Abstract C118: Influence of CYP2D6 phenotype on tamoxifen-treatment outcome in women with metastatic breast cancer

Abstract

Abstract Introduction: Cytochrome P450 2D6 (CYP2D6) plays a crucial role in the metabolism of tamoxifen into the active metabolite endoxifen. Genetic variation in the CYP2D6 gene and co-administration of CYP2D6 inhibiting medication markedly reduce endoxifen plasma concentrations in patients. The impact hereof on the outcome of tamoxifen therapy in metastatic breast cancer is insufficiently known. In this cohort study, we examined the effect of CYP2D6 predicted phenotype (the combined effect of genetic variants and concomitant use of CYP2D6 inhibiting medication) on time to progression (TTP) and overall survival (OS) in women using tamoxifen for metastatic breast cancer was examined. Methods: We selected patients treated with tamoxifen (40mg/day) for hormone receptor positive metastatic breast cancer of whom blood samples for pharmacogenetic analysis (CYP2D6*3,*4,*5,*6) were available. Patient charts were reviewed to assess patient and tumor characteristics, TTP, OS, and use of CYP2D6 inhibitors. Results: Patients with poor CYP2D6 metabolizer phenotype (PMs) had a worse OS compared to extensive metabolizers (EMs) (HR = 2.11; P=0.031; 95% CI: 1.07–4.15, see Table). Patients with an intermediate (IM) and extensive metabolizer (EM) phenotype had comparable TTP and OS, and were further considered as one group in the Kaplan-Meier estimates. For PMs, the Kaplan-Meier estimate demonstrated a shorter TTP compared to the combined group of IMs and EMs: 1.7 years (95% CI: 0.9–2.5) versus 2.9 years (95% CI: 2.3 – 3.6) respectively (P = 0.089). Overall survival of the group of IM/EM patients was significantly longer than for PM patients, being 9.9 years (95% CI: 8.2–11.6) versus 5.4 years (95% CI: 3.7–7.1), respectively (P=0.012). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and a worse TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared to patients without CYP2D6 inhibitors. Conclusions: CYP2D6 phenotype is an important predictor of treatment outcome in women treated with tamoxifen for hormone receptor positive metastatic breast cancer. Co-administration of CYP2D6 inhibitors worsens outcome of tamoxifen therapy, and should therefore be discouraged. Effect of CYP2D6 phenotype on TTP and OS CYP2D6 phenotype Time to progression (TTP) Overall Survival(OS) Cases (n=99) Cases (n=99) HR (95% CI) HR (95% CI) P-value P-value EM n=50 n=33 HR=1.00 (ref) HR=1.00 (ref) IM n=36 n=22 HR=1.05 (0.67–1.65) HR=0.88 (0.51–1.53) P=0.82 P=0.66 PM n=13 n=12 HR=1.74 (0.92–3.28) HR=2.11 (1.07–4.15) P=0.09 P=0.03 Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C118.