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Anders Kjærsgaard

Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin

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Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin. / Ahern, Thomas P.; Damkier, Per; Feddersen, Søren; Kjærsgaard, Anders; Lash, Timothy L.; Hamilton-Dutoit, Stephen; Lythjohan, Cathrine Bredal; Ejlertsen, Bent; Christiansen, Peer M.; Cronin-Fenton, Deirdre P.

I: Acta Oncologica, Bind 59, Nr. 9, 2020, s. 1009-1015.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{e3754e7a18a94e03a52245cde8072f9a,
title = "Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin",
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.",
keywords = "CIVIL REGISTRATION SYSTEM, CLINICAL DATABASE, COOPERATIVE GROUP, CYP3A5, GROUP DBCG, IMPACT, IMPLEMENTATION, SLCO1B1, STATIN USE, TREATMENT GUIDELINES",
author = "Ahern, {Thomas P.} and Per Damkier and S{\o}ren Feddersen and Anders Kj{\ae}rsgaard and Lash, {Timothy L.} and Stephen Hamilton-Dutoit and Lythjohan, {Cathrine Bredal} and Bent Ejlertsen and Christiansen, {Peer M.} and Cronin-Fenton, {Deirdre P.}",
year = "2020",
doi = "10.1080/0284186X.2020.1759820",
language = "English",
volume = "59",
pages = "1009--1015",
journal = "Acta Oncologica",
issn = "0284-186X",
publisher = "Taylor & Francis ",
number = "9",

}

RIS

TY - JOUR

T1 - Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin

AU - Ahern, Thomas P.

AU - Damkier, Per

AU - Feddersen, Søren

AU - Kjærsgaard, Anders

AU - Lash, Timothy L.

AU - Hamilton-Dutoit, Stephen

AU - Lythjohan, Cathrine Bredal

AU - Ejlertsen, Bent

AU - Christiansen, Peer M.

AU - Cronin-Fenton, Deirdre P.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - CIVIL REGISTRATION SYSTEM

KW - CLINICAL DATABASE

KW - COOPERATIVE GROUP

KW - CYP3A5

KW - GROUP DBCG

KW - IMPACT

KW - IMPLEMENTATION

KW - SLCO1B1

KW - STATIN USE

KW - TREATMENT GUIDELINES

UR - http://www.scopus.com/inward/record.url?scp=85084269436&partnerID=8YFLogxK

U2 - 10.1080/0284186X.2020.1759820

DO - 10.1080/0284186X.2020.1759820

M3 - Journal article

C2 - 32351149

AN - SCOPUS:85084269436

VL - 59

SP - 1009

EP - 1015

JO - Acta Oncologica

JF - Acta Oncologica

SN - 0284-186X

IS - 9

ER -