Pharmacogenetic variants influence tamoxifen's estrogenic effect on bone density

Abstract

Background Long-term effects from tamoxifen therapy for breast cancer include changes in bone mineral density (BMD). Methods We examined the effects of menopausal status, tamoxifen and its metabolite concentrations on BMD in 69 women treated with 20mg of tamoxifen for one year. We tested for associations between genetic variants in CYP2D6, Estrogen Receptor α (ER) and change in BMD, measured in the lumbar spine and hip. Variants in CYP2D6 (*3, *4, *5, *6 and *10) and estrogen receptor (PvuII and XbaI) were identified by RFLP assays. Results We noted a significant decrease in lumbar BMD in pre-menopausal women (Mean −0.069± 0.057 g/cm2, p=.0001). No significant changes in post-menopausal women were found (p=.27). Pre-menopausal women with non-variant CYP2D6 genotypes experienced greater decrease in lumbar BMD than those who were *1/*4 or *4/*4 (p=.041). The active tamoxifen metabolite endoxifen was significantly correlated with lumbar spinal change in this pre-menopausal group (r2= 0.22, p= 0.023). ER variants did not predict these changes in BMD. In post-menopausal women who carried the ERα PvuII TT genotype there was a significant increase in hip BMD (Mean +0.019± 0.050 g/cm2, p=.023). Conclusion Pre-menopausal women experienced loss in lumbar spine BMD during tamoxifen treatment that was associated with CYP2D6 wild-type genotype and high endoxifen concentrations. In post-menopausal women, ERα TT genotype was associated with an increase in hip BMD. Clinical Pharmacology & Therapeutics (2005) 77, P21–P21; doi: 10.1016/j.clpt.2004.11.082