Thomas P Ahern1, Per Damkier2,3, Søren Feddersen2,3, Anders Kjærsgaard4, Timothy L Lash5, Stephen Hamilton-Dutoit6, Cathrine Bredal Lythjohan6, Bent Ejlertsen7,8, Peer M Christiansen7,9, Deirdre P Cronin-Fenton4. 1. Departments of Surgery and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT, USA. 2. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. 3. Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 4. Department of Clinical Epidemiology, Aarhus University Hospital/Randers Regional Hospital, Aarhus, Denmark. 5. Department of Epidemiology, Rollins School of Public Health and Winship Cancer Institute, Emory University, Atlanta, GA, USA. 6. Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark. 7. Danish Breast Cancer Group, Rigshospitalet, Copenhagen, Denmark. 8. Department of Oncology, Rigshospitalet, Copenhagen, Denmark. 9. Department of Plastic and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark.
Abstract
Background: Statins treat hyperlipidemia and prevent cardiovascular morbidity and mortality. Evidence suggests that they also have anti-neoplastic activity. Several studies show a reduced rate of breast cancer recurrence among lipophilic statin users (e.g., simvastatin), motivating calls for clinical trials of statins in breast cancer patients. We measured the impact of genetic variation in statin-metabolizing enzymes and drug transporters on the recurrence rate in simvastatin-treated breast cancer patients. Methods: We conducted a nested case-control study among Danish women diagnosed with non-metastatic, invasive breast cancer between 2004-2010 who had filled ≥1 prescription for simvastatin after diagnosis. Cases were all breast cancer recurrences from the source population; one control was matched to each case on cancer stage, estrogen receptor and hormone therapy status, calendar period of diagnosis, and duration of simvastatin exposure. We genotyped variants in simvastatin-metabolizing enzymes (CYP3A4/rs35599367 and CYP3A5/rs776746) and drug transporters (ABCB1/rs2032582 and SLCO1B1/rs4149056), and estimated their association with recurrence with logistic regression models. Results: We observed protective (though imprecisely-measured) associations between variants in genes encoding drug transporters (ABCB1 and SLCO1B1) and simvastatin-metabolizing enzymes (CYP3A4 and CYP3A5) and breast cancer recurrence in simvastatin-treated women. For example, carrying two variant alleles in ABCB1 was associated with a 31% lower rate of recurrence (multivariable OR = 0.69, 95% CI: 0.31, 1.5). Conclusion: Our study provides weak evidence to support the use of genetic variation in ABCB1, SLCO1B1, CYP3A4, and CYP3A5 as biomarkers of breast tumor response to simvastatin. Validation of these findings within adjuvant clinical trials is encouraged.
Background: Statins treat hyperlipidemia and prevent cardiovascular morbidity and mortality. Evidence suggests that they also have anti-neoplastic activity. Several studies show a reduced rate of breast cancer recurrence among lipophilic statin users (e.g., simvastatin), motivating calls for clinical trials of statins in breast cancerpatients. We measured the impact of genetic variation in statin-metabolizing enzymes and drug transporters on the recurrence rate in simvastatin-treated breast cancerpatients. Methods: We conducted a nested case-control study among Danish women diagnosed with non-metastatic, invasive breast cancer between 2004-2010 who had filled ≥1 prescription for simvastatin after diagnosis. Cases were all breast cancer recurrences from the source population; one control was matched to each case on cancer stage, estrogen receptor and hormone therapy status, calendar period of diagnosis, and duration of simvastatin exposure. We genotyped variants in simvastatin-metabolizing enzymes (CYP3A4/rs35599367 and CYP3A5/rs776746) and drug transporters (ABCB1/rs2032582 and SLCO1B1/rs4149056), and estimated their association with recurrence with logistic regression models. Results: We observed protective (though imprecisely-measured) associations between variants in genes encoding drug transporters (ABCB1 and SLCO1B1) and simvastatin-metabolizing enzymes (CYP3A4 and CYP3A5) and breast cancer recurrence in simvastatin-treated women. For example, carrying two variant alleles in ABCB1 was associated with a 31% lower rate of recurrence (multivariable OR = 0.69, 95% CI: 0.31, 1.5). Conclusion: Our study provides weak evidence to support the use of genetic variation in ABCB1, SLCO1B1, CYP3A4, and CYP3A5 as biomarkers of breast tumor response to simvastatin. Validation of these findings within adjuvant clinical trials is encouraged.
Authors: Daniel J Schaid; Anthony J Batzler; Gregory D Jenkins; Michelle A T Hildebrandt Journal: Am J Hum Genet Date: 2006-11-03 Impact factor: 11.025
Authors: Marilu Fiegenbaum; Fabiano R da Silveira; Cézar R Van der Sand; Luiz Carlos Van der Sand; Maria E W Ferreira; Renan C Pires; Mara H Hutz Journal: Clin Pharmacol Ther Date: 2005-09-26 Impact factor: 6.875
Authors: Anders H Riis; Rune Erichsen; Eva B Ostenfeld; Carsten S Højskov; Ole Thorlacius-Ussing; Mogens Tornby Stender; Timothy L Lash; Holger Jon Møller Journal: Pharmacoepidemiol Drug Saf Date: 2019-02-19 Impact factor: 2.890