New and emerging treatments for estrogen receptor-positive breast cancer: focus on everolimus

Abstract

Management of patients with metastatic hormone receptor-positive breast cancer poses a challenge due to the inevitable development of endocrine resistance. Hormone resistance is associated with a complex interaction of the estrogen receptor with growth factors, transmembrane receptors, and intracellular growth cascades. The PI3K/Akt/mTOR pathway plays a major role in hormone resistance and proliferation of breast cancer. Preclinical and clinical data indicate that inhibitors of human epidermal growth factor receptor-2, epidermal growth factor receptor, insulin-like growth factor-1 receptor, and the mammalian target of rapamycin pathway may act synergistically with hormone therapy to circumvent endocrine resistance. Everolimus is currently approved for combination with exemestane in postmenopausal women with advanced hormone receptor-positive breast cancer. However, we still need to unfold the full potential of targeted agents in the hormone-refractory setting and to identify the subsets of patients who will benefit from combination hormonal therapy using targeted agents.

Keywords: estrogen receptor-positive breast cancer; everolimus; hormone resistance; inhibition; mammalian target of rapamycin.

Figure 1

Crosstalk between the estrogen receptor and EGFR/HER2/IGF1R membrane tyrosine kinase receptors can lead to gene expression and cell growth independent of hormonal activation, mainly via activation of the MAPK and PI3K pathways. Notes: The estrogen receptor can also be regulated by these membrane receptors, which act as coactivators and lead to phosphorylation of estrogen receptors in the absence of estrogen (ligand-independent receptor activation). The PI3K/Akt/mTOR pathway is a major downstream cellular circuit, which leads to cell proliferation via the mTORC1 complex. The mTORC2 complex activates Akt, which in turn inhibits the proteolysis of cyclin D1/E. Abbreviations: EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth factor-1 receptor; mTOR, mammalian target of rapamycin; HER2, human epidermal growth factor receptor-2; ER, estrogen receptor; TSC1/2, tuberous sclerosis complex proteins 1/2; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; Src, steroid receptor coactivator.