Gene testing to predict tamoxifen-induced hot flashes: new biological insights.

In this issue of Journal of Clinical Oncology, Jin et al report that ESR1 and ESR2 genotype predicted hot flash scores at baseline and 4 months among women with breast cancer initiating tamoxifen therapy. Among women who reported no hot flashes at baseline, women with the ESR2-02 AA genotype were substantially less likely to experience hot flashes in the first year of tamoxifen treatment. Few studies have previously explored ESR-hot flash associations. None of them were focused on women with breast cancer. One study found no association between ESR1 XbaI or ESR1 PvuII and hot flashes, a second found only ESR1 PvuII but not ESR1 XbaI to be associated with hot flashes. In the third study, the association between ESR1 XbaI and hot flashes was significantly dependent on body mass index. Specifically, compared with the AA genotype, the AG genotype was associated with increased hot flash reporting among white women with body mass index 30 kg/m, whereas it was associated with decreased hot flash reporting among women with body mass index lower than 25 kg/m. Inconsistent results across studies may be due to differing menopausal stage and ethnic compositions. What could be the mechanisms underlying ESR genotype-hot flash associations? The investigators posit that ESR1 and ESR2 genotypes may influence expression or functionality of estrogen receptors. If confirmed by additional studies, this hypothesis provides a possible explanation for evidence that it is not estrogen levels per se that determine hot flash frequency or severity. Serum follicle-stimulating hormone concentrations are positively associated with hot flash frequency, but serum estradiol concentrations are not associated with the prevalence of hot flashes after adjustment for serum folliclestimulating hormone concentrations. Published studies do not consistently point to altered serum estrogen levels in association with ESR1 XbaI and PvuII genotypes, and studies do not consistently demonstrate associations between decreased sex steroid levels and hot flash prevalence. Likewise, a study linking CYP1B1 genotype with hot flashes showed the association to be independent of serum estrogen levels. A potential role for chemotherapy in modifying the effects of tamoxifen on hot flashes is worthy of note. In this study, the increase in hot flash score during tamoxifen use was lower among premenopausal women who had previously received adjuvant chemotherapy. One might infer that chemotherapy confers some protection from tamoxifen-induced hot flashes. However, there is alternative interpretation. Participants who had received prior chemotherapy had higher hot flash scores prior to receiving tamoxifen, and at 4-month follow-up these women had similar hot flash scores to women who had not received chemotherapy. Therefore, chemotherapy may have predisposed women to have higher baseline hot flash scores, yielding an apparently blunted effect of tamoxifen on hot flash scores. It is also plausible that the same ESR genotypes associated with susceptibility to tamoxifen-induced hot flashes may also relate to breast cancer prognosis and thus receipt of chemotherapy, introducing potential sources of bias and challenges to the study tamoxifeninduced hot flashes. The temporal pattern of hot flashes associated with recently completed chemotherapy, and the potential biologic interaction of tamoxifen and chemotherapy in triggering hot flashes, warrant further study. A few methodologic considerations of the study by Jin et al deserve consideration. First, sample sizes did not allow definitive testing of how genotype-hot flash associations varied by menopause stage. Jin et al made an a priori decision to present results separately according to each menopausal stage (premenopausal, postmenopausal), while acknowledging that sample size was too low to reliably assess genotype-hot flash associations among periand postmenopausal women at baseline. Second, the 95% CI surrounding the Cox proportional hazards point estimate for development of hot flashes in the first year of tamoxifen according to ESR2-02 genotype was wide—0.10 to 0.63—possibly due to small sample size. Finally, results could not be compared among ethnic subgroups because only 6.5% of this study’s participants were not white. Other possible sources of bias in this study do not seem overly concerning. If more women with one genotype were lost to follow-up than women with another genotype (because of more severe hot flashes), results would be biased, but probably in a direction of underestimation of genotype effects on hot flashes. In addition, assessment of hot flashes early (at 4-month follow-up) lessened this potential bias. Users of selective serotonin-reuptake inhibitors and serotoninnorepinephrine reuptake inhibitors, medications that alleviate hot flashes, were included in this analysis. However, initiation of such medications most commonly occurred after assessment of the hot flash score (ie, after the 4-month follow-up). This study focused on hot flash score, a commonly used outcome in intervention studies. Hot flash scores combine symptom frequency and intensity into a single score, usually by means of multiplying frequency and severity. Thus, a woman with rare but severe hot flashes could have a similar score to a woman with frequent but mild JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 36 DECEMBER 2