Abstract
Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.
Highlights
Breast cancer (BC) is a heterogeneous disease comprising different subtypes, which can be identified through molecular biomarkers that act as predictive factors
Luminal BC is characterized by the expression of estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+), HER2-positive BC is defined by overexpression of human epidermal growth factor 2 (HER2) oncogene and triple-negative BC is characterized by lack of expression of ER/partial response (PR) and HER2
In 2002, fulvestrant was approved for metastatic BC (MBC) ER+ patients that had progressed on prior Endocrine therapy (ET) in the form of an intramuscular injection of 250 mg
Summary
Breast cancer (BC) is a heterogeneous disease comprising different subtypes, which can be identified through molecular biomarkers that act as predictive factors. Estrogen-independent ER reactivation is the main mechanism of resistance [8] This can occur through altered interactions of ER with coactivators/corepressors, via crosstalk between ER and other oncogenic signaling pathways [9], or by acquired mutations in ESR1. This mutation exists rarely in primary tumors (~1%) but is relatively common in metastatic ER+ disease representing up to 20% of patients who received aromatase inhibitors [10,11,12]. The recent addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to ET has emerged as the first-line treatment option This combination has improved prognosis in patients with advanced luminal BC compared with ET alone [1]. This review aims to facilitate the understanding of the mechanisms of action of SERDs, and to summarize the ongoing development of new oral SERDs from a practical clinical perspective
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