RESUMO
The association between CYP2D6 genotype and outcome in breast cancer patients treated with adjuvant tamoxifen remains controversial. We assessed the influence of comprehensive versus limited CYP2D6 genotype in the context of tamoxifen adherence and co-medication in a large cohort of 618 patients. Genotyping of 33 CYP2D6 alleles used two archival cohorts from tamoxifen-treated women with invasive breast cancer (Dundee, n = 391; Manchester, n = 227). Estimates for recurrence-free survival (RFS) were calculated based on inferred CYP2D6 phenotypes using Kaplan-Meier and Cox proportional hazard models, adjusted for nodal status and tumour size. Patients with at least one reduced function CYP2D6 allele (60%) or no functional alleles (6%) had a non-significant trend for worse RFS: hazard ratio (HR) 1.52 (CI 0.98-2.36, P = 0.06). For post-menopausal women on tamoxifen monotherapy, the HR for recurrence in patients with reduced functional alleles was 1.96 (CI 1.05-3.66, P = 0.036). However, RFS analysis limited to four common CYP2D6 allelic variants was no longer significant (P = 0.39). The effect of CYP2D6 genotype was increased by adjusting for adherence to tamoxifen therapy, but not significantly changed when adjusted for co-administration of potent inhibitors of CYP2D6. Comprehensive genotyping of CYP2D6 and adherence to tamoxifen therapy may be useful to identify breast cancer patients most likely to benefit from adjuvant tamoxifen.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Moduladores de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Idoso , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6 , Intervalo Livre de Doença , Interações Medicamentosas , Inibidores Enzimáticos/uso terapêutico , Moduladores de Receptor Estrogênico/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Adesão à Medicação , Pessoa de Meia-Idade , Fenótipo , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Tamoxifeno/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer. EXPERIMENTAL DESIGN: We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery. RESULTS: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7). CONCLUSIONS: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Citocromo P-450 CYP2D6/genética , Antagonistas de Estrogênios/farmacocinética , Tamoxifeno/farmacocinética , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Feminino , Genes BRCA1 , Genes BRCA2 , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida , Tamoxifeno/uso terapêuticoRESUMO
A 39-year-old Afro-Caribbean man with Crohn disease with recurrent deep vein thromboses and pulmonary emboli was commenced on lifelong warfarin treatment. The patient required high-dose warfarin (>140 mg/wk), which increased further during azathioprine treatment. Cessation of azathioprine resulted in an increase in the international normalized ratio (INR). Mutation analysis identified a Val66Met substitution in vitamin K epoxide reductase complex subunit 1 (VKORC1), consistent with severe warfarin resistance. This report is the first presentation where the patient had a defined hereditary resistance to warfarin, which was aggravated by concomitant azathioprine. It is important for clinicians to be aware of the interaction between warfarin and azathioprine, to monitor clinical response closely, and to manage the doses of both drugs accordingly.