Tamoxifen-induced Hot Flashes Research Articles

The frequencies of CYP2D6 alleles and their impact on clinical outcomes of adjuvant tamoxifen therapy in Syrian breast cancer patients

BackgroundTamoxifen is one of the fundamental pillars of adjuvant endocrine therapy for hormone receptor-positive breast cancer; however, 30–50% of patients receiving tamoxifen experience tumor relapse. CYP2D6, encoded by an extremely polymorphic CYP2D6 gene, is the rate-limiting enzyme of tamoxifen bioactivation. This study aimed at determining the frequencies of the most clinically relevant CYP2D6 alleles and evaluating their impact on the responsiveness to tamoxifen in a cohort of Syrian breast cancer patients.MethodsThis case–control study encompassed positive estrogen and/or progesterone receptor, stage 1–3 breast cancer female patients receiving tamoxifen at Al-Bairouni University Hospital, the major National Oncology Center in Syria. Successfully genotyped eligible patients (n = 97) were classified according to their response into; no recurrence group (n = 39) who had completed a five-year recurrence-free adjuvant tamoxifen therapy, and recurrence group (n = 58) who had experienced recurrence. Several star alleles including CYP2D6*4, CYP2D6*10, CYP2D6*41, and CYP2D6*69 were identified via targeted sequencing of specific polymerase chain reaction (PCR) products and phenotypes were assigned according to activity score (AS). The correlation between genotypes and disease-free survival (DFS) was assessed using Kaplan–Meier method and log-rank test. Hazard ratios were estimated using Cox proportional hazards regression models.ResultsThe allelic frequencies of CYP2D6*41, CYP2D6*10, CYP2D6*4, and CYP2D6*69 were found to be 9.28%, 7.22%, 7.22%, and 2.58%, respectively. No statistically significant differences were observed in the frequencies of CYP2D6 phenotypes between the two arms (P = 0.24), nor the incidence of tamoxifen-induced hot flashes (P = 0.109). Poor metabolizers (PMs) tended to display shorter DFS than intermediate metabolizers (IMs) and normal metabolizers (NMs) combined (adjusted HR = 2.34, 95% CI = 0.84–6.55, P = 0.104). Notably, patients homozygous for the null CYP2D6*4 allele (1847A/A) had an elevated risk of disease recurrence compared to patients with 1847G/G genotype (adjusted HR = 5.23, 95% CI = 1.22–22.49, P = 0.026).ConclusionsOur findings show no association between CYP2D6 phenotype and treatment outcomes of tamoxifen in Syrian breast cancer patients. Nevertheless, a worse DFS was revealed in patients with 1847A/A genotype (*4/*4).

Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort

Women with reduced CYP2D6 activity have low endoxifen concentrations and likely worse long term benefits from tamoxifen. We investigated the association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. We collected hot flash frequency and severity data over 12 months from 297 women initiating tamoxifen. We performed CYP2D6 genotyping using the AmpliChip CYP450 test and correlated inherited genetic polymorphisms in CYP2D6 and tamoxifen-induced hot flashes. Intermediate metabolizers had greater mean hot flash scores after 4 months of tamoxifen therapy (44.3) compared to poor metabolizers (20.6, P = 0.038) or extensive metabolizers (26.9, P = 0.011). At 4 months, we observed a trend toward fewer severe hot flashes in poor metabolizers compared to intermediate plus extensive metabolizers (P = 0.062). CYP2D6 activity may be a modest predictive factor for tamoxifen-induced hot flashes. The presence or absence of hot flashes should not be used to determine tamoxifen's efficacy.

Gene Testing to Predict Tamoxifen-Induced Hot Flashes: New Biological Insights

Gene Testing to Predict Tamoxifen-Induced Hot Flashes: New Biological Insights

Estrogen Receptor Genotypes Influence Hot Flash Prevalence and Composite Score Before and After Tamoxifen Therapy

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

The effect of CTP-347 on CYP2D6-mediated tamoxifen metabolism

11552 Background: The activity of tamoxifen is primarily mediated through its 4-hydroxy metabolites which are potent antagonists of the estrogen receptor in breast tissue. The 4-hydroxylation reaction is mediated through the cytochrome P450 isozyme CYP2D6. Unfortunately, high concentrations of endoxifen, the major 4-hydroxy metabolite, have also been implicated in the occurrence of hot flashes. Although paroxetine has been demonstrated to reduce the frequency of hot flashes in investigator trials of patients with breast cancer, co- administration would reduce the effectiveness of tamoxifen since paroxetine has been shown to be a mechanism-based inactivator of CYP2D6. CTP-347 is a new chemical entity in which key hydrogen atoms of paroxetine are replaced with deuterium atoms. CTP-347 is being developed for the treatment of post-menopausal and tamoxifen-induced hot flashes and will enter clinical trials in mid-2008. Methods: Serotonin and norepinephrine reuptake inhibition was measured in rat synaptosomes u...

