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

Abstract

IntroductionTamoxifen 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.MethodsThis 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.ResultsIn 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.ConclusionsCYP2D6*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.

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

“…The authors could prove the absence of relevance between survival and variable CYP2D6 variants and argue therefore against CYP2D6 genetic testing in a clinical setting. A separate subset analysis for allele *4 showed also no statistically significant association regarding breast cancer specific-or overall-survival [20] . ditional chemotherapy.…”

“…As a possible explanation for this relationship, the authors proposed the higher endogenous estrogen levels in premenopausal ages that require efficient transformation into anti-estrogenic metabolites [19] . In contrast to the studies mentioned above, Abraham et al [20] published results in the opposite direction. In a large cohort of 3155 patients with confirmed treatment with tamoxifen from United Kingdom, the metabolic status of CYP2D6 was associated with breast cancer survival.…”

“…A sub-group analysis regarding allele*4 alone gave consistent results. However, it should be mentioned that a large proportion of included cases had received concomitant chemotherapy [20] . Furthermore, Brooks et.al investigated a cohort of breast cancer patients, pooled from the WECARE study, and showed that the CYP2D6*4 variant is not associated with higher risk of contralateral breast cancer, in the setting of tamoxifen treatment.…”

“…Many of all existing studies analyse cohorts that include a number of patients with ER-negative disease [15,16,20,23,24] , while two other provide no sufficient data regarding the hormonal status of the enclosed population [11,13] . This condition represents a strong limitation in the interpretation of the published results.…”

“…August 10, 2014|Volume 5|Issue 3| WJCO|www.wjgnet.com Goetz et al [8] RFS DFS OS NS (P = 0.075) NS (P = 0.097) NS Worse (P = 0.005) Worse (P = 0.008) NS Scroth et al [9,10] RR MR [12] DFS 118 mo 114 mo 98 mo Bijl et al [13] RBCM NS Increased (P = 0.041) Newman et al [16] OS Worse Karle et al [17] PFS 14 mo 9 mo Abraham et al [20] BCSS NS Nowell [23] BCR, OS NS NS Rae et al [25] RR NS NS Regan et al [26] BCE prospective multicenter randomised trial (Austrian Breast and Colorectal Study 8 -ABCSG trial 8) have been newly published. In this cohort 3901 postmenopausal patients with resected ER+ early cancer were randomised to receive either five years tamoxifen or two years tamoxifen followed by anastrazole administration over three more years.…”