Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes

Abstract

Because genetically determined, impaired tamoxifen metabolism results in worse treatment outcomes, genotyping for CYP2D6 alleles *4, *5, *10, and *41 can identify patients who will have little benefit from adjuvant tamoxifen therapy. In addition to functional CYP2D6 alleles, the CYP2C19 *17 variant identifies patients likely to benefit from tamoxifen.

Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment

“…Although the present work has some limitations (the retrospective bias selection of patients, the sample size, the possible use of co-administered inhibitors and the infrequency of the CYP2D6 variants in the European population) our results clearly show a significant association between an absent or reduced enzyme function-homozygous or compound heterozygous for CYP2D6 alleles *4, *5, and *41-and worse disease-free survival. Benefits in event-free survival were similar to those found by Schroth and Goetz [14,15]. The fact that CYP2D6 poorer metabolizers have a worse clinical outcome than better metabolizers could be related to a reduced tamoxifen metabolism and lower endoxifen levels in the former; if we assume that a certain level of endoxifen is sufficient and necessary for tamoxifen efficacy, this level would not be reached by neither any CYP2D6 poor metabolizer nor by some of the patients with an intermediate metabolizer genotype.…”

“…Previous studies have evaluated the association between CYP2D6 genotype and clinical outcomes in women treated with adjuvant tamoxifen [11][12][13][14][15]. Two studies [14,15] retrospectively enrolled relatively homogeneous populations of patients who were estrogen-receptor positive.…”

“…Two studies [14,15] retrospectively enrolled relatively homogeneous populations of patients who were estrogen-receptor positive. The studies differed in that Goetz et al [14] only genotyped for the CYP2D6*4 nonfunctional variant, whereas Schroth et al [15] also tested for the *5 nonfunctional variant, and for the *10 and *41 reduced function variants. Evidence from these two studies suggests that women treated with tamoxifen who are functional poor or intermediate CYP2D6 metabolizers have a significantly shorter time to recurrence and recurrence-free survival (but not overall survival) as compared to EMs.…”

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

“…Recently, it has been shown that CYP2C19 may be a risk factor per se, or that it can be important for tamoxifen response and is further enhanced by its association with CYP2D6. 19 Our data do not confirm this observation, possibly because of the relatively low number of subjects with these SNPs variants. It has also been reported that SULT1A1 may influence tamoxifen metabolites' concentration.…”

“…18,19 Moreover, the clearance, mediated by sulfotransferase (SULT)1A1 and UDP-glucuronosyltransferase (UGT) 2B15 and UGT1A4, may regulate the metabolite concentration as reported by Nowell et al 20 So far the main focus of research has been on CYP2D6 PMs, although activity enhancement may also have clinical relevance. Genotypically, PM patients or patients receiving CYP2D6-inhibiting drugs have reduced plasma concentrations of endoxifen.…”