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Grant Details

Grant Number: 5R01CA166825-05 Interpret this number
Primary Investigator: Lash, Timothy
Organization: Emory University
Project Title: New and Integrated Perspectives on Modification of Tamoxifen Effectiveness
Fiscal Year: 2017


Abstract

DESCRIPTION (provided by applicant): About 200,000 US women are diagnosed with invasive breast cancer each year. About one-third are pre-menopausal and two-thirds have tumors that express estrogen receptor alpha (ERα). These women usually receive tamoxifen therapy, which competes with estrogen for binding to the estrogen receptor, but does not stimulate tumor growth. Five-years of tamoxifen therapy reduces recurrence risk by almost half. Efforts to identify biomarkers of tamoxifen resistance-beyond the absence of ERα-have met little success. Because tamoxifen requires metabolic activation to optimize its preventive effect,markers of metabolic inhibition are ideal biomarker candidates. Studies to date have focused only on this aspect of the competition to occupy the estrogen receptor between tamoxifen (and its metabolites) and estrogen (and its compounds). However, metabolic inhibition is unlikely to strongly predict recurrence risk in all ERα+ patients. We propose an innovative perspective that incorporates both sides of the competition, as well as the estrogen receptor itself, in the only patient group (premenopausal women) for whom tamoxifen remains the first line endocrine therapy. No study has focused on pre-menopausal women, despite guidelines recommending only tamoxifen for pre-menopausal women, and despite reason to think the modification might be most important to them. Aim #1: Include only pre-menopausal breast cancer patients, collect data on their pharmaceutical inhibition of tamoxifen metabolism, genotype 66 genetic variants in 13 enzymes that affect the concentration of the most active tamoxifen metabolites, and evaluate the association between these variants and recurrence. ERα+ breast cancer patients whose tumor also expresses ERβ may not need fully activated tamoxifen to prevent recurrence, whereas women with ERβ-negative tumors probably require full metabolic capacity. Aim #2: Assay ERβ expression, estimate the association between metabolic inhibition and recurrence in ERβ strata, and evaluate interaction between metabolic inhibition and ERβ status in the combined population. Women whose tumors do not make a lot of estrogen to compete with tamoxifen (17β-hydroxysteroid dehydrogenase 1<2) may not need fully activated tamoxifen to prevent recurrence, whereas women whose tumors make a lot of estrogen to compete with tamoxifen probably require full metabolic capacity. Aim #3: Assay 17βHSD1 and 17βHSD2 expression, estimate the association between 17βHSD1/2 ratio >1-, versus d1-and recurrence, and evaluate the interaction between metabolic inhibition and this ratio.



