Tamoxifen Use in Postmenopausal Breast Cancer: CYP2D6 Matters

Abstract

The question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome in patients with early postmenopausal breast cancer has been a matter of debate. With the recent negative results with regard to CYP2D6 genotyping from the Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen, Alone or in Combination (ATAC) studies, the study investigators suggest that testing for CYP2D6 has no value in clinical practice.1,2 The authors of the accompanying editorial conclude that this matter can be likely laid to rest.3 However, pharmacogenetic experts demanded the retraction of the BIG 1-98 CYP2D6 study4 on the basis of massive departures from Hardy-Weinberg equilibrium (HWE; Table 1), possibly because of the bias that may result when the CYP2D6 genotype is obtained from the tumor (somatic) genome and not the host genome (germline DNA). Various authors in their letters attribute the highly distorted genotype frequencies to allelic imbalance associated with loss of heterozygosity (LOH) in breast tumor tissue,4,5 deviation from the standard genotyping assay protocol,5 or the presence of pseudogenes neighboring the CYP2D6 locus.6 Because the BIG 1-98 and ATAC pharmacogenetic studies may be considered sufficient to settle the issue of the value of CYP2D6 in decision making regarding endocrine therapy in postmenopausal women with breast cancer, we revisit the hypothesis, comment on the complementary evidence, and discuss pros and cons of the validity of CYP2D6 tamoxifen pharmacogenetics.