Rational management of endocrine resistance in breast cancer

Abstract

Endocrine therapy for breast cancer was introduced more than 100 years ago. In the last 30 years, it has been demonstrated that tamoxifen significantly improves outcomes for patients with hormone-responsive breast tumors. Aromatase inhibitors, which suppress the production of estrogen, are recognized today as an KEYWORDS: endocrine therapy, metastatic breast cancer, fulvestrant, endocrine resistance, tamoxifen, aromatase inhibitors.T he influence of ovarian hormones on breast cancer was appreciated first more than 100 years ago, when Beatson demonstrated that inoperable breast tumors regress after oophorectomy. 2 Today, 2 classes of antihormone endocrine agents are considered the standard of care for primary treatment of earlyor late-stage HR1 breast cancer: tamoxifen, which blocks ER activity within tumor cells, and aromatase inhibitors (AIs), such as anastrozole, letrozole, or exemestane, which inhibit the production of estrogen through the aromatase enzyme pathway. Whereas tamoxifen is effective in both premenopausal and postmenopausal women, AIs are indicated only in women who are postmenopausal. In the adjuvant setting, several studies have demonstrated that AIs are tolerated well and offer improved disease-free survival compared with

Interferon Regulatory Factor-1 Signaling Regulates the Switch between Autophagy and Apoptosis to Determine Breast Cancer Cell Fate

“…The routine use of antiestrogens (AEs), such as tamoxifen (TAM) and fulvestrant (Faslodex; ICI 182,780; ICI), and aromatase inhibitors (AIs) including letrozole and anastrozole, are now established as effective therapies for the treatment of breast cancer (2, 3). The widespread use of endocrine therapy is a major contributor leading to the decline in breast cancer mortality in women with ER+ disease (4). However, clinical efficacy of these therapies is often limited by aberrations in prosurvival and prodeath signaling leading to drug resistance.…”

Delineation of a FOXA1/ERα/AGR2 Regulatory Loop That Is Dysregulated in Endocrine Therapy–Resistant Breast Cancer

“…Specifically, ERα can be effectively targeted at the level of (a) receptor activity, using selective estrogen receptor modulators (SERMs), such as tamoxifen, and selective estrogen receptor degraders (SERDs) or (b) ligand availability, using aromatase (cyp19) inhibitors. However, close to 60% of ERα-positive tumors exhibit intrinsic resistance or rapidly acquire resistance to endocrine interventions (especially in the metastatic setting), requiring the subsequent use of largely ineffective cytotoxic therapies (2-4). Unfortunately, it has been difficult to predict de novo resistance to endocrine therapy and/or assess the likelihood of early relapse.…”

“…Although the mechanisms underlying acquired resistance to tamoxifen treatment are multifaceted and diverse, most studies have implicated alterations in kinase signaling pathway activation or epigenetic changes that enable the tamoxifen:ERα complex to activate transcription (4, 6). Additionally, several recent studies have described the identification of proto-oncogenes whose expression and/or activities are positively up-regulated by endocrine manipulation and which alter tamoxifen pharmacology.…”

ObRb downregulation increases breast cancer cell sensitivity to tamoxifen

“…About 70 % of all patients with breast cancer have estrogen receptor (ER)-positive tumors; thus, selective ER modulators such as tamoxifen are widely used for treating these patients [2,3]. Unfortunately, up to half of all responsive tumors eventually develop resistance to tamoxifen, illustrating the fact that endocrine resistance is a crucial problem in the management of breast cancer [4][5][6].…”