Abstract PD10-09: CYP2D6 and adjuvant tamoxifen: Impact on outcome in pre- but not postmenopausal breast cancer patients

Abstract

Abstract Background: The therapeutic effect of tamoxifen in adjuvant treatment of hormone receptor positive breast cancer might be impaired in patients with cytochrome P450 2D6 (CYP2D6) genotypes that predispose to decreased formation of potent anti-estrogenic tamoxifen metabolites. However, previous studies have shown inconsistent findings in this regard. In light of two recent studies failing to show an impact of CYP2D6 genotype on outcome in postmenopausal patients, we hypothesized that deficient CYP2D6 might be of greater importance in premenopausal patients with high levels of circulating estrogen. We therefore aimed to study the effect of CYP2D6 activity in both pre- and postmenopausal patients who were adherent to tamoxifen treatment for at least one year. Methods: 382 patients, from a population-based cohort of unselected breast cancer patients that were prescribed adjuvant tamoxifen for five years, constituted the base of the study. Information on menopausal status, tumor characteristics, treatment data including compliance and outcome was retrieved from medical records. Comprehensive CYP2D6 genotyping was performed and functionally translated into constitutive, metabolic activity. Results: In patients adherent to tamoxifen for at least one year (n = 313) there was an association of reduced CYP2D6 activity (≤50% of normal) to both recurrence (p = 0.02) and breast cancer-specific mortality (p = 0.03). In a multivariable analysis including CYP2D6 activity, age at diagnosis, tumor size, lymph node status, grade, adjuvant chemotherapy and concomitant use of CYP2D6 inhibitors, CYP2D6 remained an independent predictor of recurrence (HR = 0.39, 95% CI: 0.18–0.85, p = 0.02) and breast cancer specific survival (HR = 0.33, 95% CI 0.12–0.90, p = 0.03). Gradually decreasing CYP2D6 activity paralleled increasing risk of recurrence and breast cancer related mortality. The effect of CYP2D6 derived mainly from premenopausal patients with an association to both recurrence (p = 0.01) and breast cancer specific survival (p = 0.04). There was no such association in the postmenopausal group. Conclusion: In a prospectively collected cohort of tamoxifen-treated breast cancer patients, an association between CYP2D6 genotype and outcome was evident in patients that were adherent to tamoxifen treatment for at least a year. Importantly, this effect derived from premenopausal patients only. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-09.