Abstract OT2-1-05: 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 Kathleen , Jongen Lynn , Dieudonné Anne-Sophie , Lintermans Anneleen , Blomme Chantal , Brouckaert Olivier , Lambrechts Diether , Wildiers Hans , Christiaens Marie-Rose , Timmerman Dirk , Van Calster Ben , Decloedt Jan , Berteloot Patrick , Verhoeven Didier , Joerger Markus , Zaman Khalil , Dezentjé Vincent , Neven Patrick 
Published: May 2015

Abstract
Background
Tamoxifen is commonly used to treat and prevent hormone receptor positive breast cancers. This drug is metabolized into more active metabolites by liver enzymes such as cytochrome P450 (CYP) enzymes. Endoxifen is considered to be the principal active metabolite of tamoxifen. As CYP enzymes are highly polymorphic in humans, endoxifen plasma levels are modulated by the patient’s genotype. It, however, is not yet clear if lowered endoxifen plasma levels have an effect on tamoxifen efficacy. This is the first prospective study where the association between endoxifen plasma concentrations, multiple CYP-genotypes and clinical outcome in postmenopausal patients treated with tamoxifen is investigated.
Trial Design
CYPTAM-BRUT 2 is a prospective multi-center open label, single-arm, non-randomized observational study. Postmenopausal women with measurable, estrogen receptor positive breast cancer receiving tamoxifen as neo-adjuvant or as first-line metastatic treatment are included in this study. The objective treatment response and clinical benefit are observed to investigate the efficacy of 20 mg tamoxifen daily. Patients are allowed to have started tamoxifen before inclusion but not more than three months. Further, if more than twelve months have passed after completion of the adjuvant therapy prior endocrine therapy in the adjuvant setting is allowed. Patients receiving neo-adjuvant tamoxifen will be assessed no more than four months after starting with tamoxifen.
The primary endpoint is a statistical association between steady-state endoxifen plasma concentrations and the objective response rate (ORR) after 3-6 months of tamoxifen, 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 the relation between endoxifen plasma concentrations and clinical benefit (CR+PR+SD at 6 months). The study has to include 270 patients to detect a statistically significant association with endoxifen with 90% 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%). For both endpoints the RECIST criteria are used. Other endpoints are progression-free survival, tolerability of tamoxifen treatment and the association between CYP2D6 genotype and clinical outcome.
Patient accrualPatients from 22 participating centers in Belgium and Switzerland are included in this trial. In May 2014, the predefined sample size of 270 patients was reached. Follow-up of the last patients will continue until all required data are obtained (i.e blood samples and response evaluation).
Citation Format: Kathleen Van Asten, Lynn Jongen, Anne-Sophie Dieudonné, Anneleen Lintermans, Chantal Blomme, Olivier Brouckaert, Diether Lambrechts, Hans Wildiers, Marie-Rose Christiaens, Dirk Timmerman, Ben Van Calster, Jan Decloedt, Patrick Berteloot, Didier Verhoeven, Markus Joerger, Khalil Zaman, Vincent Dezentjé, Patrick Neven. 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 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-05.