Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence

Abstract

Fulvestrant is the first selective estrogen receptor (ER) downregulator available in clinical practice. It is a pure antiestrogen with no agonistic effects, leading to degradation of ER alpha, with activity in tamoxifen-resistant breast cancer (BC) models. Pharmacokinetic and pharmacodynamic studies and several postmarketing clinical trials led to the definition of the optimal dose at 500 mg intramuscularly on days 1, 15, and 29 and then every 28 days. Targeting ER alpha, fulvestrant is a cornerstone of treatment in luminal BCs, whose growth is largely driven by the ER pathway. In endocrine therapy-naïve patients with hormone receptor-positive, HER2− advanced BC (ABC), fulvestrant yielded significantly longer progression-free survival compared to anastrozole in the Phase III FALCON study. Due to its mechanism of action and pharmacokinetic properties, fulvestrant is an ideal backbone for combination therapies. Preclinical studies have shown synergism with drugs acting on signaling pathways involved in the development of endocrine resistance, among which the cyclin D/cyclin-dependent kinase 4-6/retinoblastoma pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, contributing to overcoming or delaying endocrine resistance. In the Phase III PALOMA-3 trial, a combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib with fulvestrant significantly improved progression-free survival over fulvestrant alone in women with hormone receptor positive, HER2− ABC progressing during prior endocrine therapy. This led to approval of the combination in this clinical setting. Similar results were obtained with abemaciclib and ribociclib. Combination with pan-PI3K inhibitors, though showing some efficacy, was hampered by the toxicity of these agents, and studies in combinations with more selective inhibitors of the α-catalytic subunit of PI3K are ongoing. Fulvestrant has shown partial activity also in patients with tumors harboring mutations of the ESR1 gene. It is thus a key drug in the treatment of ABC, whose role in combination with new targeted agents is still evolving.

Long non‑coding RNA UCA1 confers tamoxifen resistance in breast cancer endocrinotherapy through regulation of the EZH2/p21 axis and the PI3K/AKT signaling pathway

“…Breast cancer currently remains the most common female malignancy in the world (45). Tamoxifen is the most frequently used endocrinotherapy for ER + breast cancer (46). Despite great treatment advances in improving the survival rate of patients with breast cancer, almost 30% of patients treated with tamoxifen may develop resistance to the drug (47).…”

Current State of Breast Cancer Diagnosis, Treatment, and Theranostics

“…This is the first selective ER down regulator that is available clinically. This pure anti-estrogen results in degradation of ER alpha (α), has no agonistic effects, and has also demonstrated activity in tamoxifen-resistant breast cancer models [ 122 ]. Fulvestrant is the first SERD to enter into the clinical arena and a suitable backbone for combination therapy with new targeted agents for endocrine treatment of breast cancer.…”

Aromatase Inhibitors—Induced Musculoskeletal Disorders: Current Knowledge on Clinical and Molecular Aspects

“…However, the advent of Fulvestrant, with indications partially overlapping those of AIs (first- and second line hormonal therapy in advanced and metastatic BC), may give rise for the question if comparable, or even improved therapeutic outcomes are achievable by the former, with less toxicity, although there are no reliable disclosures on non-autoimmune and autoimmune rheumatological musculoskeletal adverse effects related to SERDs [ 189 , 190 ].…”