Tamoxifen-induced hot flashes are associated with estrogen receptor polymorphisms

501 Background: Hot flashes are the most common side effect of tamoxifen. The pharmacogenetic predictors of hot flashes are not known. We hypothesized that estrogen receptor (ER) genotypes that have been associated with clinical phenotypes may predict the frequency and composite score of tamoxifen-associated hot flashes. Methods: We conducted a prospective observational study in 3 academic centers to evaluate the associations between ER and hot flash composite scores in women with breast cancer during the first year of adjuvant tamoxifen treatment. Menopausal status and prior chemotherapy history were collected at baseline. Medication records and validated hot flash diaries were prospectively collected before and following 1, 4, 8 and 12 months of starting tamoxifen. ERa (ESR1) PvuII (rs2234693) and XbaI (rs9340799) genotypes were determined using a Restriction Fragment Length Polymorphism (RFLP) assay; and ERβ (ESR2–02; rs4986938) genotype was determined using a Taqman™ assay. The haplotype of two ESR1 SNPs and their association with the baseline hot flash score were analyzed with haplo.stat function in R. Individual SNPs and their interactions in baseline hot flash score and month 4 hot flash score change were analyzed with SAS PROC GLM. Results: Of the 298 women recruited to the trial, 286 returned their baseline diaries and 251, 239, 214, and 213 women returned their diaries 1, 4, 8, and 12 months after tamoxifen treatment. At baseline, premenopausal women who were homozygous for the ESR1 CG haplotype reported higher hot flash scores (17.2±3.7) than carriers with one or less CG allele (5.2±3.9), p=0.01. After tamoxifen treatment, postmenopausal women with ESR1 PvuII CC and ESR2–02 GG genotype had the greatest increase (p=0.0004) in hot flash score (53.9±16.4) as compared with women with other genotypes (12.5±3.6). Women who were homozygous for the ESR2–02 AA allele were significantly less likely to experience tamoxifen-induced hot flashes than women with at least one G allele (OR=4.0, P=0.0006) regardless of menopausal status and chemotherapy history. CYP2D6 analysis in underway and results will be available for the meeting. Conclusions: Menopausal status, history of prior chemotherapy, and ER genotype may be used to predict who may suffer hot flashes during tamoxifen treatment. [Table: see text]

Results of a randomized double-blind clinical trial of Shugan-liangxue prescription for relieving hot flashes in breast cancer patients

9086 Background: Hot flashes are a common side effect for BC pts during endocrine treatment. An oral solution of TCM is prescribed for the purpose of clearing heat and cooling blood. There is no phytoestrogen in TCM compound and each herbal with luciferase activity detection. 66 patients involved in the study from October 2004 to November 2006. Methods: A placebo controlled randomized double blind clinical trial was designed. The endpoint is hot flashes relieving. The second point is improving the sleeping disturbance. Sample numbers designed by statistician. Daily average of hot flashes was recorded by pts for a week as a baseline. The age, ER and PR status, hot flashes scores were distributed approximately equal between the two groups. Hot flashes scores were evaluated according to Kupperman menopausal index (KI). TCM or placebo liquid (100ml) was administrated orally three times a day for 3 weeks by a randomized envelope method. Results: Total 66 patients were evaluated. For hot flashes in placebo group 69.7%(23/33) no change, 30.3%(10/33) relieved, no pts report symptom disappear. There are 42.4%(14/33) hot flashes no change, 42.4 % (14/33) relieved, 15.2 %(5/33) hot flashes disappearance in TCM group (P=0.006). For sleeping disturbance in placebo group is 60.6%(20/33) no change, 39.4%(13/33) sleep improvement. In TCM group is 36.4%(12/33) no change, 63.6%(21/33) sleep improvement (P=0.049). Conclusions: According to the principle of TCM treatment hot flashes and ER and/or PR positive BC endocrine treatment characteristic, the TCM prescription is effective in alleviating tamoxifen-induced hot flashes and sleep disturbance while there is no phytoestrogen. No significant financial relationships to disclose.

