Abstract OT3-2-04: Prospective multicenter 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
Authors: Van Asten K , Dieudonné A-S , Lintermans A , Blomme C , Brouckaert O , Lambrechts D , Wildiers H , Christiaens M-R , Timmerman D , Van Calster B , Decloedt J , Berteloot P , Verhoeven D , Joerger M , Zaman K , Dezentjé V , Neven P 
Published: August 2014

Abstract
Background
Tamoxifen is often used for the prevention and treatment of hormone receptor positive breast cancer. It is a prodrug which is metabolized by human liver enzymes to more active metabolites. The principal active metabolite of tamoxifen is considered to be endoxifen, which is formed by cytochrome P450 (CYP) enzymes. These enzymes are highly polymorphic in humans and endoxifen plasma levels are modulated by the patient's genotype. The effect of lowered endoxifen plasma levels on tamoxifen efficacy, however, is not yet clear as results remain contradictory. However, the association between endoxifen plasma concentrations, multiple CYP-genotypes and clinical outcome has not been studied so far in a prospective study in patients with advanced breast cancer receiving first-line tamoxifen treatment.
Trial design
CYPTAM-BRUT 2 is a prospective multicenter 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 association between endoxifen steady-state plasma concentrations and objective response rate after 3-6 months of treatment using RECIST criteria. Main secondary endpoint is the relation between endoxifen plasma concentrations and clinical benefit (CR+PR+SD at 6 months) according to the RECIST criteria. Other secondary endpoints include progression-free survival, toxicity and the association between CYP2D6 genotype and clinical outcome. In addition, we will assess how much of the variation in endoxifen levels is explained by the genetic variants and CYP2D6 inhibitors.
The trial is designed to detect a statistical association between endoxifen and objective tumor response rate (ORR), under the assumption that the relationship is linear with an odds ratio (OR) of 1.49 per 10 nmol/l. Using available data on endoxifen concentrations, this OR is chosen to reflect an improvement from 10% ORR in the lowest endoxifen quartile to 30% in the highest endoxifen quartile when the overall ORR is around 18%. To have 90% power at a 5% significance level, 180 patients have to be included into the study. The main secondary study endpoint is clinical benefit at 6 months. The study has to include 243 patients to detect a statistically significant association with endoxifen with 80% power at a 5% significance level, assuming an OR of 1.28 per 10 nmol/l. This OR is chosen to reflect an improvement of clinical benefit at 6 months from 30% in the lowest endoxifen quartile to 50% in the highest endoxifen quartile (overall clinical benefit around 39%).
Patient accrual
Currently 257 patients from 22 participating centers in Belgium and Switzerland are included (May 2013). As the sample size calculation did not account for missing data, inclusions will continue until 243 patients who fulfill the inclusion criteria are included (i.e. target lesions, blood sample and response evaluation).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-04.