A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)97-108
Number of pages12
JournalBreast Cancer Research and Treatment
Volume159
Issue number1
DOIs
Publication statusPublished - Aug 1 2016

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Keywords

  • Biomarkers
  • Breast cancer
  • CYP2D6
  • IGF-I
  • Pharmacogenetics
  • Prevention
  • Tamoxifen

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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