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CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen

DOI: 10.1186/bcr2629

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This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis.In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups.CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.Tamoxifen has been the standard treatment for oestrogen receptor (ER)-positive breast cancer for more than three decades. Indications for its use [1] include: metastatic disease in women (pre- and post-menopausal) and men; adjuvant therapy in pre- and post-menopausal women with breast cancer (lymph node positive and negative); preventative therapy in women at high risk of breast cancer; ductal carcinoma in situ post-resection; and for the prevention of contra-lateral breast cancer. There are proven benefits ass


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