Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy

Abstract

Reduced CYP2D6 activity is associated with poor treatment outcomes, in terms of increased risk of recurrence and shorter recurrence free survival, in breast cancer patients on adjuvant tamoxifen therapy.

RRM1, TUBB3, TOP2A, CYP19A1, CYP2D6: Difference between mRNA and protein expression in predicting prognosis of breast cancer patients

“…In the present study, the pattern of cytoplasmic CYP19A1 (16,39). Additionally, CYP2D6 activity has been proven to be associated with poor treatment outcomes, in terms of increased risk of recurrence and shorter recurrence-free survival (40).…”

“…A statistically significant difference in cytoplasmic RRM1 staining was observed in tumor tissues when compared with TATs (P<0.001). Negative RRM1 staining was identified in 9.57% of tumors vs. 40 (Table II). Tubulin-β-III and CYP2D6 expression were correlated significantly with tumor grade (P= 0.021 for tubulin-β-III and P= 0.029 for CYP2D6, respectively).…”

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

“…The meta-analysis of the association between the variant/variant genotype (or inferred poor metabolizer phenotype) and breast cancer recurrence or mortality, as compared with the wild-type/wild-type genotype (or inferred extensive or ultrametabolizer phenotype), included 21 of the 31 studies. In 16 (76%) of these 21 studies, researchers extracted DNA from nonneoplastic tissue (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), and in 5 of them (24%) they extracted DNA from tumor-infiltrated tissue (26-28, 46, 72). The summary estimates of association with and without bias analysis are reported in Table 3 and displayed in Figure 1.…”

“…Lash et al (23) previously published this plausibility limit on the basis of pooled clinical trial evidence of tamoxifen's effectiveness and the proportion of breast cancer patients expected to have fully functional or impaired alleles. In the variant/variant analysis, 8 of the 16 studies using nonneoplastic tissue DNA found ratio estimates of association greater than the plausibility limit of 2 (63)(64)(65)(66)(67)(68)(69)(70), whereas none of the 5 studies based on tumor-infiltrated tissue DNA found a ratio estimate of association greater than the plausibility limit.…”

The antiestrogen 4-hydroxytamoxifen protects against isotretinoin-induced permeability transition and bioenergetic dysfunction of liver mitochondria: comparison with tamoxifen

“…In fact, it has been observed a synergistic action between retinoids and tamoxifen (TAM), a nonsteroidal antiestrogenic compound, on breast cancer cell death (Saez et al 2003;Wang et al 2007;Searovic et al 2009). However, TAM is a prodrug with serious side effects (Wong & Ellis 2004) and patients present a large variation in both therapeutic efficacy and side effects due to CYP3A4 and CYP2D6 polymorphisms (Damodaran et al 2012). 4-hydroxytamoxifen (OHTAM), a major active metabolite, responsible for the anticancer activity of TAM, is a promising compound since this metabolite has a higher affinity for ER, and it is 30-to 200-times more potent than TAM (Lim et al 2005;Kiyotani et al 2012).…”