| Title |
A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen
|
|---|---|
| Published in |
Breast Cancer Research and Treatment, August 2016
|
| DOI | 10.1007/s10549-016-3932-7 |
| Pubmed ID | |
| Authors |
Harriet Johansson, Sara Gandini, Davide Serrano, Jennifer Gjerde, Monia Lattanzi, Debora Macis, Aliana Guerrieri-Gonzaga, Valentina Aristarco, Gunnar Mellgren, Ernst Lien, Andrea DeCensi, Bernardo Bonanni |
| Abstract |
Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 2 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 52 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 52 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 10 | 19% |
| Student > Ph. D. Student | 7 | 13% |
| Student > Master | 6 | 12% |
| Student > Bachelor | 5 | 10% |
| Professor > Associate Professor | 3 | 6% |
| Other | 7 | 13% |
| Unknown | 14 | 27% |
| Readers by discipline | Count | As % |
|---|---|---|
| Pharmacology, Toxicology and Pharmaceutical Science | 10 | 19% |
| Medicine and Dentistry | 9 | 17% |
| Biochemistry, Genetics and Molecular Biology | 7 | 13% |
| Chemistry | 3 | 6% |
| Agricultural and Biological Sciences | 2 | 4% |
| Other | 6 | 12% |
| Unknown | 15 | 29% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 November 2017.
All research outputs
#17,811,816
of 22,881,964 outputs
Outputs from Breast Cancer Research and Treatment
#3,578
of 4,661 outputs
Outputs of similar age
#269,076
of 366,909 outputs
Outputs of similar age from Breast Cancer Research and Treatment
#61
of 109 outputs
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