A multi-ancestry genome-wide study of tamoxifen metabolism and breast cancer recurrence

Abstract

Background: the therapeutic activity of tamoxifen is mainly due to its principal active metabolites 4-hydroxy-tamoxifen and Z-endoxifen. Serum levels of these metabolites have been shown to be under strong genetic control of the highly polymorphic extended CYP2D6 gene region whilst the influence of other variants in the genome has been inconclusive. We conducted a multi-ethnic genome-wide association study (GWAS) to further delineate the genotypic-phenotypic impact of CYP2D6 and potentially other functional variants in the genome.

Methods: discovery GWAS was conducted on 636 hormone-receptor positive (HR+) breast cancer (BC) patients who have received 20mg tamoxifen daily for at least 8 weeks. Significant associations (P < 5×10-8) were followed up in a validation cohort comprising 869 patients. Association between genetic determinants of endoxifen pharmacokinetics and outcomes was examined in 1326 non-metastatic HR+ BC patients treated with adjuvant tamoxifen.

Findings: a genome-wide significant association with Z-endoxifen levels was observed on chromosome 22 at CYP2D6 and its downstream region at TCF20 rs932376 A>G. Both CYP2D6 metabolizer status and TCF20 rs932376 A>G were independent predictors of endoxifen levels, after adjustment for age, ethnicity, weight, and menopausal status. Each copy of the TCF20 rs932376-G allele was associated with a 7.48nM reduction (95% CI -10.58 to -4.39; P=2.16×10-6) in mean endoxifen levels. Compared with CYP2D6 normal/ultra-rapid metabolizers, the mean endoxifen levels of CYP2D6 intermediate and poor metabolizers were lower by 13.09nM (95% CI -17.21 to -8.97; P=4.81×10-10) and 25.69nM (95% CI -28.31 to -23.08; P=1.33×10-82), respectively. In relation to a model containing both predictors, CYP2D6 metabolizer status accounted for a higher percentage of the predictive information on mean endoxifen levels compared to TCF20 rs932376 A>G (91.2% vs 48.8%). These findings were replicated in the validation cohort. Neither TCF20 rs932376 nor CYP2D6 metabolizer status was significantly associated with BC outcomes after adjustment for known prognostic factors.

Interpretation: our study revealed that while CYP2D6 metabolizer status remained the prime predictor of steady-state Z-endoxifen levels in this study, TCF20 rs932376 A>G is an independent contributor, albeit to a much lesser extent. However, the relation of these genetic determinants to BC outcomes remains elusive.

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Identifiers

ORCID for Diana Eccles: orcid.org/0000-0002-9935-3169

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