摘要：

Long-term adjuvant tamoxifen therapy for five years is the anti-estrogenic standard of care for ER-positive breast cancer in premenopausal patients. The metabolic activation of tamoxifen into the active metabolite endoxifen is mediated by Cytochrome P450 (CYP) 2D6 and it has been shown that CYP2D6 polymorphims can influence the clinical outcome of postmenopausal breast cancer patients (Schroth et al. JAMA 2009, Mürdter et al.CPT 2011). While this is currently still under debate awaiting the denouement (Brauch et al. JCO 2011), no such relationship has been investigated for premenopausal patients. We used the Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH) collection to explore the pharmacogenetic relationship between CYP2D6 polymorphisms and tamoxifen outcome in premenopausal patients. POSH is an observational cohort study established to explore the effect of genetic factors on breast cancer prognosis (Eccles et al. BMC Cancer 2007). We genotyped genomic DNA of 772 patients with adjuvant tamoxifen (age 18 to 41 years) for CYP2D6 and other CYP enzymes by MALDI TOF-MS. Patients were assigned for CYP2D6 metabolizer status, poor (PM), intermediate (IM), and extensive (EM), and tested for clinical associations using Kaplan-Meier and Cox regression analyses. After a median follow-up of 4 years (0.1 - 8 years) with 24.6% of study participants reporting a relapse, Kaplan Meier survival analysis did not show an association between CYP2D6 metabolizer status and the occurrence of relapse. In contrast, CYP3A5 functional status predicted by the *1 genotype was associated with worse outcome compared to the CYP3A5 deficient status (*3). Since chemotherapy is a suggested confounder of the CYP2D6 tamoxifen pharmacogenetic effect and the majority of POSH patients had received chemotherapy prior to tamoxifen, there is a possibility that variation in the metabolism and cytotoxic effects of these agents may mask CYP2D6 dependent tamoxifen outcome. However, in premenopausal patients due to higher plasma estrogen concentrations, the inhibition of tumor ER signaling may likely depend on factors other than endoxifen formation. While this is currently being explored with respect to the underlying ER pharmacodynamic effects, the polymorphic CYP3A5, one of the major drug metabolizing enzymes, appears to be a candidate marker for the prognosis of premenopausal breast cancer.

展开