Al-Matrafi Abdullah R, Bedair Khaled F, Srinivasan Sundararajan, Palmer Colin, Campbell Archie, Hayward Caroline, Pearson Ewan R, Petty Russell D
Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK.
Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
BMC Cancer. 2025 Jun 1;25(1):974. doi: 10.1186/s12885-025-14162-4.
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.
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).
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, CYP2D64 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.
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.
研究他莫昔芬剂量、CYP2D6抑制剂、CYP2D6*4基因型及非遗传参数对接受他莫昔芬治疗的女性乳腺癌患者预后的影响。
我们回顾性纳入了3218例确诊乳腺癌后开始服用他莫昔芬且进行长期随访（中位随访时间7.5年）的女性患者。还对303例进行基因分型且中位随访时间为9.7年的患者进行了亚组分析。感兴趣的结局指标为总生存期（OS）和乳腺癌特异性生存期（BCS）。
在整个队列中，六个月期间他莫昔芬剂量额外增加20 mg与全因死亡率降低1.6%（风险比：0.984，95%置信区间：0.982 - 0.985，P < 0.001）及乳腺癌死亡率降低1.9%（风险比：0.981，95%置信区间：0.979 - 0.984，P < 0.001）相关。在基因分型亚组中，CYP2D64杂合子的全因死亡风险比4非携带者高76%（风险比：1.76，95%置信区间：1.07 - 2.9，P = 0.025）。对于乳腺癌特异性死亡率，CYP2D6*4杂合子和纯合子的风险分别增加3.7倍（风险比：3.7，95%置信区间：1.32 - 10.6，P = 0.01）和11.6倍（风险比：11.6，95%置信区间：1.3 - 103.5，P = 0.03）。
我们的研究表明，CYP2D6*4携带者的携带者的全因死亡率和乳腺癌特异性死亡率均较高，且表明较长的随访时间对于确定影响可能至关重要。既往研究随访时间较短可能是结果相互矛盾的关键原因。有必要开展一项长期随访的大型真实世界药物基因组学研究，以确定CYP2D6基因分型的影响及其对临床决策的意义。
