开题报告内容Content：（包括拟研究或解决的问题、采用的研究手段及文献综述，不少于2000字）Including objectives, methods adopted and literature review, no less than 2000 words
Introduction:
Tamoxifen is a selective estrogen receptor modulator which could be used to prevent the recurrence of estrogen receptor positive breast cancer in the adjuvant treatment of pre- and post-menopausal woman, as well as for treatment of metastatic disease and ductal carcinoma in situ. [1] The concentrations of metabolites of tamoxifen including 4-hydroxyTAM and particularly endoxifen would be essential for the efficacy of the tamoxifen treatment. [2,3,4] As is shown in Figure 1, the major metabolic pathway involves initial conversion of tamoxifen to N-desmethyl-tamoxifen via CYP3A4/5 followed by conversion of N-desmethyl-tamoxifen to endoxifen, via CYP2D6. In addition, some Tamoxifen is initially metabolized by CYP2D6 to the active metabolite 4-hydroxy-tamoxifen, which in turn is either degraded or converted by CYP3A4/5 to endoxifen. [5] Prior studies have reported association between tamoxifen and its metabolites for common functionally consequential single nucleotide polymorphisms (SNPs) in non-CYP and CYP genes. [6] Our study is to determine the impacts of SNPs in non-CYP and CYP genes on steady-state concentrations of tamoxifen, endoxifen and other metabolites which could lead to the improvement of personalized tamoxifen dosing algorithms.
Figure 1. Tamoxifen metabolism and its metabolites. Adapted from Desta et al. [7]
Objectives:
Primary: Tamoxifen bioactivation to endoxifen is mediated by different genes including non-CYP genes (ABCB1, SLCO1B1, OPRM1, etc) and CYP genes (CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, etc). Our objective is to conduct a comprehensive assessment of the effect of genetic variation in the metabolism from tamoxifen to endoxifen.
Secondary: Our secondary objective is to conduct a comprehensive assessment of the effect of genetic variation in the concentration of tamoxifen and its metabolites.
Aims with testable hypotheses:
- Primary hypothesis:
Carriers of genotypes that lead to greater CYP2D6 metabolizer activity phenotype will have greater steady state endoxifen concentration (poor lt; intermediate lt; normal lt; ultra-rapid).
