Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

Abstract

About 70% of breast cancers are hormone receptor (HR) positive, meaning an estrogen receptor (ER) and/or a progesterone receptor (PgR) are present in the tumor. Compounds that modulate ER or PgR signaling, by either competing for estrogen binding to estrogen receptors (synthetic estrogen receptor modulators [eg, tamoxifen]) or opposing the production of estrogen in the body (aromatase inhibitors in postmenopausal women), are dominant among those used to treat HR-positive breast cancer. Although HRpositive tumors are associated with a better prognosis, in the case of advanced disease, most will develop resistance to hormonal treatments over time. Multiple mechanisms of endocrine resistance have been proposed, including ER receptor loss and cross-talk between the ER and HER2/neu (human epidermal growth factor receptor 2; also known as ErbB-2) receptor signaling pathways. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway may result from genetic alterations in critical components in this pathway. Therapeutic targeting of alternate pathways of growth signaling in ER-positive tumors has the potential to translate into practice-changing therapeutic strategies. This article discusses the concept of primary and secondary endocrine resistance, outlines the proposed mechanisms, and reviews the emerging evidence for interventions designed to overcome resistance and restore ER sensitivity. The recently reported result of the BOLERO-2 study using an mTOR inhibitor (everolimus or RAD001) in combination with an aromatase inhibitor (exemestane) is discussed in some detail.

Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer

“…In vitro, combining ER targeted therapies with IGF1R inhibitors has been shown useful [213], but dual targeting in clinical phase III studies has so far failed to show any benefit ( [218] and references therein). As mentioned above, the use of mTOR inhibitors in combination with aromatase inhibitors has been shown successful [7] and is today clinically approved.…”

Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

“…The appearance of mutations in the ligand-binding domain of ER-α has led to the emergence of resistance mechanisms and stimulated interest in developing selective estrogen receptor degraders (SERDs). This novel class of ER ligands can potentially overcome resistance mechanisms by utilizing a pathway that involves ER-antagonism and removal from the signaling pathway …”