CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study Journal Article

Authors: Brooks, J. D.; Comen, E. A.; Reiner, A. S.; Orlow, I.; Leong, S. F.; Liang, X.; Mellemkjær, L.; Knight, J. A.; Lynch, C. F.; John, E. M.; Bernstein, L.; Woods, M.; Doody, D. R.; WECARE Study Collaborative Group; Malone, K. E.; Bernstein, J. L.
Contributors: Capanu, M.; Robson, M.
Article Title: CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study
Abstract: Background: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. Methods: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. Results: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). Conclusion: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC. © 2018 The Author(s).
Keywords: tamoxifen; contralateral breast cancer; cyp2d6
Journal Title: Breast Cancer Research
Volume: 20
ISSN: 1465-5411
Publisher: Biomed Central Ltd  
Date Published: 2018-12-10
Start Page: 149
Language: English
DOI: 10.1186/s13058-018-1083-y
PROVIDER: scopus
PMCID: PMC6288916
PUBMED: 30526633
Notes: Breast Cancer Res. -- Export Date: 2 January 2019 -- Article -- CODEN: BCRRC C2 - 30526633 -- Source: Scopus C7 - 49
Citation Impact
MSK Authors
  1. Anne S Reiner
    195 Reiner
  2. Mark E Robson
    609 Robson
  3. Irene Orlow
    231 Orlow
  4. Marinela Capanu
    337 Capanu
  5. Elizabeth Comen
    66 Comen
  6. Jonine L Bernstein
    130 Bernstein
  7. Xiaolin Liang
    52 Liang
  8. Meghan   Woods
    22 Woods
  9. Siok Fun Leong
    9 Leong