Are Estrogen Receptor Genomic Aberrations Predictive of Hormone Therapy Response in Breast Cancer?

Abstract

ContextBreast cancer is the most common cancer in women worldwide. Estrogen receptor (ER) positive breast cancer constitutes the majority of these cancers. Hormone therapy has significantly improved clinical outcomes for early- and late-stage hormone receptor positive breast cancer. Although most patients with early stage breast cancer are treated with curative intent, approximately 20% - 30% of patients eventually experience a recurrence. During the last two decades, there have been tremendous efforts to understand the biological mechanisms of hormone therapy resistance, with the ultimate goal of implementing new therapeutic strategies to improve the current treatments for ER positive breast cancer. Several mechanisms of hormone therapy resistance have been proposed, including genetic alterations that lead to altered ER expression or ERs with changed protein sequence.Evidence AcquisitionA Pubmed search was performed utilizing various related terms. Articles over the past 20 years were analyzed and selected for review.ResultsOn the basis of published studies, the frequencies of ESR1 (the gene encoding ER) mutations in ER positive metastatic breast cancer range from 11% to 55%. Future larger prospective studies with standardized mutation detection methods may be necessary to determine the true incidence of ESR1 mutations. ESR1 amplification in breast cancer remains a controversial issue, with numerous studies either confirmed or challenged the reports of ESR1 amplification. The combination of intra-tumor heterogeneity regarding ESR1 copy number alterations and low level ESR1 copy number increase may account for these discrepancies.ConclusionsWhile numerous unknown issues on the role of ESR1 mutations in advanced breast cancer remain, these new findings will certainly deepen current knowledge on molecular evolution of breast cancer and acquired resistance to hormone therapy.

Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds

“…The non‐genomic mode of action of oestradiol (and in general for all steroid hormones) is a rapid process that does not require the synthesis of new proteins, and is mediated by receptors localised in the membrane . The rapid oestrogenic action includes the regulation of ion fluxes, discharge of secretory vesicles and activation of protein kinases associated with the membrane . In 1967, the idea that oestradiol could induce its cellular effects via non‐genomic mechanisms was introduced, as indicated by the increase in the production of cyclic AMP (cAMP) in vivo .…”

“…The expression of these receptors by glial cells allows them to partially mediate the action of oestrogenic compounds in the brain . Indeed, the response induced by each receptor stimulates cell survival, differentiation and connectivity of neurones and glial cells in the brain, including the medulla . Also, neurosteroids play an important role in the development of the prenatal CNS, at the same time as regulating behaviour and neuroendocrine signalling in the adult brain .…”

Genomics Role in Cancer Immunosurveillance: Impact on Immunotherapy Response

“…T cells to recognize and respond to neoantigens. Comprehensive understanding of resistance mechanisms can lead to the discovery of biomarkers of response to immunotherapies, similar to biomarkers of response to other cancer therapies (54)(55)(56)(57).…”

Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer

“…It exhibits a partial ERα agonistic feature with net antagonistic activities on breast cancer tissue. Selective ER degraders, such as fulvestrant affect the stability of the ER and downregulate the receptor protein [ 21 ]. Although these medications reduce relapse rates when administered prophylactically after surgery and chemotherapy, resistance to endocrine therapy leading to the development of fatal metastatic cancer commonly occurs and has become a major clinical problem [ 22 ].…”