CYP2D6*4 polymorphism as blood predictive biomarker of breast cancer relapse in patients receiving adjuvant tamoxifen

Abstract

590 Background: Polymorphisms in cytochrome P450 2D6 gene affect the plasma concentration of tamoxifen active metabolites (endoxifen). Some drugs are known to be CYP2D6 inhibitors. We aim to determine the relationship between CYP2D6*4 polymorphisms, concomitant CYP2D6 inhibitors use and clinical outcomes of breast cancer patients receiving adjuvant tamoxifen (TAM). Patients and Methods: CYP2D6*4 (1934 G>A+1) genotype was determinated from DNA of blood samples using PCR-RFLP technique and Taqman Allelic Discrimination Assay in a series of 84 breast cancer patients receiving adjuvant TAM. CYP2D6 inhibitors were recorded. Chi-square test and logistic regression models were used to determinate association between genotype, use of concomitant CYP2D6 inhibitors and disease relapse rate. Results: In our 84 patients series mean age was 51.5y. (33–71). 14.8% were stage I, 58.0% stage II and 27.2% stage III. 61.4% were nodes positive and 98.7% tumors had positive hormonal receptors. We observed disease recurrence in 36.9% of cases. The mean following-up was 5.5 y. Genotype frequency was: wt/wt (57.1%), wt/*4 (40.5%) and *4/*4 (2.4%). 50% (18 of 36) of patients with the wt/*4 + *4/*4 genotypes had disease relapse compared with 27% (13 of 48) with wt/wt genotype (P= 0.041). Only 6 patients received concomitants CYP2D6 inhibitors, mainly antidepressants, all of them with the wt/*4 genotype. 50% presented disease relapse. Clinical pathological variables were evaluated and significant relation was found between stage and disease relapse by univariate analysis (P= 0.001). We investigated whether CYP2D6*4 genotype and stage to diagnosis could influence in disease relapse. For these analyses we use as reference group the genotype wt/wt. We observed that combined genotype wt/*4 + *4/*4 was more strongly associated with disease recurrence than wt/wt genotype (adjusted hazard ratio [HR], 2.82, 95% confidence interval [CI] 1.0- 7.9) P= 0.049. Conclusions: Breast cancer patients with the CYP2D6 *4/*4 or wt/*4 genotype could have lower benefit of TAM adjuvant treatment and tend to have a higher risk of disease relapse. Pre-treatment CYP2D6 genotype determination from blood sample could predicts TAM clinical outcomes and help to oncologist in treatment decision. No significant financial relationships to disclose.