CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations

Clin Pharmacol Ther. 2014 Feb;95(2):216-27. doi: 10.1038/clpt.2013.186. Epub 2013 Sep 23.

Abstract

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents, Hormonal / pharmacokinetics
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Cytochrome P-450 CYP2D6 / genetics*
  • Female
  • Genetic Variation / genetics
  • Genotype
  • Humans
  • Menopause
  • Middle Aged
  • Pharmacogenetics / methods
  • Survival Analysis
  • Tamoxifen / pharmacokinetics
  • Tamoxifen / therapeutic use*
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Hormonal
  • Tamoxifen
  • Cytochrome P-450 CYP2D6

Grant support