is by using a combination of endocrine and HER2-targeting agents.

In trials conducted with a combination of anti-HER2 agents and an aromatase inhibitor, significant clinical benefit and improved progression-free survival have been observed.

Trastuzumab is an example of an anti-HER2 agent which mainly depresses the growth of cells which are over-expressing HER2.

Many endocrine resistant breast cancers which don’t respond to aromatase inhibitors still depend on ER signalling.

Selective Estrogen Receptor Degraders (SERDs) can be used in these cases as they destabilize the ER and act as pure antagonists at the ER receptor. An example SERD is Fulvestrant which binds to the ER to block its dimerization and nuclear localisation. The fulvestrant-ER complex is unstable, resulting in degradation.

There has also been research into the combined inhibition of the ER and EGFR. An example of a pure EGFR inhibitor is gefitinib, which has been used in phase II trials to evaluate its addition to tamoxifen in patients with HR-positive advanced breast cancer.

The PI3K-Akt-mTOR signalling pathway and crosswalk with the ER signalling pathway is thought to be involved in the development of resistance to endocrine therapy. Therefore, studies have been done to assess the efficacy of using mTOR inhibitors, such as everolimus or temsirolimus, in ER-positive breast cancers.

Some preclinical and clinical studies have shown the possibility of mTOR inhibitors as a first step treatment to shrink the breast cancer tumour before the main treatment of an aromatase inhibitor is given. It is agreed that more clinical trials are needed to confirm this issue.

Additionally, CDK 4/6 inhibition has shown to improve the efficacy of endocrine treatment.