Significant Effect of Polymorphisms Clinical Outcomes of Tamoxifen Therapy

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Significant Effect of Polymorphisms in CYP2D6 and ABCC2 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Breast Cancer Patients
J Clin Oncol. 2010 Feb 1; Epub ahead of print, K Kiyotani, T Mushiroda, CK Imamura, N Hosono, T Tsunoda, M Kubo, Y Tanigawara, DA Flockhart, Z Desta, TC Skaar, F Aki, K Hirata, Y Takatsuka, M Okazaki, S Ohsumi, T Yamakawa, M Sasa, Y Nakamura, H Zembutsu

Supplementary editorial provided by OncologySTAT

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Genetic variants of CYP2D6 and ABCC2 were linked with reduced disease-free survival in breast cancer patients treated with tamoxifen.

STUDY IN CONTEXT

Up to 50% of patients with hormone-receptor−positive breast cancer who are treated with tamoxifen experience a relapse and subsequently die of their disease. This variability in response to tamoxifen is thought to be related to individual differences in the formation and elimination of 2 of the drug’s active metabolites, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen). CYP2D6 is a key enzyme active in the production of these metabolites. Loss of CYP2D6, or decrease in its function caused by genetic polymorphisms, is associated with poorer outcomes to treatment with tamoxifen. However, individual differences in outcome remain even when CYP2D6 polymorphisms are taken into account. This suggests that other genetic factors may play a role in tamoxifen efficacy.

Kiyotani et al examined possible genetic polymorphisms that could lead to reduced formation or greater excretion of metabolites and thus reduced efficacy of tamoxifen. The investigators focused on 3 transporter genes that may be involved in the transport of tamoxifen or its metabolites, evaluating their association, as well as that of CYP2D6, with outcomes.

Between 2007 and 2009, the study enrolled 282 patients with primary breast cancer (including 67 previously reported patients) at several Japanese centers. All patients had hormone-receptor−positive invasive breast cancer without distant metastases. They received only tamoxifen 20 mg/d for 5 years postsurgery. Median follow-up was 7.1 years (range, 0.8 to 23.5 years).

Patients were tested for polymorphisms of CYP2D6 and 3 adenosine triphosphate−binding cassette (ABC) transporter genes: ABCB1 (also known as multidrug resistance 1 [MDR1]), ABCC2 (also known as multidrug resistance−associated protein 2 [or MDR2]), and ABCG2 (also known as breast cancer resistance protein [BCRP]). These 3 ABC genes were selected for study because they have been reported to transport glucuronides, the primary form in which tamoxifen is excreted. Polymorphisms of these transporter genes could lead to reduced elimination of tamoxifen metabolites.

The results of the study showed that patients who harbored 1 (wt/V) or 2 (V/V) variant alleles of CYP2DG did, in fact, have significantly shorter recurrence-free survival compared with patients carrying homozygous wild-type alleles (wt/wt) (P = .0002). This finding held after adjustment for tumor size and nodal status (P = .000036). The adjusted hazard ratio (HR) for recurrence-free survival was 4.44 in wt/V patients and 9.52 in V/V patients, compared with wt/wt patients.

Among 51 haplotype-tagging single nucleotide polymorphisms (tag-SNPs) genotyped in the 3 ABC transporter genes, 5 SNPs in ABCC2 were significantly associated with recurrence-free survival, with the lowest P value seen at ABCC2 rs3740065. This SNP was an independent predictor of recurrence-free survival (P = .00017).

An analysis based on the number of risk alleles of CYP2DG and ABCC2 (0 to 4) showed a cumulative effect on recurrence-free survival. The adjusted HR for risk of recurrence increased from 4.93-fold for patients with 2 risk alleles to 45.25-fold for those with 4 risk alleles (P = .000000055).

The researchers also recruited another 98 tamoxifen-treated patients for a pharmacokinetic study to explore the effects of the relevant polymorphisms on plasma levels of the tamoxifen metabolites. These tests showed significantly lower levels of endoxifen and 4-hydroxytamoxifen in patients with CYP2D6 risk alleles, but not in those with ABCC2 rs3740065. For patients with V/V and wt/V, median endoxifen levels were 15.5 ng/mL and 27.2 ng/mL, respectively, compared with 35.4 ng/mL for patients with wt/wt. These findings suggest that the efficacy of tamoxifen may be lower in patients with the CYP2D2 genotype because of lower systemic exposure to endoxifen. The lack of an effect of ABCC2 rs3740065 on endoxifen levels suggested that ABCC2 might regulate local exposure of the metabolite to breast cancer cells.

Thus, on the basis of the results of this study, it appears that genetic polymorphisms in the CYP2D6 and ABCC2 genes may be able to predict clinical outcomes of tamoxifen therapy for breast cancer patients. Testing for these variants could potentially aid physicians in selecting optimal hormonal therapy for patients with hormone-receptor−positive disease.

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