Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy

Abstract

Purpose: Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes.

Patients and methods: We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen.

Results: Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001).

Conclusion: Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.

Fig A1.

Hot flash prevalence rate before and during the first year of tamoxifen. †P < .01 compared with premenopausal group; *P = .015 compared with premenopausal group.

Fig A2.

Effects of estrogen receptor (ESR) genotype on hot flash score before tamoxifen. The number of participants in each genotype is in parentheses. (Error bars) Standard errors of the mean. (A) Effect of ESR genotype on hot flash score before tamoxifen treatment in premenopausal women. *P = .015 when ESR1 XbaI GG group was compared with AG and AA groups (P = .025 for gene-dose effect.); #P = .025 when ESR1 PvuII CC group was compared with CT and TT groups (P = .032 for gene-dose effect). (B) Effect of ESR1 CG haplotype on hot flash score before tamoxifen treatment in premenopausal women. (•) Individual data points; P = .0026 for gene-dose effect. (C) Hot flash score by ESR genotypes before tamoxifen treatment in postmenopausal women. None of the differences was statistically significant.

Fig 1.

Effect of estrogen receptor (ESR) genotype on changes in hot flash composite scores after 4 months of tamoxifen treatment. ESR1 and ESR2 gene interactions and tamoxifen-associated change in hot flash score. (•) Individual data points; *P = .0005 for ESR1 PvuII CC and ESR2-02 GG group compared with other haplotypes.

Fig 2.

Effect of estrogen receptor (ESR) genotypes on risk of developing hot flashes during the first year of tamoxifen treatment. (A) Kaplan-Meier curves for the effect of ESR2-02 AA genotype on hot flash–free survival during the first year of tamoxifen treatment (n = 115). Patients who had baseline hot flashes were excluded. (B) Odds ratio of experiencing hot flashes before and during the first year of tamoxifen treatment according to genotype. Error bars represent 95% CI (n = 122).