Genotype-guided tamoxifen therapy: time to pause for reflection?

Tamoxifen remains a cornerstone of adjuvant therapy for patients with early stage breast cancer and oestrogen-receptor-positive tumours. Accurate markers of tamoxifen resistance would allow prediction of tamoxifen response and personalisation of combined therapies. Recently, it has been suggested that patients with inherited non-functional alleles of the cytochrome P450 CYP2D6 might be poor candidates for adjuvant tamoxifen therapy, because women with these variant alleles have reduced concentrations of the tamoxifen metabolites that most strongly bind the oestrogen receptor. In some studies, women with these alleles have a higher risk of recurrence than women with two functional alleles. However, dose-setting studies with clinical and biomarker outcomes, studies associating clinical outcomes with serum concentrations of tamoxifen and its metabolites, and a simple model of receptor binding, all suggest that tamoxifen and its metabolites should reach concentrations sufficient to achieve the therapeutic effect regardless of CYP2D6 inhibition. Ten epidemiology studies on the association between CYP2D6 genotype and breast cancer recurrence report widely heterogeneous results with relative-risk estimates outside the range of reasonable bounds. None of the explanations proposed for the heterogeneity of these results adequately account for the variability and no design feature sets apart any study or subset of studies as most likely to be accurate. The studies reporting a positive association might receive the most attention, because they report a result consistent with the profile of metabolite concentrations; not because they are more reliable by design. We argue that a recommendation for CYP2D6 genotyping of candidates for tamoxifen therapy, and its implicit conclusion regarding the association between genotype and recurrence risk, is premature.