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

Breast Cancer Research

The WECARE Study collaborative group¹  Leslie Bernstein²  Lene Mellemkjær³  Esther M. John⁴  David R. Doody⁵  Kathleen E. Malone⁵  Elizabeth A. Comen⁶  Xiaolin Liang⁶  Irene Orlow⁶  Siok F. Leong⁶  Meghan Woods⁶  Jonine L. Bernstein⁶  Anne S. Reiner⁶  Charles F. Lynch⁷  Jennifer D. Brooks⁸  Julia A. Knight⁸ 

[1] ;Beckman Research Institute, City of Hope National Medical Centre;Danish Cancer Society Research Center;Department of Medicine and Stanford Cancer Institute, Stanford University School of Medicine;Fred Hutchinson Cancer Research Center;Memorial Sloan Kettering Cancer Center;University of Iowa;University of Toronto, Dalla Lana School of Public Health Sciences;

关键词: Contralateral breast cancer;    Tamoxifen;    CYP2D6;   

DOI  :  10.1186/s13058-018-1083-y

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown