Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is a standard endocrine therapy for the treatment of steroid receptor positive breast cancer. Tamoxifen efficacy depends on the formation of clinically active metabolites 4-hydroxytamoxifen and endoxifen which have a greater affinity to the oestrogen receptor and ability to control cell proliferation as compared to the parent drug. The cytochrome P450 2D6 enzyme plays a key role in this biotransformation and lack of tamoxifen efficacy has been linked to low activity. There is now considerable mechanistic, pharmacologic and clinical pharmacogenetic evidence in support of the notion that CYP2D6 genetic variants and phenocopying effects through drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and negatively impact tamoxifen outcome. These interrelations are particularly critical for patients with non-functional (poor metaboliser) and severely impaired (intermediate metaboliser) CYP2D6 variants, and, moreover, for patients in need of co-medication such as serotonin re-uptake inhibitors to control adverse effects such as hot flashes and other menopausal symptoms. Therefore, in the future, a personalised approach for an optimal tamoxifen benefit should consider a CYP2D6 genotype guided adjuvant endocrine treatment strategy and avoid non-adherence as well as strong CYP2D6 inhibitors such as co-medications.
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PMID:Targeting of tamoxifen to enhance antitumour action for the treatment and prevention of breast cancer: the 'personalised' approach? 1959 33

Genetic variability in drug-metabolizing enzymes and signaling pathways affects chemotherapy-related toxicity and treatment outcome in cancer. In breast and colorectal cancer, polymorphisms in metabolic enzymes involved in tamoxifen and irinotecan therapies has led the U.S. Food and Drug Administration to address genetic factors relevant to patient consideration of treatment with these compounds. Tamoxifen therapeutic failure in breast cancer has been associated with reduced CYP2D6 activity due to inefficient activation of tamoxifen. Irinotecan toxicity in colorectal cancer is more common in patients with reduced-activity UGT1A alleles, resulting in excessive exposure to the potent SN-38 metabolite. In colorectal and lung cancers, somatic mutations in the epidermal growth factor receptor and downstream signaling molecules have been associated with the therapeutic outcome of epidermal growth factor receptor-directed therapies. This review discusses the current knowledge regarding the utility of single gene-UGT1A1, CYP2D6, EGFR, and KRAS-or multigene analysis, for optimizing breast, colorectal, and lung cancer therapy. Current advances in these areas highlight how pharmacogenetics help personalized decision-making for patient management.
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PMID:Pharmacogenetics of solid tumors: directed therapy in breast, lung, and colorectal cancer: a paper from the 2008 william beaumont hospital symposium on molecular pathology. 1964 23

Tamoxifen remains a cornerstone of adjuvant therapy for patients with early stage breast cancer and oestrogen-receptor-positive tumours. Accurate markers of tamoxifen resistance would allow prediction of tamoxifen response and personalisation of combined therapies. Recently, it has been suggested that patients with inherited non-functional alleles of the cytochrome P450 CYP2D6 might be poor candidates for adjuvant tamoxifen therapy, because women with these variant alleles have reduced concentrations of the tamoxifen metabolites that most strongly bind the oestrogen receptor. In some studies, women with these alleles have a higher risk of recurrence than women with two functional alleles. However, dose-setting studies with clinical and biomarker outcomes, studies associating clinical outcomes with serum concentrations of tamoxifen and its metabolites, and a simple model of receptor binding, all suggest that tamoxifen and its metabolites should reach concentrations sufficient to achieve the therapeutic effect regardless of CYP2D6 inhibition. Ten epidemiology studies on the association between CYP2D6 genotype and breast cancer recurrence report widely heterogeneous results with relative-risk estimates outside the range of reasonable bounds. None of the explanations proposed for the heterogeneity of these results adequately account for the variability and no design feature sets apart any study or subset of studies as most likely to be accurate. The studies reporting a positive association might receive the most attention, because they report a result consistent with the profile of metabolite concentrations; not because they are more reliable by design. We argue that a recommendation for CYP2D6 genotyping of candidates for tamoxifen therapy, and its implicit conclusion regarding the association between genotype and recurrence risk, is premature.
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PMID:Genotype-guided tamoxifen therapy: time to pause for reflection? 1964 3

