We provided CYP2D6 genotype results to clinicians and patients and evaluated the impact of this information on the proportion of women who changed hormone therapy. Approximately 5% of women were PMs and 6 out of 13 (46%) changed treatment after discussion with their physicians. This was a significantly higher percentage than the rate of therapy change in those with UM, EM or IM phenotypes, suggesting that in this setting phenotype results affected treatment decisions. The association between medication change was not confounded by method of referral to the study or by prior interest in CYP2D6 testing.
For pre-menopausal women, change in hormone therapy included both an AI as well as ovarian suppression that leads to significant side effects associated with early menopause. Thus, despite the limited evidence and the risk of side effects from an alternative treatment, physicians and patients frequently changed therapy in response to a PM phenotype. Treatment with an AI alone in younger women who have amenorrhea due to chemotherapy may lead to inadequate hormonal suppression [40
]. We did not directly make any treatment recommendations. But five of the six women who had changed to an AI also received OS. The only woman who received AI alone was aged 56 years and was known to be post-menopausal prior to breast cancer treatment. Therefore, the physicians who referred to our study appear to be aware of the risks of inadequate hormonal therapy and to have used combination therapy when appropriate.
The association between CYP2D6
genotype and efficacy of tamoxifen in women with early stage, hormone receptor-positive breast cancer remains unclear. CYP2D6
activity clearly correlates with endoxifen levels, but the association with outcome has been far more controversial. Several studies have demonstrated an association [11
], but other studies, including the two largest, have failed to confirm an impact of enzyme activity and breast cancer outcome [20
]. A recent meta-analysis found a trend towards association between CYP2D6
genotype and disease free survival but not overall survival [41
]. However, the authors noted considerable heterogeneity among the studies in both the reported associations and in the way subsets of genotypes were grouped. More recently, two large randomized controlled trials, the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial [25
] and the Breast International Group (BIG) 1-98 trial [26
], evaluated the impact of CYP2D6
polymorphisms in patients treated with tamoxifen. Neither study demonstrated an association between the risk of breast cancer recurrence and CYP2D6
Our study had completed all the enrollment and the follow-up by September 2010, prior to the presentation of the genotyping data from the ATAC and BIG 1-98 trials in December 2010. Thus, at the time that patients and clinicians were deciding how to interpret the genotypes, these results could not be taken into consideration, but could have a significant impact on decisions regarding testing and treatment change. However, as part of our presentation to patients prior to testing, we showed the results of both prior positive and negative studies testing for associations between CYP2D6 and breast cancer. Since physicians and patients were aware of the controversial results, our study demonstrates that many clinicians and patients are generally willing to make treatment decisions even in the curative setting based on non-definitive and retrospective pharmacogenetic information when accompanied by a reasonable hypothesis.
The prevalence of CYP2D6
polymorphisms varies across ethnic groups. The frequency of CYP2D6
PMs in our study is consistent with previous reports [15
]. Like other investigators [14
], we found that the most frequent variant present in Asians was CYP2D6*10
, an allele with reduced activity. Results examining the association between the *10 allele and clinical outcomes have also been mixed [14
]. The rate of medication change among patients with the IM CYP2D6
phenotype, including patients homozygous for this allele, was similar to that in patients with the UM/EM phenotype, suggesting that physicians do not consider these patients at significantly increased risk of recurrence.
Endoxifen concentration varies not only according to the number of functional CYP2D6
] but also in the presence of potent CYP2D6
enzyme inhibitors. Agents such as the SSRIs paroxetine or fluoxetine, and the anti-arrhythmic quinidine are among the most potent inhibitors [9
]. When these medications are co-administered with tamoxifen to women with an EM phenotype, endoxifen concentrations are similar to those observed in PM and have the potential, therefore, to reduce tamoxifen efficacy [9
]. Other commonly used medications such as buproprion, duloxetine, clomipramine, thioridazine, pherphenazine, and pimozide exhibit inhibition close to that of paroxetine, fluoxetine and quinidine [44
]. While we found that some women did change their co-medications, this was unrelated to CYP2D6
genotype. Our study did not collect enough information from physicians to distinguish between those two possibilities.
Our study is unique in that, to our knowledge, no prior pharmacogenetic studies on change in therapy for CYP2D6
have been previously published. Several studies have examined the issue of incorporating pharmacogenetic data in dosing warfarin [47
]; however, genetic testing for warfarin dosing does not involve a change to a different medication. Several studies have also shown that genetic testing for BRCA1
leads to selection of risk-reducing surgeries [49
], the use of post-menopausal hormone therapy [52
], and pre-implantation genetic diagnosis [53
Our study also has several important limitations. First, the evidence for the association between CYP2D6 polymorphisms and outcomes remains mixed in the literature and the availability of the most recent results may have changed the decisions that patients and providers in our study made. Second, our sample may have been biased by referral patterns and by patient participation. Physicians and patients who are interested in testing and in changing therapy based on test results may have been more likely to participate in our study. However, we found no association between prior knowledge or interest in CYP2D6 genotype testing and choice of therapy at follow-up. In addition, there were no other significant predictors within our data. Third, our sample may not be universally generalizable. Our patients tended to be mostly Caucasians and Asians, highly educated on average, with a relatively high income level, and most were already being followed at a University medical center for breast cancer. Furthermore, our study used patient self-report of medication use rather than chart review or physician report. However, both patient report and physician report may have limitations. More studies should be conducted to determine how genotyping results would be used in community settings.