Publications

Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin.
Authors: Ahern T.P. , Damkier P. , Feddersen S. , Kjærsgaard A. , Lash T.L. , Hamilton-Dutoit S. , Lythjohan C.B. , Ejlertsen B. , Christiansen P.M. , Cronin-Fenton D.P. .
Source: Acta oncologica (Stockholm, Sweden), 2020 Sep; 59(9), p. 1009-1015.
EPub date: 2020-04-30.
PMID: 32351149
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Improving the transparency of meta-analyses with interactive web applications.
Authors: Ahern T.P. , MacLehose R.F. , Haines L. , Cronin-Fenton D.P. , Damkier P. , Collin L.J. , Lash T.L. .
Source: BMJ evidence-based medicine, 2020-03-27; , .
EPub date: 2020-03-27.
PMID: 32220861
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Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients.
Authors: Ahern T.P. , Collin L.J. , Baurley J.W. , Kjærsgaard A. , Nash R. , Maliniak M.L. , Damkier P. , Zwick M.E. , Isett R.B. , Christiansen P.M. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 03; 29(3), p. 582-590.
EPub date: 2020-01-13.
PMID: 31932415
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17β-Hydroxysteroid dehydrogenase 1:2 and breast cancer recurrence: a Danish population-based study.
Authors: Collin L.J. , Ulrichsen S.P. , Ahern T.P. , Goodman M. , McCullough L.E. , Waller L.A. , Bang Christensen K. , Damkier P. , Hamilton-Dutoit S. , Lauridsen K.L. , et al. .
Source: Acta oncologica (Stockholm, Sweden), 2020 Mar; 59(3), p. 329-333.
EPub date: 2019-10-31.
PMID: 31671023
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Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study.
Authors: Ahern T.P. , Broe A. , Lash T.L. , Cronin-Fenton D.P. , Ulrichsen S.P. , Christiansen P.M. , Cole B.F. , Tamimi R.M. , Sørensen H.T. , Damkier P. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019-07-20; 37(21), p. 1800-1809.
EPub date: 2019-04-17.
PMID: 30995175
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Multi-drug resistance protein 2 (MRP2) expression, adjuvant tamoxifen therapy, and risk of breast cancer recurrence: a Danish population-based nested case-control study.
Authors: Hjorth C.F. , Nielsen A.S. , Sørensen H.T. , Lash T.L. , Damkier P. , Hamilton-Dutoit S. , Cronin-Fenton D. .
Source: Acta oncologica (Stockholm, Sweden), 2019 Feb; 58(2), p. 168-174.
EPub date: 2018-11-20.
PMID: 30458661
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Expression of survivin does not appear to influence breast cancer recurrence risk.
Authors: Collin L.J. , Cronin-Fenton D.P. , Ahern T.P. , Christensen K.B. , Damkier P. , Hamilton-Dutoit S. , Kjaersgaard A. , Lauridsen K.L. , Yacoub R. , Christiansen P. , et al. .
Source: Acta oncologica (Stockholm, Sweden), 2019 Feb; 58(2), p. 154-161.
EPub date: 2018-10-23.
PMID: 30351173
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Cohort Profile: the Predictors of Breast Cancer Recurrence (ProBe CaRE) Premenopausal Breast Cancer Cohort Study in Denmark.
Authors: Collin L.J. , Cronin-Fenton D.P. , Ahern T.P. , Christiansen P.M. , Damkier P. , Ejlertsen B. , Hamilton-Dutoit S. , Kjærsgaard A. , Silliman R.A. , Sørensen H.T. , et al. .
Source: BMJ open, 2018-08-01; 8(7), p. e021805.
EPub date: 2018-08-01.
PMID: 30068618
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Stanniocalcin Expression as a Predictor of Late Breast Cancer Recurrence.
Authors: Brantley K.D. , Kjærsgaard A. , Cronin-Fenton D. , Yacoub R. , Nielsen A.S. , Lauridsen K.L. , Hamilton-Dutoit S. , Lash T.L. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2018 06; 27(6), p. 653-659.
EPub date: 2018-03-28.
PMID: 29593009
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Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics.
Authors: Cronin-Fenton D.P. , Damkier P. .
Source: Advances in pharmacology (San Diego, Calif.), 2018; 83, p. 65-91.
EPub date: 2018-05-07.
PMID: 29801584
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The effect of 14-3-3ζ expression on tamoxifen resistance and breast cancer recurrence: a Danish population-based study.
