Overcoming Endocrine Therapy Resistance in Breast Caner

Abstract

Estrogens are steroid hormones that regulate growth, differentiation and function in a broad range of target tissues in the body and the exposure to estrogens is an important determinant for risk of breast cancer. The biologic effects of estrogens are mediated through estrogen receptor (ER) αand β. Endocrine therapies first used more than 100 years ago and progressed toward an understanding of antigestrgen action and successful clinical development of antiestrogen for the treatment of breast cancer. Endocrine therapies are the most effective treatment for breast cancer expressing ER but resistance remained major problem. Endocrine therapy resistance is commonly associated with ER mutation, Aromatase mutation, loss of ER, pharmacogenetic change, change of coactivators and corepressors, and crosstalk between ER and growth factor pathways. Preclinical models demonstrate that growth factor receptor tyrosine kinase inhibitors can restore Tamoxifen resistance and delay acquired resistance to estrogen deprivation therapy. Several clinical trials have been reported the results about combined treatment of endocrine agents and target agents to overcome or delay endocrine resistance. The addition of trastuzumab to the aromatase inhibitor and tyrosine kinase inhibitor lapatinib to letrozole has significantly improved progression-free survival in ER-positive/HER2-positive metastatic breast cancer. Epidermal growth factor receptor (EGFR) inhibitor gefitinib combined with endocrine therapies demonstrated small benefit in ER-positive metastatic breast cancer. Target agents to downstream signal pathway, such as mammalian target of rapamycin (mTOR) inhibitor and farnesyltransferase inhibitors (FTIs), showed the possibility for combine aged to prevent endocrine resistance. We need to understand and evaluate various signaling elements from multiple networks that crosstalk with ER. Combined therapy with selected targeted agents remains a promising approach to enhancing the efficacy of current endocrine therapies for breast cancer.