The assessment of randomized double blind clinical trial of Shugan-liangxue prescription used for the treatment of hot flashes in breast cancer patients

8584 Background: Hot flashes are a common side effect for breast cancer (BC) pts with TAM treatment. Traditional Chinese medicine (TCM) is typically given to BC pts in China. This trial is to assess the effects of TCM for relieving hot flashes. TCM oral solution is prescribed for clearing heat and cooling blood. The compound was tested and contained no phytoestrogen. A randomized, double blind clinical trial was designed to examine the effects of TCM over a 3-week period. Methods: From October 2004 to October 2005, 49 BC pts undergoing treatment with TAM who having hot flashes at least 3 times a day involved the study. Daily average of hot flashes was recorded by the pts for a week as a baseline. TCM or placebo liquid (100 ml) was administered orally three times a day for 3 weeks by a randomized double-blind method. The number of hot flashes and quantity of sleep disturbance in the two groups were evaluated. Results: 45 pts were evaluated in TCM group (n = 22) and the placebo group (n = 23). The severity of the hot flash symptoms was evaluated according to the Kupperman menopausal index (KI). Pts were distributed approximately equally between the two groups. There were 31% (7/22) and 26% (6/23)pts with mild hot flashes in TCM and placebo groups, and 68% (15/22) and 73% (17/23) with severe hot flashes in TCM and placebo groups. Hot flash relief was described as either symptom disappearing, a decrease from severe to mild symptoms, or no change. In TCM group, 50% showed no change, 27% decrease and 23% symptoms disappearing. In the placebo group, 70% no change, 30% decrease and no pts reporting symptoms disappearing. A statistically significant difference exists between the two groups (P < 0.05). In TCM group, 73% of pts sleep improvement compared to 35% in the placebo group (P < 0.05). No adverse events or any side effects were reported. Conclusion: The oral solution of TCM is effective in alleviating tamoxifen-induced hot flashes and sleep disturbance. The study of the drug’s mechanism and an expanded clinical trial are underway. No significant financial relationships to disclose.

Centrally active nonhormonal hot flash therapies

Given the problems associated with hormonal therapy, and the prominent problem of hot flashes in menopausal women, there is a need for nonhormonal agents to alleviate hot flashes. Several compounds that appear to act on the central nervous system have been investigated. Potential mechanisms for their effects on hot flashes have been described. Bellergal (no longer available on the US market, where it was known as Bellergal-S), a combination preparation sedative that consists of low-dose phenobarbital, ergotamine tartrate, and levorotatory alkaloids of belladonna, is an old agent that was popular approximately 20 years ago; however, there is limited suggestion of efficacy for this agent. Clonidine, an older antihypertensive drug, is another centrally active agent that has been studied. Randomized trials have demonstrated that it clearly works for reducing hot flashes, but the magnitude of efficacy is somewhat limited. Toxicity from this agent limits its utility in the clinic. Methyldopa is another centrally active agent that has been studied but to a more limited degree. It appears to have minimal efficacy and too much toxicity to make it clinically useful. Anecdotal observations from a number of sources suggested that newer antidepressants can alleviate hot flashes. This led to pilot trials of venlafaxine and paroxetine, with results suggesting benefit from both drugs. Subsequently, randomized, placebo-controlled, double-blind clinical trials of venlafaxine, paroxetine, and fluoxetine were conducted. All 3 of these clinical trials demonstrated statistically significant reductions in hot flashes with these newer antidepressants compared with placebo. Pilot trials of citalopram and mirtazapine, 2 other newer antidepressants, have also suggested efficacy. Toxicity evaluations have suggested that these agents are, again, well tolerated by the majority of patients. A recent trial, however, was unable to demonstrate any benefit for fluoxetine or citalopram over a placebo. Anecdotal observations also suggested that gabapentin was helpful for alleviating hot flashes. This led to pilot trials that again suggested efficacy. Subsequently, 2 large placebo-controlled, randomized, double-blind clinical trials were conducted. Both of these demonstrated statistically significant efficacy for gabapentin compared with a placebo. This drug is relatively well tolerated by most patients. Thus, centrally active nonhormonal agents clearly do decrease hot flashes in women. The most efficacious and clinically appropriate agents for use are newer antidepressants and gabapentin. Continued evaluation of the efficacy and toxicity of these agents is ongoing.

261. Newer antidepressants for alleviation of tamoxifen-induced hot flashes in breast cancer survivors

Background Hot flashes are symptoms of vasomotor instability reported in least 50–60% of breast cancer survivors taking tamoxifen. Based on information that venflaxine, one of the newer antidepressants, was able to alleviate hot flashes, we conducted an open-label pilot study to evaluate potential effect of the newer antidepressants (citalopram, venlafaxine and fluoxetin) to treat tamoxifeninduced hot flashes. Patients and methods From October 2002 to January 2003 in two centres in Poland, 36 breast cancer survivors who were receiving tamoxifen therapy and having at least one hot flash a day were enrolled on the study. Twenty two of women received citalopram (61%), nine (25%), fluoxetin, and five (14%) venlafaxine. About choice of kind of antidepressant decided financial possibilities of each patient In a daily diary, patients recorded number, duration and severity of hot flushes and overall quality of life score (on a 6-point scale) during a baseline-week and then every two weeks of treatment. Results A total of twenty two women completed the 8-week study. Data collected on 10/16 patients who received citalopram, 4/7 fluoxetin and 2/3 venflaxine, showed a decrease in hot flashes duration, frequency and severity. 18/26 women reported considerable improvement in quality of life. Nine (35%) women had complete elimination of hot flushes. Regarding toxicity information, each agent appears to be well tolerated overall. Side effect data suggest that used agents appear to ameliorate other menopausal related symptoms such as difficulty sleeping, disturbances of appetite, disturbances of concentration, lowering sexual activities and depression. Conclusion This data support newer antidepressants as potentially effective new nonhormonal agents for managing tamoxifen-induced hot flushes do. Complete data from all patients and long term observation of her quality of life will be available by November 2003.

