Clinical and pharmacogenomic predictors of survival in tamoxifen treated breast cancer female patients: a real-world study

TY - JOUR

T1 - Clinical and pharmacogenomic predictors of survival in tamoxifen treated breast cancer female patients

T2 - a real-world study

AU - Al-Matrafi, Abdullah R

AU - Bedair, Khaled F

AU - Srinivasan, Sundararajan

AU - Palmer, Colin

AU - Campbell, Archie

AU - Hayward, Caroline

AU - Pearson, Ewan R

AU - Petty, Russell D

N1 - © 2025. The Author(s).

PY - 2025/6/1

Y1 - 2025/6/1

N2 - 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.

AB - 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.

KW - Humans

KW - Female

KW - Tamoxifen/therapeutic use

KW - Breast Neoplasms/drug therapy

KW - Cytochrome P-450 CYP2D6/genetics

KW - Middle Aged

KW - Retrospective Studies

KW - Antineoplastic Agents, Hormonal/therapeutic use

KW - Aged

KW - Adult

KW - Genotype

KW - Pharmacogenetics

KW - Follow-Up Studies

KW - Prognosis

KW - Cytochrome P-450 CYP2D6 Inhibitors/therapeutic use

U2 - 10.1186/s12885-025-14162-4

DO - 10.1186/s12885-025-14162-4

M3 - Article

C2 - 40452016

SN - 1471-2407

VL - 25

JO - BMC Cancer

JF - BMC Cancer

IS - 1

M1 - 974

ER -