The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen is metabolized to an array of metabolites with estrogenic effects but also to reactive intermediates that may form protein and DNA adducts. The aim of this study was to investigate cellular [(3)H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemical analysis of glucose-regulating protein 78 (GRP78), nuclear factor kappaB (NF-kappaB), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed selective [(3)H]tamoxifen adduct formation in glandular and surface epithelia after incubation with a nontoxic concentration of [(3)H]tamoxifen (6 nM). There was also a selective expression of the endoplasmic reticulum stress chaperone GRP78 and activated caspase 3 at these sites after incubation with cytotoxic concentrations of tamoxifen (10-100 microM). The cell stress was preferentially observed in samples from women in the proliferative menstrual phase. No treatment-related expression of NF-kappaB was observed. Constitutive expression of the tamoxifen-metabolizing enzymes CYP1B1, CYP2A6, CYP2B6, CYP2C8/9/19, CYP2D6, and SULT2A1 in glandular and surface epithelia was shown, but there was a large interindividual variation. The colocalization of [(3)H]tamoxifen adducts, expression of GRP78, caspase 3, and tamoxifen-metabolizing enzymes in human glandular and surface epithelia suggest a local bioactivation of tamoxifen at these sites and that epithelial cells are early target sites for tamoxifen-induced cell stress.
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PMID:Tamoxifen-induced adduct formation and cell stress in human endometrial glands. 1981 51

Treatment decisions for breast cancer patients are currently based on a small number of crude predictive markers, despite the known complexity and heterogeneity of the disease. The field of pharmacogenetics can increase the precision with which therapeutic decisions are made. Discovering associations between genetic variation and treatment response will allow clinicians to tailor therapies to most effectively treat that specific tumor in that patient. In this review we outline two genes with potential clinical relevance in breast cancer treatment. A common polymorphism in the gene encoding Fc fragment of IgG low affinity IIIa receptor (FCGR3A; gene: FCGR3A) may substantially influence a patient's likelihood of responding to trastuzumab. The other gene that will be discussed in the review is cytochrome P450 2D6 (CYP2D6; gene: CYP2D6), which has many genetic variants that impair the bioactivation and effectiveness of tamoxifen therapy.
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PMID:Pharmacogenetics of breast cancer therapies. 1991 45

Selective estrogen receptor modulators (SERMs) and selective estrogen down regulators (SERDs) act as estrogen receptor (ER) agonists or antagonist depending on the targeted tissue and the specific configuration of the used SERM or SERD. Effects on bone, endometrium and breast cancer are of interest. Endocrine treatments have been used in breast cancer since the end of the 19th century. In the second part of the last century different compound of SERMs and SERDs have been developed and we will discuss them mainly as used in the treatment and prevention of breast cancer. Tamoxifen is the widely investigated and most used representative of these drugs and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting and for prevention of the disease. Its role has been challenged in the last years by the introduction of third generation aromatase inhibitors that have proven a higher activity than tamoxifen and a different toxicity pattern. Several other SERMs have been investigated, but none of them was clearly superior to tamoxifen. The main interest in different SERMs has to be seen in the slightly different safety profile between the different compounds. SERDs act as pure estrogen antagonist. They have been used in the treatment of advanced breast cancers and their role in other settings still needs further investigation. The increased use of aromatase inhibitors as first line endocrine therapy raises new questions on the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies and the combination of endocrine therapies with new targeted therapies in hormone sensitive breast cancer remains a very important research issue. Polymorphisms in genes coding for tamoxifen metabolizing enzymes, as for instance, the CYP2D6 genotype, have the potential of becoming clinically useful predictive marker for tamoxifen response. With this meaningful newer knowledge it is possible that the place of tamoxifen in the treatment of breast cancer will be redefined in the future.
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PMID:Clinical use of selective estrogen receptor modulators and down regulators with the main focus on breast cancer. 1994 39