Clonidine was effective for reducing tamoxifen associated hot flashes in postmenopausal women with breast cancer

Source Citation Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer C...

Using the Medicine Clonidine To Treat Hot Flashes in Breast Cancer Patients Taking Tamoxifen

Summaries for Patients16 May 2000Using the Medicine Clonidine To Treat Hot Flashes in Breast Cancer Patients Taking TamoxifenSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-132-10-200005160-00038 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail What is the problem and what is known about it so far?Tamoxifen, an antiestrogen medicine commonly used for treating breast cancer, often causes hot flashes as a side effect. Hot flashes can be uncomfortable and disrupt a woman's normal activities, including sleep. Estrogen replacement hormones are used to treat hot flashes in women without breast cancer but cannot be used in breast cancer patients because they might cause the cancer to grow. Some studies have shown that clonidine, a nonhormonal medicine sometimes used to treat high blood pressure, can reduce hot flashes in women who have gone through natural ... Author, Article, and Disclosure InformationAffiliations: The summary below is from the full report titled “Oral Clonidine in Postmenopausal Patients with Breast Cancer Experiencing Tamoxifen-Induced Hot Flashes: A University of Rochester Cancer Center Community Clinical Oncology Program Study.” It is in the 16 May 2000 issue of Annals of Internal Medicine (volume 132, pages 788-793). The authors are K.J. Pandya, R.F. Raubertas, P.J. Flynn, H.E. Hynes, R.J. Rosenbluth, J.J. Kirshner, H.I. Pierce, V. Dragalin, and G.R. Morrow.Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoOral Clonidine in Postmenopausal Patients with Breast Cancer Experiencing Tamoxifen-Induced Hot Flashes: A University of Rochester Cancer Center Community Clinical Oncology Program Study Kishan J. Pandya , Richard F. Raubertas , Patrick J. Flynn , Harry E. Hynes , Richard J. Rosenbluth , Jeffrey J. Kirshner , H. Irving Pierce , Vladimir Dragalin , and Gary R. Morrow Metrics Cited byPatients with Cancer and Survivors 16 May 2000Volume 132, Issue 10Page: 788KeywordsBreast cancerCancer treatmentEstrogen replacement therapyMenopauseMouthPrimary hypertensionQuality of lifeSleep ePublished: 15 August 2000 Issue Published: 16 May 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.Loading ...

Tamoxifen-Induced Hot Flashes

Hot flashes are the most prominent side effect of tamoxifen, the most frequently prescribed antitumor agent in the world. Little detailed information is available to predict who will develop hot flashes on tamoxifen, to describe the natural history of these hot flashes, and/or to predict who will request therapy for such a side effect. This current trial was developed to address these items. Women who were about to begin adjuvant tamoxifen for locally treated breast cancer were approached for this trial. Before initiating tamoxifen, patients completed a short questionnaire designed to inquire about potential prognostic factors. Upon starting tamoxifen, women were asked to complete a hot flash diary daily for 3 months, and then daily for 1 week of each of the subsequent 9 months. Fifty patients, aged 51-83 years, provided data for this report. Approximately half of the women reported that they did not have any substantial hot flashes while the other half reported hot flashes of variable intensity. On average, these hot flashes gradually increased over 3 months and then plateaued. Baseline factors that appeared to predict for subsequent hot flash problems included a prior history of moderate to severe hot flashes with menopause and a history of prior estrogen therapy use. Overall, 16% of the women reported the desire for therapy for their hot flashes. Thirty-seven and one-half percent of the women (6/16) had a history of both prior estrogen use and moderate to severe hot flashes with menopause as compared to none (0/14) of the women without either of these factors. The data from this study can be utilized to better identify and educate women as to their probability of developing hot flashes after starting tamoxifen, to describe the average time frame for these hot flashes, and to predict the likelihood of whether resultant hot flashes will be substantial enough to have a woman request therapy for them.

Transdermal Clonidine for Ameliorating Tamoxifen-Induced Hot Flashes

The 1994 report by Goldberg et al, entitled "Transdermal Clonidine for Ameliorating Tamoxifen-induced Hot Flashes" (J Clin Oncol 12:155–158), included an incorrect version of Figure 1. The correct figure is as follows: Please see the PDF for Figure.