Polymorphism in the <i>CYP2D6</i> Tamoxifen-Metabolizing Gene Influences Clinical Effect but Not Hot Flashes: Data From the Italian Tamoxifen Trial

Bonanni, Bernardo; Macis, Debora; Maisonneuve, Patrick; Johansson, Harriet; Gucciardo, G; Oliviero, P.; Travaglini, Roberto; Muraca, Maria Grazia; Rotmensz, Nicole; Veronesi, Umberto; DeCensi, Andrea

doi:10.1200/jco.2006.06.8072

Cited by 101 publications

(67 citation statements)

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“…25 In this study, we have expanded the allele coverage for the CYP2D6 genotyping by including more alleles that may affect tamoxifen metabolism. Furthermore, we included two additional enzymes known to affect tamoxifen metabolism, CYP2C19 and SULT1A1, for a more comprehensive investigation of the resulting phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…After a median 81.2 month followup, we diagnosed 79 subjects with BC (34 in the tamoxifen arm and 45 in the placebo arm, HR (95% CI) 0.75 (0.48-1.18)). 24 To develop a more tailored and more effective chemoprevention strategy, we have recently published preliminary data on this study, 25 indicating that subjects with the CYP2D6*4/*4 genotype were less likely to benefit from tamoxifen as a chemopreventive agent of BC in the prevention setting. Here we present a more comprehensive analysis of allelic variants of CYP2D6, CYP2C19, in the same cohort, using the AmpliChip CYP450 Test (Roche Diagnostics, Monza, Italy).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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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 ¼ 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 ¼ 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 pharmacogenomics in tailoring tamoxifen treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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“…The influence of CYP2D6*4 on chemoprevention with tamoxifen was evaluated in a small subset of 46 patients with breast cancer and 136 controls pooled from a large Italian trial. The authors concluded that patients homozygous for allele *4 may be less likely to benefit from tamoxifen in the course of chemoprevention, as the cancer events were significantly higher in this study arm [15] . The effect of variation in CYP2D6 activity on the clinical course of patients with familial breast cancer was approached in another study from United Kingdom.…”

Section: Researchmentioning

confidence: 84%

“…In five of them the investigation focused exclusively on allele*4, while in the study of Newmann et al [16] performed in patients with familiar breast cancer, a subanalysis for *4 alone has also been performed [7,8,11,13,15] . In six other, the analysis included a larger pool of intermediate/poor metabolizers based on a combined basis of common non-functional alleles, including allele*4 [6,7,9,11,14,16] .…”

Section: Discussionmentioning

confidence: 99%

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Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Markopoulos

Kykalos

Mantas

2014

WJCO

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Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: CYP2D6; Tamoxifen; Breast cancer; Adjuvant treatment Core tip: Currently, routine cytochrome P450 (CYP)2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.Markopoulos C, Kykalos S, Mantas D. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen.

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Oral Chemotherapeutic Agents

Ogita

LoRusso

2012

Encyclopedia of Drug Metabolism and Interactions

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Oral chemotherapeutic agents have been available for decades, and there has been an accelerated expansion in their development during the recent decade. Oral chemotherapeutic agents offer obvious advantages in terms of convenient and noninvasive administration, flexibility and adaptability of dosing, as well as financial and staff time savings. Compared to intravenous agents, oral chemotherapeutic agents generally exhibit substantial interindividual pharmacokinetic variability. Many factors contribute to this variability, including physiological, pathological, environmental, and genetic factors. Unique to oral agents, poor and variable bioavailability is one important source of the interindividual pharmacokinetic variability. This chapter discusses the factors influencing bioavailability of oral chemotherapeutic agents, with focus on the first‐pass metabolism by cytochrome P450 3A4 (CYP3A4), intestinal efflux by ABCB1 transporter, and other factors such as concomitant administration of antiacid medications, food effect, and surgery. Oral chemotherapeutic agents can be classified as traditional cytotoxic agents and novel molecularly targeted agents, hormonal agents, and immune‐modulating agents. Each class of agents is unique with regard to its mechanisms of action, pharmacokinetics, mechanisms of drug resistance, and clinical use. This chapter provides an overview of the major classes of oral chemotherapeutic agents, particularly highlighting examples whereby genetic variations in the genes involved in the drug disposition or drug–target interaction influence the pharmacokinetics and/or response.

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Polymorphism in the CYP2D6 Tamoxifen-Metabolizing Gene Influences Clinical Effect but Not Hot Flashes: Data From the Italian Tamoxifen Trial

Cited by 101 publications

References 2 publications

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Oral Chemotherapeutic Agents

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