Impaired tamoxifen metabolism reduces survival in familial breast cancer patients.
Authors
Newman, William GHadfield, Kristen D
Latif, Ayshe
Roberts, Stephen A
Shenton, Andrew
McHague, Christopher
Lalloo, Fiona
Howell, Sacha J
Evans, D Gareth R
Affiliation
Department of Medical Genetics, St. Mary's Hospital, University of Manchester, Manchester, United Kingdom. William.newman@manchester.ac.ukIssue Date
2008-09-15
Metadata
Show full item recordAbstract
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.Citation
Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. 2008, 14 (18):5913-8 Clin. Cancer Res.Journal
Clinical Cancer ResearchDOI
10.1158/1078-0432.CCR-07-5235PubMed ID
18794105Type
ArticleLanguage
enISSN
1078-0432ae974a485f413a2113503eed53cd6c53
10.1158/1078-0432.CCR-07-5235
Scopus Count
Related articles
- Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen.
- Authors: Siegelmann-Danieli N, Kurnik D, Lomnicky Y, Vesterman-Landes J, Katzir I, Bialik M, Loebstein R
- Issue date: 2011 Jan
- Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy.
- Authors: Damodaran SE, Pradhan SC, Umamaheswaran G, Kadambari D, Reddy KS, Adithan C
- Issue date: 2012 Jul
- Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer.
- Authors: Dezentjé VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ
- Issue date: 2010 May 10
- The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users.
- Authors: Bijl MJ, van Schaik RH, Lammers LA, Hofman A, Vulto AG, van Gelder T, Stricker BH, Visser LE
- Issue date: 2009 Nov
- Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment.
- Authors: Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, Jin Y, Storniolo AM, Nikoloff DM, Wu L, Hillman G, Hayes DF, Stearns V, Flockhart DA
- Issue date: 2006 Jul