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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
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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 (ER?). 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 ER?-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 ER?+ 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. ER?+ breast cancer patients whose tumor also expresses ER? may not need fully activated tamoxifen to prevent recurrence, whereas women with ER?-negative tumors probably require full metabolic capacity. Aim #2: Assay ER? expression, estimate the association between metabolic inhibition and recurrence in ER? strata, and evaluate interaction between metabolic inhibition and ER? status in the combined population. Women whose tumors do not make a lot of estrogen to compete with tamoxifen (17?-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 17?HSD1 and 17?HSD2 expression, estimate the association between 17?HSD1/2 ratio >1-, versus d1-and recurrence, and evaluate the interaction between metabolic inhibition and this ratio.

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Publications

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), 2018-10-23; , p. 1-8.
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 00:00:00.0; 8(7), p. e021805.
EPub date: 2018-08-01 00:00:00.0.
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, 2018-03-28 00:00:00.0; , .
EPub date: 2018-03-28 00:00:00.0.
PMID: 29593009
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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 00:00:00.0; 7(1), p. 7727.
EPub date: 2017-08-10 00:00:00.0.
PMID: 28798474
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The effect of 14-3-3? 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, 2017-06-22 00:00:00.0; , .
EPub date: 2017-06-22 00:00:00.0.
PMID: 28643021
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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 00:00:00.0; 185(2), p. 75-85.
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 Jul; 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.
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 00:00:00.0; 121(19), p. 3507-14.
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.
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 / Esmo, 2014 Dec; 25(12), p. 2419-25.
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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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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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.
PMID: 24498107
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