Authors: Thistle J.E. , Hellberg Y. , Mortensen K. , Hamilton-Dutoit S. , Kjærsgaard A. , Cronin-Fenton D. , Sørensen H.T. , Lash T.L. .
Source: Breast cancer research and treatment, 2017 Oct; 165(3), p. 633-643.
EPub date: 2017-06-22.
PMID: 28643021
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CYP2C19*2 and CYP2C19*17 variants and effect of tamoxifen on breast cancer recurrence: Analysis of the International Tamoxifen Pharmacogenomics Consortium dataset.
Authors: Damkier P. , Kjærsgaard A. , Barker K.A. , Cronin-Fenton D. , Crawford A. , Hellberg Y. , Janssen E.A.M. , Langefeld C. , Ahern T.P. , Lash T.L. .
Source: Scientific reports, 2017-08-10; 7(1), p. 7727.
EPub date: 2017-08-10.
PMID: 28798474
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Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.
Authors: Ahern T.P. , Hertz D.L. , Damkier P. , Ejlertsen B. , Hamilton-Dutoit S.J. , Rae J.M. , Regan M.M. , Thompson A.M. , Lash T.L. , Cronin-Fenton D.P. .
Source: American journal of epidemiology, 2017-01-15; 185(2), p. 75-85.
EPub date: 2016-12-17.
PMID: 27988492
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Low-dose Aspirin, Nonsteroidal Anti-inflammatory Drugs, Selective COX-2 Inhibitors and Breast Cancer Recurrence.
Authors: Cronin-Fenton D.P. , Heide-Jørgensen U. , Ahern T.P. , Lash T.L. , Christiansen P. , Ejlertsen B. , Sørensen H.T. .
Source: Epidemiology (Cambridge, Mass.), 2016 07; 27(4), p. 586-93.
PMID: 27007644
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Pak1, adjuvant tamoxifen therapy, and breast cancer recurrence risk in a Danish population-based study.
Authors: Ahern T.P. , Cronin-Fenton D.P. , Lash T.L. , Sørensen H.T. , Ording A.G. , Hamilton-Dutoit S.J. , Hellberg Y. .
Source: Acta oncologica (Stockholm, Sweden), 2016 Jun; 55(6), p. 734-41.
EPub date: 2016-04-08.
PMID: 27056567
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Opioids and breast cancer recurrence: A Danish population-based cohort study.
Authors: Cronin-Fenton D.P. , Heide-Jørgensen U. , Ahern T.P. , Lash T.L. , Christiansen P.M. , Ejlertsen B. , Sjøgren P. , Kehlet H. , Sørensen H.T. .
Source: Cancer, 2015-10-01; 121(19), p. 3507-14.
EPub date: 2015-07-24.
PMID: 26207518
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Autoimmune diseases and breast cancer recurrence: a Danish nationwide cohort study.
Authors: Lietzen L.W. , Cronin-Fenton D. , Christiansen P. , Sørensen H.T. , Lash T.L. .
Source: Breast cancer research and treatment, 2015 Jan; 149(2), p. 497-504.
EPub date: 2015-01-03.
PMID: 25555832
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Glucocorticoid prescriptions and breast cancer recurrence: a Danish nationwide prospective cohort study.
Authors: Lietzen L.W. , Ahern T. , Christiansen P. , Jensen A.B. , Sørensen H.T. , Lash T.L. , Cronin-Fenton D.P. .
Source: Annals of oncology : official journal of the European Society for Medical Oncology, 2014 Dec; 25(12), p. 2419-2425.
EPub date: 2014-09-15.
PMID: 25223486
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Statins and breast cancer prognosis: evidence and opportunities.
Authors: Ahern T.P. , Lash T.L. , Damkier P. , Christiansen P.M. , Cronin-Fenton D.P. .
Source: The Lancet. Oncology, 2014 Sep; 15(10), p. e461-8.
PMID: 25186049
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Manganese superoxide dismutase and breast cancer recurrence: a Danish clinical registry-based case-control study, and a meta-analysis.
Authors: Cronin-Fenton D.P. , Christensen M. , Lash T.L. , Ahern T.P. , Pedersen L. , Garne J.P. , Ewertz M. , Autrup H. , Sørensen H.T. , Hamilton-Dutoit S. .
Source: PloS one, 2014; 9(1), p. e87450.
EPub date: 2014-01-31.
PMID: 24498107
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Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy.
Authors: Cronin-Fenton D.P. , Damkier P. , Lash T.L. .
Source: Future oncology (London, England), 2014 Jan; 10(1), p. 107-22.
PMID: 24328412
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