Endoxifen is the key active metabolite of tamoxifen, a widely used breast cancer drug. Orally administered tamoxifen, is extensively metabolized by cytochrome P450 (CYP) enzymes, namely CYP3A4 and CYP2D6, into active metabolites, especially endoxifen. Due to genetic polymorphism of CYP2D6, significant numbers of women metabolize tamoxifen to varying degree and may not receive the optimal benefit from tamoxifen treatment. We show that oral administration of endoxifen achieved the optimally effective systemic levels reliably, which may eliminate variability associated with tamoxifen metabolism that leads to unpredictability in efficacy. Furthermore, use of endoxifen may avoid a potential serious drug interaction found between tamoxifen and commonly used selective serotonin reuptake inhibitors, antidepressants. Endoxifen was active in inhibiting the growth of various breast tumor cell lines in NCI 60-Cell Line Screen. Orally administered endoxifen is rapidly absorbed and systemically available when tested in female rats. The endoxifen-treated rats showed 787% higher exposure (AUC(0-infinity)) and 1,500% higher concentration (C (max)) levels of endoxifen when compared with tamoxifen. Oral endoxifen administration once a day for 28 consecutive days at dosages 2, 4, and 8 mg/kg proved safe and resulted in progressive inhibition of the growth of the human mammary tumor xenografts in female mice. This is the first ever in vivo report on endoxifen as a potentially new therapeutic agent for breast cancer.
Breast Cancer Res Treat 2010 Jul
PMID:Orally administered endoxifen is a new therapeutic agent for breast cancer. 2005 38

Despite recent advances in hormonal therapy for breast cancer, tamoxifen remains a major therapeutic option, with indications ranging from primary prevention to metastatic disease. Understanding the variation in response to tamoxifen may significantly improve our ability to personalize cancer care and maximize therapeutic efficacy. One area of particular interest is the impact of cytochrome P450 CYP2D6 genetic polymorphisms on tamoxifen metabolism. Tamoxifen is considered a prodrug, whose efficacy may be dependent on active metabolites, including endoxifen. Patients with reduced CYP2D6 enzymatic activity tend to have lower endoxifen levels, but clinical relevance of reduced endoxifen levels remains to be determined. Several small to moderately sized retrospective studies have suggested an intriguing association between poor metabolizer status and increased disease recurrence. However, these data are limited by sample size and methodologic challenges, including the inability to adjust for major prognostic and confounding factors. Several subsequent studies have failed to find an association or found improved outcomes among reduced CYP2D6 metabolizers. Therefore, current findings are conflicting and should be considered preliminary. Nevertheless, the CYP2D6 test is commercially available, making clinical use possible even as evidence in this area is still evolving. More definitive clinical research is needed before routine CYP2D6 testing can be recommended and considered standard of care. Anticipated data from retrospective analysis of large adjuvant randomized trials of tamoxifen should help address the clinical utility of CYP2D6 testing.
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PMID:CYP2D6 testing in breast cancer: ready for prime time? 2012 Aug 36

Tamoxifen is a prodrug mainly metabolized by the CY2D6 cytochrome. More than 80 variants of the CYP2D6 gene have been identified. They predict four different enzymatic phenotypes: ultra-rapid metabolizers (UM), extensive metabolizers (EM), intermediate metabolizers (IM) and poor metabolizers (PM). Six retrospectives studies suggest a link between some polymorphisms of the CYP2D6 and tamoxifen efficacy and two studies have found no statistically significant data. Today, level of proof remains insufficient to recommend the testing of a patient's genotype before tamoxifen prescription. Designing prospective studies is necessary before considering therapy strategies based on pharmacogenetics data. In pre-menopausal breast cancer PM or IM patients, an increase in dosage of tamoxifen or a treatment with LH-RH analogues with aromatase inhibitors (AI) may be beneficial instead of the actual recommendations of a 5-year tamoxifen therapy. In postmenopausal EM patients, tamoxifen may be as efficient as AI. In post-menopausal PM patients, a switch strategy may be inferior to a 5-year IA strategy, which would therefore be the standard of care.
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PMID:[CYP2D6 polymorphisms and tamoxifen: therapeutic perspectives in the management of hormonodependent breast cancer patients]. 2012 49

The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P=0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P=0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmaco-genomics in tailoring tamoxifen treatment.
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PMID:Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial. 2030 15


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