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Hubungan antara Genotip dan Fenotip CYP2D6 dengan Kadar Z-Endoksifen pada Subjek Kanker Payudara yang Diterapi Tamoksifen = Association of CYP2D6 Genotype and Phenotype with ZEndoxifen Concentration in Subjects with Breast Cancer Treated with Tamoxifen.

Tamoksifen (TAM) merupakan prodrug yang perlu diaktivasi oleh CYP2D6 menjadi Z-endoksifen (Z-END). Efek antiestrogen TAM bersifat concentration dependent, dan diketahui dari penelitian sebelumnya bahwa minimal threshold concentration (MTC) Z-END adalah 5,9 ng/mL. Penelitian ini bertujuan menentukan persentase penderita kanker payudara (KPD) yang mencapai MTC Z-END pada saat steady state, hubungan genotip, fenotip, dan berbagai variabel terhadap pencapaian kadar Z-END dalam plasma, dan variabel yang paling berperan dalam pencapaian kadar Z-END. Penelitian cross sectional dilakukan di RS.Kanker Dharmais pada bulan Oktober 2017Februari 2018 terhadap 125 penderita KPD rawat jalan yang mengonsumsi TAM 20 mg/hari minimal 4 bulan. Tiga jam pasca minum sirup dekstrometorfan 30 mg dilakukan pengambilan darah untuk pemeriksaan kadar Z-END, serta genotyping dan phenotyping CYP2D6. Analisis deskriptif dilakukan pada semua variabel yang diteliti. Uji Chi-square dan Fisher digunakan untuk menentukan hubungan genotip, fenotip, karakteristik demografik, dan klinis terhadap pencapaian kadar Z-END. Analisis regresi logistik dilakukan pada variabelvaribel yang memenuhi syarat untuk menentukan variabel yang paling berperan dalam pencapaian kadar Z-END plasma. Batas kemaknaan statistik yang digunakan adalah p < 0,05. Penderita KPD yang mencapai kadar MTC Z-END ≥ 5,9 ng/mL pada saat steady state ada 52,8%. Persentase genotip CYP2D6*10 (c.100C>T) adalah C/C (22,4%), C/T(29,6%), dan T/T (48%). Persentase poor metabolizer (48,8%) dan non-poor metabolizer (51,2%). Tidak ditemukan hubungan bermakna antara genotip CYP2D6*10 (c.100C>T), karakteristik demografik, dan karakteristik klinis terhadap pencapaian kadar Z-END dalam plasma pada saat steady state. Analisis multivariat menunjukkan fenotip merupakan satu-satunya variabel yang berhubungan bermakna terhadap pencapaian kadar Z-END dalam plasma saat steady state. (OR = 0,064; 95%IK 0,0180,227; p < 0,001). Simpulan: Fenotip merupakan satu-satunya variabel yang berhubungan secara bermakna terhadap pencapaian kadar Z-END dalam plasma pada saat steady state pada penderita KPD di Indonesia.
Kata Kunci: CYP2D6*10 (c.100C>T), fenotip, genotip, kanker payudara, tamoksifen, Z-endoksifen


Tamoxifen (TAM) is a prodrug that needs to be activated by CYP2D6 into Zendoxifen (Z-END). The anti-estrogenic effect of TAM is concentration dependent and it is known from previous studies that the minimal threshold concentration (MTC) of Z-END is 5.9 ng/mL. The purpose of the present study was to determine the percentage of patients with breast cancer (BC) who attain steady state Z-END MTC, as well as the association of the phenotype, genotype, and several other variables with the attainment of plasma Z-END concentrations, and to find the variable with the greatest role in the attainment of the Z-END concentrations. This cross-sectional study was conducted at the Dharmais Cancer Hospital from October 2017 to February 2018 on 125 ambulatory BC patients who consumed TAM at 20 mg/day for a minimum of 4 months. Three hours after administration of 30 mg dextrometorphan syrup the subjects underwent collection of venous blood samples for determination of plasma Z-END concentration, as well as CYP2D6 genotyping and phenotyping. Descriptive analysis was performed on all variables under study. The chi-square test and Fisher’s test were used to determine the association of genotype, phenotype, demographic characteristics, and clinical characteristics with attainment of Z-END concentrations. Logistic regression analysis was used on variables meeting the requirements to determine the variable with the greatest role in the attainment of the plasma Z-END concentrations. The limit of statistical significance used was p < 0.05. The proportion of BC patients who attained a steady state Z-END MTC of ≥ 5.9 ng/mL was 52.8%. The percentages of the CYP2D6*10 (c.100C>T) genotypes C/C, C/T, and T/T were 22.4%, 29.6%, and 48%, respectively. The percentages of poor metabolizers and non-poor metabolizers were 48.8% and 51.2%, respectively. There was no significant association of the CYP2D6*10 (c.100C>T) genotype, demographic characteristics, and clinical characteristics with attainment of steady state plasma Z-END concentrations. Multivariate analysis showed that phenotype was the sole variable that had a significant association with attainment of steady state plasma Z-END concentrations (OR = 0.064; 95%CI 0.0180.227; p < 0.001). Conclusion: Phenotype is the sole variable that has a significant assoiation with attainment of steady state plasma Z-END concentrations in BC patients in Indonesia.
Keywords: breast cancer, CYP2D6*10 (c.100C>T), genotype, phenotype, tamoxifen, Z-endoxifen