However, a more thorough consideration of the details of these two studies still leaves open the possibility that CYP2D6 genotyping is clinically relevant.
Both studies involved the retrospective analysis of a subgroup from a larger prospective randomized trial. Their strengths include large sample sizes and analysis restricted to tamoxifen monotherapy. But there are multiple limiting factors.
In the ATAC study, only 92.5% of the tumors were HR positive. All tumors in BIG were HR positive.
In both studies, the genetic analyses were performed on a convenience sample of tumor blocks from which adequate DNA could be extracted, and both had statistical anomalies that might suggest sampling bias. In ATAC, there were significant differences between the genotyped subgroup and the overall study population with respect to frequency of surgical, radiation, and chemotherapy treatment prior to adjuvant tamoxifen therapy. In BIG, the frequencies of genotyped subjects with 0, 1, or 2 copies of one of the most common variants (CYP2D6*4) were inconsistent with the expected proportions in a random population sample.
The genetic analyses looked at only six or nine known CYP2D6 variants.
Only ATAC adjusted for potent and intermediate CYP2D6 inhibitors, although those drugs did not appear to affect the results.
Neither study included significant numbers of premenopausal patients, so the results may apply only to postmenopausal women.
Despite the relatively large populations studied, modest effects of CYP2D6 variation may have been missed. ATAC was estimated to be able to identify a 35% or greater variation associated with PM status; BIG was powered to detect only a 55% or greater effect size.
Neither study measured actual endoxifen levels or had any other way of assessing adherence to therapy.
In summary, it is certainly possible that CYP2D6 variation is not valuable in predicting clinical response to tamoxifen therapy. Perhaps endoxifen is not the most biologically relevant metabolite, or perhaps the effect of reduced CYP2D6 activity is small enough that it does not account for a significant proportion of tamoxifen failures. But it is also possible that CYP2D6 activity is clinically important for at least a subset of tamoxifen-treated patients. A more definitive answer awaits results from truly prospective trials that control for multiple confounding factors and measure actual endoxifen levels.
For now, in the absence of better data to address this issue, it does not seem appropriate to order CYP2D6 genotyping prior to starting tamoxifen therapy. Likewise, even if the CYP2D6 genotype is known, it should not influence the choice between tamoxifen and an aromatase inhibitor, or the dosing of tamoxifen. However, if a patient receiving tamoxifen requires medication for depression and/or hot flashes, it certainly seems reasonable to start with something other than fluoxetine, paroxetine, or bupropion, just in case those potent CYP2D6 inhibitors do turn out to reduce clinical efficacy.
Dr. Levy is at the division of general internal medicine and the McKusick-Nathans Institute of Genetic Medicine of Johns Hopkins University, Baltimore. He reports having no conflicts of interest.