Abstract
AIM: To investigate the impact of tamoxifen dose, CYP2D6 inhibitors, CYP2D6*4 genotype, and non-genetic parameters on the outcomes of tamoxifen treated female breast cancer patients. METHOD: We retrospectively included 3218 female patients who initiated tamoxifen following a diagnosis of breast cancer with long-term follow-up (median 7.5 years). A subgroup analysis of 303 genotyped patients with a median follow-up of 9.7 years was also conducted. The outcomes of interest were overall survival (OS) and breast-cancer-specific survival (BCS). RESULTS: In the whole cohort, an additional 20 mg of tamoxifen during six-month duration was associated with a 1.6% reduction in all-cause mortality (HR: 0.984, 95% CI: 0.982-0.985, P < 0.001) and a 1.9% decrease in breast cancer mortality (HR: 0.981, 95% CI: 0.979-0.984, P < 0.001). In the genotyped subgroup, CYP2D6*4 heterozygotes had a 76% greater risk of all-cause mortality than *4 non-carriers (HR: 1.76, 95% CI: 1.07-2.9, P = 0.025). For breast cancer-specific mortality, CYP2D6*4 heterozygotes and homozygotes had increased risk by 3.7-fold (HR: 3.7, 95% CI: 1.32-10.6, P = 0.01) and 11.6-fold (HR: 11.6, 95% CI: 1.3-103.5, P = 0.03), respectively. CONCLUSION: Our study demonstrates that carriers of CYP2D6*4 have a higher risk of both all-cause and breast cancer-specific mortality and indicates that longer follow-up time may be crucial to determining impact. The shorter follow-up in previous studies may be a key reason for the conflicting results. A large real-world pharmacogenomic study with long-term follow-up is warranted to determine the impact of CYP2D6 genotyping and its implications for clinical decision making.