Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is the most common endocrine therapy administered worldwide to women with hormone receptor-positive metastatic breast cancer or as adjuvant therapy for early stages of the disease. Tamoxifen may also be prescribed to women with ductal carcinoma in situ or to decrease the risk of breast cancer in women at high risk of developing the disease. While the use of aromatase inhibitors is increasing in the postmenopausal treatment setting, tamoxifen remains the drug of choice for premenopausal women. Several factors may contribute to reduced benefit from tamoxifen. It has been increasingly recognized in recent years that pharmacogenetics may play a role in tamoxifen's metabolism, efficacy, and safety. Cytochrome P450 (CYP) 2D6 encodes for a liver enzyme that is responsible for the conversion of tamoxifen into its active metabolite, endoxifen. Variant alleles in CYP2D6 or the use of medications that inhibit the enzyme clearly influence tamoxifen's metabolism into endoxifen. In addition, several retrospective studies suggest that variants in CYP2D6 may influence long term outcomes. In this review, we will summarize recent data that examined associations between CYP2D6 activity and effects on tamoxifen's metabolism and efficacy.
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PMID:Tamoxifen metabolism and its effect on endocrine treatment of breast cancer. 1939 43

Breast cancer is a heterogeneous disease affecting thousands of people every year. Multiple factors are responsible in causing breast cancer while a number of treatment options are also available for the disease. Tamoxifen is the most widely used anti-estrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit estrogen receptor positive breast cancer. The pharmacological activity of Tamoxifen is dependent on its conversion to its active metabolite, endoxifen, by CYP2D6. Tamoxifen reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy and provides effective palliation for patients with metastatic breast cancer. In this review we focus on the role of Tamoxifen in breast cancer treatment including mechanisms and side-effects. Finally, we discuss in detail the exciting prospects that lie ahead.
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PMID:Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. 2371 94

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.
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PMID:First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer. 2885 71

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.
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PMID:Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. 3100 68