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Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic  CYP2D6  gene.  CYP2D6  variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment  CYP2D6  gene testing assay is available. However, evidence from published studies evaluating  CYP2D6  variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of  CYP2D6  testing. We investigated the association of  CYP2D6  variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen.    Methods  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.    Results  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.    Conclusions   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.

breast cancer research

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