We performed a cross-sectional analysis of women taking tamoxifen to identify predictors of commonly reported side effects. We found that the risk of side effects was lower among women who were on tamoxifen for longer durations. In addition, we found that younger age, previous use of post-menopausal hormone therapy and higher serum endoxifen levels were the most significant predictors in a multi-variate model. We did not detect an association between CYP2D6 genotype and side effects.
The rate of side effects in our study is consistent with previous studies; about half of the women experienced hot flashes, vaginal dryness and sleep problems were also among the most prevalent side effects. Loprinzi et al., conducted 2 studies of tamoxifen side effects and found that approximately 50% of women in both studies had hot flashes [35
]. The incidence of hot flashes was slightly lower in their studies compared to in our population; however, since all of their patients were post-menopausal, while most of ours were pre-menopausal, and since younger age was predictive of more side effects in our study, the higher incidence in our population may be expected. Loprinzi et al., also found that a history of moderate to severe hot flashes and a history of prior estrogen therapy use were associated [35
]. Our finding of an association between severity of tamoxifen side effects and prior use of HT is consistent with previous reports in which women who use HT are more likely to have side effects with menopause. Although these findings do not point to an etiology, they may help clinicians predict which women may have the most severe side effects.
Demissie et al., identified predictors of adjuvant tamoxifen use, side effects, and discontinuation in older women. They found that women who were ≥ 75 years of age were significantly less likely to report side effects. Although our population is younger, the association of fewer side effects among older women is consistent with our data. Demissie et al., also found that women with better emotional health had significantly lower odds of reporting side effects. A similar finding was seeing when the researchers restricted the analysis to hot flashes. In addition, they also observed that educational attainment, especially women who completed at least the 12th
grade were more than 5 times likely to report hot flashes than those who did not complete high school [37
]. We did not find any association between level of education and increase reported of hot flashes; however, women in our study were highly educated on average so that the variation may not have been the same as in the Demissie et al.
Our study is the first, to our knowledge, to report the association between any side effects from tamoxifen and endoxifen levels. We found that only endoxifen, the most active metabolite of tamoxifen significantly associated with side effects. We did not see any association between tamoxifen levels and side effects, suggesting that the association between serum endoxifen levels and side effects is not a marker of adherence since adherence would presumably have a more direct effect on tamoxifen levels. We observed a trend towards association between side effects and 4-hydroxy-tamoxifen. While this association was not significant, the trend may be consistent with other data that 4-hydroxy-tamoxifen is a highly active metabolite. However, since endoxifen has much higher bioavailability compared to 4-hydroxy-tamoxifen, its effect may be clinically more important.
We did not observe an association between CYP2D6
genotype and side effects. Recently, the WHEL study [31
] reported that women with the lowest level of endoxifen have higher incidence of recurrence. They found no association between recurrence and CYP2D6
genotype. Women who experienced hot flashes from tamoxifen in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial were significantly more protected from recurrence [18
]. However, the ATAC study also recently reported no association between CYP2D6
genotype and recurrence [38
]. Taken together, these findings may indicate that endoxifen levels may predict both side effects from tamoxifen and risk of recurrence. In contrast, CYP2D6
genotype appears to be a less consistent predictor of recurrence, possibly because the CYP2D6
genotype only partially explains the variability in endoxifen levels. Endoxifen concentration varies not only according to the number of functional CYP2D6
] but also in the presence of medications that inhibit CYP2D6
enzyme. Agents such as the selective serotonin reuptake inhibitors (SSRIs) paroxetine or fluoxetine, and the antiarrhythmic quinidine are among the most potent inhibitors [20
]. 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. Other commonly used medications such as buproprion, duloxetine, clomipramine and pimozide exhibit inhibition close to that of paroxetine, fluoxetine and quinidine [40
]. Beside CYP2D6
are responsible for converting tamoxifen to its active metabolites. Murdter et al., found that CYP2C9
carriers of reduced-function (*2 and *3 alleles) had lower plasma concentrations of active metabolites, pointing to the role of additional pathways [41
]. The inter-individual variations of the activity of these enzymes due to genetic polymorphisms could therefore be predictors of outcome during tamoxifen treatment. These findings suggest that future studies of tamoxifen efficacy and side effects should focus on direct assessment of endoxifen levels.
Our study found an association between increased risk of side effects and use of medications which inhibit CYP2D6. Since serotonin selective receptor inhibitors (SSRI’s) are among the most common CYP2D6 inhibitors used, it is likely that these medications were prescribed to treat side effects among some of the women. Therefore, the association between them and side effects may be due to the confounding effect of physicians prescribing these medications for patients with side effects.
Another important aspect of predicting side effects is ensuring adherence to treatment. Hot flashes are common among tamoxifen users and are associated with drug discontinuation [37
]. In both ATAC and the Breast International Group (BIG) 1–98 trials, hot flashes were reported significantly less frequently with the aromatase inhibitors [43
] compared to tamoxifen [44
]. Thus, accurately predicting hot flashes may help clinicians target certain patients with pharmacologic and non-pharmacologic interventions (or treatments) to prevent or reduce the severity of hot flashes in patients who are candidates for tamoxifen treatment. In addition, in situations in which equally effective alternative treatments may be available (such as raloxifene for breast cancer prevention) accurately predicting side effects may help clinicians select therapies.
Few studies have identified specific factors that predict which women will experience side effects from tamoxifen. Predictors of menopausal hot flashes, a mechanistically related phenotype, include smoking, maternal history of hot flashes, early age of menopause, surgical menopause, higher body mass index, lower physical activity, higher follicle-stimulating hormone (FSH) levels, anxiety, alcohol use, higher parity, and lower socioeconomic status [46
]. However, it is unknown whether any of these factors predict which women may experience hot flashes associated with tamoxifen therapy.
Although our findings identify some factors that may affect side effects from tamoxifen, our study also has several important limitations. First, our study included women who were mostly Caucasian and Asian and were well-educated; thus, our study may not be generalizable to all populations. There are reports that Asian American women report fewer peri-menopausal hot flashes [52
], although it is unknown whether the same finding is seen with tamoxifen. Our study did include 55 Asian American women and we saw no significant difference in the report of side effects in this group. However, we were likely underpowered to detect a clinically important difference. Second, we used a cross-sectional study design. Therefore, we were unable to determine whether these side effects diminished among individual women with time or whether they led to discontinuation of the treatment.. In addition, the cross-sectional study design may have biased the results in other ways since the women on Tamoxifen for more than 1 year may be a biased subset of the women who started the therapy and thus may have different risk factors for side effects. Third, we studied tamoxifen use during a period of time when the therapeutic guidelines were changing and more new clinical trials results were recommending the use of aromatase inhibitors in clinical practice for post-menopausal women. Finally, our study only had information on co-medication use from 166 of 241 participants.
In summary, we found that women who are younger, taking tamoxifen for less than 12 months, those with higher endoxifen levels, and who had previously used post-menopausal hormone therapy are more likely to report side effects from tamoxifen. The association between side effects and endoxifen levels is intriguing because of the connection of higher endoxifen levels with breast cancer outcomes (no breast events, breast cancer recurrence and new primary breast cancer) in the WHEL trial. Large scale studies of endoxifen levels, side effects and recurrence should be pursued to definitively determine the association between these factors.