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Originally published as JCO Early Release 10.1200/JCO.2008.19.5040 on November 17 2008 © 2008 American Society of Clinical Oncology.
Gene Testing to Predict Tamoxifen-Induced Hot Flashes: New Biological InsightsDavid Geffen School of Medicine at University of California, Los Angeles, UCLA Medicine/General Internal Medicine, Los Angeles, CA In this issue of Journal of Clinical Oncology, Jin et al1 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,2 a second found only ESR1 PvuII but not ESR1 XbaI to be associated with hot flashes.3 In the third study, the association between ESR1 XbaI and hot flashes was significantly dependent on body mass index.4 Specifically, compared with the AA genotype, the AG genotype was associated with increased hot flash reporting among white women with body mass index 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 follicle-stimulating hormone concentrations.5 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.2,3,6-10 Likewise, a study linking CYP1B1 genotype with hot flashes showed the association to be independent of serum estrogen levels.11 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 tamoxifen-induced 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 al1 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 peri- and 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 serotonin-norepinephrine 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.12,13 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 hot flashes. Future studies may consider the possibility that ESR genotype preferentially influences one or the other of these aspects of intensity or frequency to a greater extent than the other during tamoxifen therapy (or in women without breast cancer). ESR genotype testing may ultimately be used as a tool to personalize cancer therapy. Researchers, including Jin et al, are already pursuing a possible role of genotype testing related to tamoxifen metabolism in the selection of antiestrogen therapy.14,15 Although it seems unlikely that routine genotype testing for the purpose of predicting hot flash symptoms will be pursued, if women are tested for ESR genotypes for other purposes, knowledge of ESR genotype may help identify women who should be carefully assessed for hot flash symptoms. The most notable contribution of this study is that its results enhance our understanding of the biology of hot flashes. AUTHOR's DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Jin Y, Hayes DF, Li L, et al: Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy. J Clin Oncol [epub ahead of print on November 17, 2008] 2. Woods NF, Mitchell ES, Tao Y, et al: Polymorphisms in the estrogen synthesis and metabolism pathways and symptoms during the menopausal transition: Observations from the Seattle Midlife Women's Health Study. Menopause 13:902-910, 2006[CrossRef][Medline] 3. Malacara JM, Perez-Luque EL, Martinez-Garza S, et al: The relationship of estrogen receptor-alpha polymorphism with symptoms and other characteristics in post-menopausal women. Maturitas 49:163-169, 2004[CrossRef][Medline] 4. Crandall CJ, Crawford SL, Gold EB: Vasomotor symptom prevalence is associated with polymorphisms in sex steroid-metabolizing enzymes and receptors. Am J Med 119:S52-S60, 2006[CrossRef][Medline] 5. Randolph JF Jr, Sowers M, Bondarenko I, et al: The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition. J Clin Endocrinol Metab 90:6106-6112, 2005 6. Sowers MR, Jannausch ML, McConnell DS, et al: Endogenous estradiol and its association with estrogen receptor gene polymorphisms. Am J Med 119:S16-S22, 2006[Medline] 7. Aksel S, Schomberg DW, Tyrey L, et al: Vasomotor symptoms, serum estrogens, and gonadotropin levels in surgical menopause. Am J Obstet Gynecol 126:165-169, 1976[Medline] 8. Badawy SZ, Elliott LJ, Elbadawi A, et al: Plasma levels of oestrone and oestradiol-17beta in postmenopausal women. Br J Obstet Gynaecol 86:56-63, 1979[Medline] 9. James CE, Breeson AJ, Kovacs G, et al: The symptomatology of the climacteric in relation to hormonal and cytological factors. Br J Obstet Gynaecol 91:56-62, 1984[Medline] 10. Studd JW, Chakravarti S, Collins WP: Plasma hormone profiles after the menopause and bilateral oophorectomy. Postgrad Med J 54:25-30, 1978 (suppl 2) 11. Visvanathan K, Gallicchio L, Schilling C, et al: Cytochrome gene polymorphisms, serum estrogens, and hot flushes in midlife women. Obstet Gynecol 106:1372-1381, 2005[Medline] 12. Stearns V, Beebe KL, Iyengar M, et al: Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 289:2827-2834, 2003 13. Loprinzi CL, Kugler JW, Sloan JA, et al: Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet 356:2059-2063, 2000[CrossRef][Medline] 14. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005 15. van Schaik RH: CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat 11:77-98, 2008[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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30 kg/m2, whereas it was associated with decreased hot flash reporting among women with body mass index lower than 25 kg/m2. Inconsistent results across studies may be due to differing menopausal stage and ethnic compositions. 
