Tamoxifen is a well-established adjuvant therapy for estrogen and/or progesterone receptor (HR)–positive breast cancer, and is the only hormonal treatment available to premenopausal patients. Tamoxifen itself is considered a relatively clinically inactive prodrug. Its most abundant metabolite, endoxifen, has much greater affinity for the estrogen receptor than tamoxifen, and is thought to be the primary compound responsible for clinical benefit.
Bioactivation of tamoxifen to endoxifen depends in large part upon the function of the P450 enzyme CYP2D6. This enzyme is known to have significant genetic variability, and can also be inhibited by several medications, especially fluoxetine, paroxetine and bupropion. There is ample evidence that diminished activity of CYP2D6 (whether caused by pharmacogenetic variation or use of an inhibiting drug) correlates with reduced circulating levels of endoxifen in humans treated with tamoxifen.
In theory, patients with normal CYP2D6 activity (extensive metabolizers, EM) should have a better clinical response to tamoxifen than those with moderately reduced (intermediate metabolizers, IM) or severely reduced/absent CYP2D6 activity (poor metabolizers, PM). In addition, strong inhibitors of CYP2D6 would also reduce the efficacy of tamoxifen.
However, clinical outcome studies have been mixed, with some confirming a reduced recurrence-free interval in IM and PM patients, while others showed no correlation with CYP2D6 phenotype. Most of these are small, retrospective studies that suffer from multiple limitations. The result is uncertainty as to whether pharmacogenetic testing of CYP2D6 prior to prescribing tamoxifen, and/or drug or dose selection based upon CYP2D6 phenotype, is clinically appropriate.
A review of 17 independent retrospective studies of CYP2D6 and tamoxifen response evaluated several possible factors that might explain some of this discrepancy (Oncologist 2012;17:620-30). Some of the more significant cofounders were misclassification of CYP2D6 activity and failure to account for tamoxifen adherence or use of concurrent treatments.
• Hormone receptor classification. Some of the studies included patients whose cancers were HR negative. Since tamoxifen is only effective in HR-positive cancers, inclusion of HR-negative patients could easily confound the data. However, there was no obvious correlation between inclusion of HR-negative cases and finding or not finding a CYP2D6 effect on outcome.
• Menopausal status. In postmenopausal women, tamoxifen and one of its many other non-endoxifen metabolites saturate more than 99.9% of estrogen receptors, as opposed to only 90%–95% saturation by these two molecules in premenopausal women. This leads to speculation that endoxifen availability (and thus CYP2D6 activity) is only relevant in premenopausal women. Again, however, this review found no obvious influence of menopausal status on the results of these studies of CYP2D6 and tamoxifen response.
• Tamoxifen combination therapy. Coadministration of chemotherapy or an aromatase inhibitor with tamoxifen could mask the variability in tamoxifen response attributable to CYP2D6 variation. Indeed, there was a clear trend toward not finding a CYP2D6 effect in studies with fewer patients receiving tamoxifen monotherapy and positive CYP2D6 effects in studies with more monotherapy patients.
• Genotyping comprehensiveness. The normal (EM) version of the CYP2D6 gene cannot actually be positively identified. Rather, it is assumed to be present when a known variant conferring IM or PM status is not found. There are several dozen known genetic variants in CYP2D6, but most of the published studies only looked at one or a few of them. The result can be misclassification of IM or PM patients as EM, thus masking possible pharmacogenetic effects. This review showed a trend toward positive CYP2D6 effects in studies that used more extensive genotyping.
• CYP2D6 inhibitor coadministration. Studies that accounted for inhibitor use were more likely to indicate CYP2D6 effects than those that did not. Furthermore, two studies that did not support a CYP2D6 association despite accounting for inhibitor use appeared to overestimate the effects of some relatively weak or noninhibitory drugs, which might have confounded the results.
• Tamoxifen adherence. Tamoxifen can be a difficult drug to take, especially because of hot flashes, and discontinuation is more common in CYP2D6 EM patients (who have higher circulating endoxifen levels). On average, just under 80% of patients are adherent at 1 year, with further declines to as low as 50% by the fourth year. Only one of the studies adjusted their analysis for estimated tamoxifen adherence, which resulted in a stronger correlation between CYP2D6 activity and tamoxifen benefit.
Two recent reports from large randomized trials – ATAC (Arimidex, Tamoxifen, Alone or in Combination) and BIG (Breast International Group 1-98) – failed to identify any significant difference in clinical outcome among EM, IM, and PM patients treated with tamoxifen (J. Natl. Cancer Inst. 2012;104:452-60; J. Natl. Cancer Inst. 2012;104:441-51). The accompanying editorial asserts that the question of CYP2D6 clinical utility for tamoxifen therapy "has likely been laid to rest" (J. Natl. Cancer Inst. 2012;104:427-8).