Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence.
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Rocca A, Maltoni R, Bravaccini S, Donati C, Andreis D
Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence.
Cancer Manag Res. 2018 Aug 30;10:3083-3099. doi: 10.2147/CMAR.S137772. eCollection 2018.
- PubMed ID
- 30214302 [ View in PubMed]
- 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-naive 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 alpha-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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Fulvestrant Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAlpelisibPhenytoin The serum concentration of Alpelisib can be decreased when it is combined with Phenytoin. AlpelisibPentobarbital The serum concentration of Alpelisib can be decreased when it is combined with Pentobarbital. AlpelisibCarbamazepine The serum concentration of Alpelisib can be decreased when it is combined with Carbamazepine. AlpelisibMitotane The serum concentration of Alpelisib can be decreased when it is combined with Mitotane. AlpelisibPrimidone The serum concentration of Alpelisib can be decreased when it is combined with Primidone.