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

Summary

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.

Introduction

Patients with early stage breast cancer and oestrogen-receptor-positive tumours are candidates for adjuvant hormonal therapy, which nearly halves their recurrence risk.¹ Current guidelines recommend the following adjuvant hormonal therapies to reduce recurrence risk in patients with breast cancer with oestrogen-receptor-positive disease.2, 3, 4 Premenopausal patients should receive tamoxifen, a selective oestrogen-receptor modulator, for 5 years. Postmenopausal patients should receive aromatase inhibitors either as initial therapy or after treatment with tamoxifen. Postmenopausal women with contraindications to aromatase inhibitors or who decline aromatase inhibitors should receive 5 years of tamoxifen therapy. Thus, tamoxifen remains a cornerstone of adjuvant breast cancer therapy.

Tamoxifen and aromatase inhibitors prevent the oestrogen receptor from promoting tumour-cell growth by different mechanisms.⁵ Aromatase inhibitors block the conversion of circulating adrenal androgens to oestrogen by the enzyme aromatase in peripheral tissues,⁶ thus almost entirely removing the main source of oestrogen production in postmenopausal women, and leaving little or no hormone to stimulate the oestrogen receptor. Tamoxifen's metabolites antagonise the effects of oestrogen in breast tumours by competing with the hormone at receptor-binding sites.⁷

Mechanisms of resistance to tamoxifen therapy, and predictive markers of susceptibility to resistance, have been widely researched.8, 9, 10 Accurate markers would allow prediction of tamoxifen response and personalisation of combined therapies (figure 1).11, 12 The suggestion has been made that patients with oestrogen-receptor-positive breast cancer with inherited non-functional alleles of the cytochrome P450 CYP2D6 gene might be poor candidates for adjuvant tamoxifen therapy.13, 14, 15 The postulation that CYP2D6 inhibition might reduce the protection conferred by tamoxifen therapy is based on two lines of evidence.¹⁶ First, women with CYP2D6 variant alleles that reduce the enzyme function, or who take CYP2D6-inhibiting drugs, such as some selective serotonin-reuptake inhibitors (SSRIs), have reduced concentrations of the tamoxifen metabolites that most strongly bind the oestrogen receptor.¹⁷ Second, in some studies, women with CYP2D6 variant alleles have a higher risk of recurrence than women with two functional alleles.¹³

Our objective is to critically consider both the pharmacological and epidemiological evidence regarding the association between CYP2D6 inhibition and risk of breast cancer recurrence.