Impaired tamoxifen metabolism reduces survival in familial breast cancer patients.

2.50
Hdl Handle:
http://hdl.handle.net/10541/59213
Title:
Impaired tamoxifen metabolism reduces survival in familial breast cancer patients.
Authors:
Newman, William G; Hadfield, Kristen D; Latif, Ayshe; Roberts, Stephen A; Shenton, Andrew; McHague, Christopher; Lalloo, Fiona; Howell, Sacha J; Evans, D Gareth R
Abstract:
PURPOSE: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer. EXPERIMENTAL DESIGN: We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery. RESULTS: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7). CONCLUSIONS: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.
Affiliation:
Department of Medical Genetics, St. Mary's Hospital, University of Manchester, Manchester, United Kingdom. William.newman@manchester.ac.uk
Citation:
Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. 2008, 14 (18):5913-8 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
15-Sep-2008
URI:
http://hdl.handle.net/10541/59213
DOI:
10.1158/1078-0432.CCR-07-5235
PubMed ID:
18794105
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Christie Publications ; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorNewman, William G-
dc.contributor.authorHadfield, Kristen D-
dc.contributor.authorLatif, Ayshe-
dc.contributor.authorRoberts, Stephen A-
dc.contributor.authorShenton, Andrew-
dc.contributor.authorMcHague, Christopher-
dc.contributor.authorLalloo, Fiona-
dc.contributor.authorHowell, Sacha J-
dc.contributor.authorEvans, D Gareth R-
dc.date.accessioned2009-04-02T16:06:39Z-
dc.date.available2009-04-02T16:06:39Z-
dc.date.issued2008-09-15-
dc.identifier.citationImpaired tamoxifen metabolism reduces survival in familial breast cancer patients. 2008, 14 (18):5913-8 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid18794105-
dc.identifier.doi10.1158/1078-0432.CCR-07-5235-
dc.identifier.urihttp://hdl.handle.net/10541/59213-
dc.description.abstractPURPOSE: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer. EXPERIMENTAL DESIGN: We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery. RESULTS: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7). CONCLUSIONS: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectFamilial Breast Canceren
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCytochrome P-450 CYP2D6-
dc.subject.meshEstrogen Antagonists-
dc.subject.meshFemale-
dc.subject.meshGenes, BRCA1-
dc.subject.meshGenes, BRCA2-
dc.subject.meshGenotype-
dc.subject.meshHumans-
dc.subject.meshMiddle Aged-
dc.subject.meshMutation-
dc.subject.meshSurvival Analysis-
dc.subject.meshTamoxifen-
dc.titleImpaired tamoxifen metabolism reduces survival in familial breast cancer patients.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Genetics, St. Mary's Hospital, University of Manchester, Manchester, United Kingdom. William.newman@manchester.ac.uken
dc.identifier.journalClinical Cancer Researchen

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