Abstract P3-07-46: CYPTAM-BRUT 3: Endometrial thickness cannot be used as a marker for tamoxifen metabolization in postmenopausal breast cancer patients
Authors: A Poppe, A-S Dieudonné, A Lintermans, A Laenen, C Blomme, D Lambrechts, H Wildiers, M-R Christiaens, D Timmerman, B Van Calster, C Vereecke, G Vandeputte, C Fontaine, J Decloedt, P Berteloot, H Depypere, M Joerger, V Dezentjé, P Neven
Journal: Cancer Research (2016)

Abstract Background: Tamoxifen is commonly used for the treatment of all stages of estrogen receptor (ER) positive breast cancer (BC), the largest group of BC. In postmenopausal women, known endometrial side-effects are cystic appearance, hyperplasia, polyps and endometrial cancer. Tamoxifen is converted through several CYP450 enzymes into the active metabolite endoxifen. Patients with particular single nucleotide polymorphisms (SNPs) in those CYP450 enzymes (e.g. CYP2D6) have lower endoxifen concentrations and therefore could experience less benefit from tamoxifen. However, the clinical significance stays controversial in the literature as results remain contradictory. Our primary hypothesis is that women with lower endoxifen levels do not have the typical tamoxifen-induced increase in endometrial thickness. The aim of this study is to test the association between endoxifen concentration and the increase in double endometrial thickness (DET). Patients and methods: CYPTAM-BRUT 3 is a prospective, multicentric study including postmenopausal women with an ER positive BC receiving tamoxifen in the adjuvant setting. Primary objective is the association between serum endoxifen levels and change in DET between baseline and follow-up after 3 - 6 months. Secondary objectives are investigating the relation between serum endoxifen levels and other endometrial changes (i.e. the presence of cysts/polyps), menopausal symptoms assessed with a questionnaire and serum levels of follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). Other objectives are the association between the 'CYP2D6 tamoxifen activity score', based on SNPs and co-medication, and DET, other endometrial changes, FSH and SHBG. The CYPTAM-BRUT 3 study is a sub-study of the CYPTAM study in Leiden, The Netherlands, with survival as primary outcome. Results: 144 women were included in 19 hospitals. There was no significant association found between endoxifen and change in DET (p=0.888), as for the association between endoxifen and the development of cysts or polyps (p=0.208). For the questionnaire items no correlation was found (p≥0.051). Changes of FSH and SHBG were in the range of what would be expected during tamoxifen treatment in the general population and there was no association with endoxifen (p=0.726 and p=0.181). In addition, no association was found between the CYP2D6 TAS score and DET (p=0.613), other endometrial changes (p=0.196), FSH (p=0.976) and SHBG (p=0.900). Conclusion: Our study is one of the first studies that prospectively investigated the relation between tamoxifen metabolization, in correlation with endometrial thickness and SNPs. We can conclude that the typical increase in endometrial thickness seen in a significant proportion of postmenopausal women under tamoxifen cannot be used to predict that those women have a high endoxifen concentration or that women without an increased endometrial thickness have a significantly lower endoxifen concentration. The same conclusions can be made for the other tamoxifen-induced changes as cysts and polyps, menopausal symptoms, FSH and SHBG. It may also apply to tamoxifen efficacy but further prospective studies looking at survival are needed to answer that question. Citation Format: Poppe A, Dieudonné A-S, Lintermans A, Laenen A, Blomme C, Lambrechts D, Wildiers H, Christiaens M-R, Timmerman D, Van Calster B, Vereecke C, Vandeputte G, Fontaine C, Decloedt J, Berteloot P, Depypere H, Joerger M, Dezentjé V, Neven P. CYPTAM-BRUT 3: Endometrial thickness cannot be used as a marker for tamoxifen metabolization in postmenopausal breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-46.