Abstract OT2-2-02: Prospective multicentre study evaluating the effect of impaired tamoxifen metabolization on efficacy in breast cancer patients receiving tamoxifen in the neo-adjuvant or metastatic setting - The CYPTAM-BRUT 2 trial.

Abstract

Abstract Background: Tamoxifen is often used for the prevention and treatment of hormone receptor positive breast cancer. It is metabolized in the liver through cytochrome P450 (CYP) enzymes to more active metabolites, of which endoxifen is considered the most important. It is known that certain genetic variants in CYP enzymes result in lower serum endoxifen levels, but their effect on tamoxifen efficacy is not yet clear as results remain contradictory. Trial design: CYPTAM-BRUT 2 is a prospective multicentre open label single arm non randomized observational trial approved by the UZ Leuven Ethics Committee. Eligibility criteria are postmenopausal women with estrogen receptor positive invasive breast cancer receiving tamoxifen as first line therapy in the metastatic or neo-adjuvant setting. Prior adjuvant endocrine therapy is allowed if there is more than 12 months after completion of the adjuvant therapy. Primary endpoint is the relation between endoxifen levels and objective response rate. Secondary endpoints are the relation between endoxifen levels and the proportion of patients who are failure-free at 6 months, clinical benefit, tolerability of tamoxifen and the predictive value of the tamoxifen activity score, based on the presence of genetic variants and CYP inhibiting drugs. Patients with bone-only lesions will only be included in the analysis of the secondary endpoints. The trial is designed to show an improvement of the objective tumor response rate from 5% in patients with an unfavorable endoxifen profile (steady-state concentrations < 90nM) to 20% in patients with a favorable endoxifen profile (steady-state concentrations ≥ 90nM). With a type I error of 5% and a power of 90%, 231 patients have to be included into the study. The main secondary study endpoint is progression-free survival (PFS) at 6 months. With a total number 260 patients eligible for PFS, the study has a power of 80% to detect a 20% improvement of PFS at 6 months (i.e. from 50% to 70%) in patients with a favorable endoxifen as compared to patients with an unfavorable endoxifen profile, and a type-I error of 5%. Patient accrual: Total sample size is 260 and currently 202 patients from 22 participating centres in Belgium and Switzerland are included (May 2012). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-02.