Abstract
Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.
Highlights
Breast cancer (BC) is a complex disease that comprises different clinical and histopathological subtypes
We focus on the pre-clinical and clinical studies investigating ESR1 mutations in estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), highlighting their potential prognostic and predictive roles, and how awareness of mutational ESR1 status might impact upon clinical decision-making and the potential for biomarker discovery
A major challenge remains in overcoming endocrine resistance in metastatic ER+ disease
Summary
Breast cancer (BC) is a complex disease that comprises different clinical and histopathological subtypes. The interaction between ER and growth factor receptor signaling (including crosstalk with HER2) or cellular kinase pathways (including MAPK, stress-related kinases, PI3K/AKT/mTOR, and CDK4/6 pathways) can modulate ER activity via phosphorylation of ER itself and/or its co-regulators, resulting in fundamental modification of ER nuclear activity, which leads to endocrine resistance [7,11]. Hyperactivation of such signaling pathways can result from genetic alterations in a number of different genes, including NF-1. A biomarker is defined as prognostic if it provides information about cancer outcome regardless of therapy, whereas a predictive biomarker is prospectively reflective of the effect of a therapeutic intervention [16]
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