CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study

Abstract

Purpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41 and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (PM, AS=0) phenotype were compared to patients with AS>0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p>0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio (HR)=1.43, 95% confidence interval: 1.00–2.04, p=0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS>0, were associated with superior RFS (each p=0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

Impacts of Cytochrome P450 2D6 (CYP2D6) Genetic Polymorphism in Tamoxifen Therapy for Breast Cancer

“…A recent retrospective cohort of 957 subjects found no evidence of decreased TMX effectiveness in patients with CYP2D6 polymorphism phenotypes. 24 In contrast, after adjusting for clinical variables, a positive association between low CYP2D6 activity and superior TXM treatment outcomes was found, which is consistent with the results of two previous studies. 22,23 An international randomized, phase III double-blind trial obtained tumor tissues and isolated the DNA from 4,861 postmenopausal women with hormone receptor-positive breast cancer and found no association between CYP2D6 metabolism phenotypes and breast cancer-free interval among patients receiving tamoxifen monotherapy; effects were only observed in those who had undergone previous chemotherapy (p ¼ 0.35).…”

“…Some studies have shown no alterations in the efficacy of TMX in patients with breast cancer carrying the CYP2D6 gene polymorphism in terms of recurrence and overall survival, 12,20,21 while other studies demonstrated that CYP2D6 gene polymorphisms (especially *3, *4, and *6) significantly affected the efficacy of TMX. [22][23][24] Because of these controversial results, available recommendations do not suggest the use of CYP2D6 genetic testing to select the best endocrine therapy regimen for patients. 18 Considering previous studies of the role of CYP2D6 polymorphisms in the TMX resistance mechanism and in the pharmacokinetics of its active metabolite, including CYP2D6 allele heterogeneity among different populations, the present study was conducted to analyze how mutations in the CYP2D6 gene affect patients undergoing breast cancer therapy with TMX.…”

Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics

“…Since the publication of our metaanalysis, using the same search criteria through November 2017 (D. P. Cronin-Fenton et al, 2013), over 20 additional published studies have investigated the impact of CYP2D6 genetic polymorphisms on breast cancer prognosis. (Argalacsova, Slanar, Bakhouche, & Pertuzelka, 2017;Chamnanphon et al, 2013;De Ameida Melo et al, 2016;Dezentje et al, 2013;Dezentje et al, 2015;Goetz et al, 2017;Hertz et al, 2017;Johansson et al, 2016;Lei et al, 2016;Marcath et al, 2017;Markkula, Hjertberg, Rose, Ingvar, & Jernstrom, 2014;Martins, Vidal, Souza, Brusaca, & Brito, 2014;Mwinyi et al, 2014;Powers et al, 2016;Sanchez-Spitman et al, 2017;Sensorn et al, 2013;Zhang et al, 2015) Most suggest little evidence of an association of the CYP2D6 *4 or *10 variant with recurrence and mortality in tamoxifen-treated breast cancer patients. Here, we provide some highlight some of these studies.…”

“…A population-based cohort study by Hertz et al genotyped six CYP2D6 variants and copy number variants among 500 tamoxifen-treated patients and 500 ER+ patients who did not undergo systemic therapy. (Hertz et al, 2017) The design of the study is commendable, and somewhat similar to a previously published case-control study design. (Lash et al, 2011) The tamoxifen-treated cohort aimed to address the utility of CYP2D6 as a predictor of tamoxifen effectiveness (i.e., a determinant of response to tamoxifen treatment).…”

CYP2D6-inhibiting medication use and inherited CYP2D6 variation in relation to adverse breast cancer outcomes after tamoxifen therapy

“…Results from studies of the association between CYP2D6 inhibition and adverse breast cancer outcomes have been heterogeneous, with several finding an increased risk [10,25,26,27] (potentially only in relevant subgroups [28,29]) and others finding a null association [11,30,31,32,33,34,35,36,37,38,39]. However, the majority of studies have focused exclusively on either CYP2D6-inhibiting medication use or CYP2D6 genotype and have not considered their joint actions.…”