Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.
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PMID:Aromatase inhibitors: a new paradigm in breast cancer treatment. 1557 17

(1) For postmenopausal women with hormone-receptor-positive breast cancer, the reference adjuvant treatment after surgical excision is tamoxifen (an anti-estrogen), taken orally at a dose of 20 mg/day for 5 years. (2) Anastrozole is the first aromatase inhibitor to be licensed for this use in France. (3) Marketing authorisation was based on the short-term results of a double-blind trial comparing anastrozole (1 mg/day) with tamoxifen (20 mg/day) in 9366 women. The trial is planned to last five years. The results obtained after median follow-up of 4 years showed no difference between the groups in overall survival (109 deaths in each group). But first pathological events were significantly less frequent in the group taking anastrozole (13% versus 15%). Note that these results are undermined by a number of methodological flaws, including relatively short follow-up and definition of relapses using an endpoint mixing heterogeneous prognostic factors. (4) Musculoskeletal disorders, fractures (7.1% versus 4.4%) and hypercholesterolemia were statistically more common with anastrozole than with tamoxifen. Women taking anastrozole found their sex lives less satisfactory than women taking tamoxifen. The following adverse events were statistically less common with anastrozole than with tamoxifen: hot flushes (35.0% versus 40.3%), metrorrhagia, venous thromboembolism (1.1% versus 1.8%), ischaemic stroke (1.1% versus 2.3%), and endometrial cancer (3 versus 15 cases at 4 years). (5) In practice, anastrozole may be beneficial for women who cannot use tamoxifen, such as those at high risk of thrombosis. Anastrozole costs ten times more per day than tamoxifen. Tamoxifen remains the reference adjuvant treatment for all other women.
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PMID:Anastrozole: new indication. Adjuvant treatment of non metastatic breast cancer: useful for some patients. 1587 34

Adjuvant endocrine therapy plays an important role in the management of hormone-receptor-positive early breast cancer, and has increased life expectancy for millions of women. Many patients receive adjuvant treatment for at least 5 years following tumor resection, hence good long-term safety is important for endocrine agents to gain widespread acceptance. Tamoxifen has been used as adjuvant therapy for early breast cancer for many years, and safety data have been well documented, but a poor risk:benefit profile limits treatment duration to 5 years. Increased efficacy over tamoxifen and good tolerability have recently made the third-generation aromatase inhibitors (AIs) the first-choice agents for adjuvant endocrine therapy; however, it is currently not known whether AI therapy, like tamoxifen, will be limited to 5 years. Many side effects of endocrine therapy, such as hot flushes and mood disturbances, are related to estrogen deprivation and are common to tamoxifen and AIs, reflecting the mechanism of action of these drugs. In addition, tamoxifen has estrogenic effects that are beneficial in some tissues: tamoxifen lowers serum cholesterol levels and protects against bone loss and cardiovascular disease, but is also associated with potentially life-threatening side effects, such as endometrial cancer and thromboembolic disease. As AIs lack estrogenic activity, they are not associated with these serious adverse events. Clinical trials comparing AIs with tamoxifen in the adjuvant setting have shown that AIs are well tolerated and are associated with a lower incidence of gynecological symptoms and hot flushes than tamoxifen. However, AIs are associated with musculoskeletal side effects, such as arthralgia, myalgia and bone loss, but these events are preventable or manageable. The effects of AIs on lipid metabolism and the cardiovascular system are still debatable, but placebo-controlled trials provide no evidence to suggest that AIs adversely affect these systems. Furthermore, the AIs allow women to maintain a good quality of life, comparable with women receiving tamoxifen or placebo, and are a cost-effective therapeutic option. Ongoing trials will provide more information regarding the long-term effects of AI therapy and will provide comparative data on the efficacy and safety of the different AIs, thereby helping to determine the optimal treatment strategy for these highly effective and well-tolerated drugs.
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PMID:Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer. 1789 Feb 11

The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial was the first trial to explore the use of aromatase inhibitors in post-menopausal women with early breast cancer and is the largest published cancer treatment trial in breast cancer. The main results have been published at 33-, 47- and 68-month median follow-up, and further analyses are planned for the end of 2007 and in 2010. This trial demonstrated that 5 years of treatment with anastrozole was generally better tolerated than 5 years of treatment with tamoxifen, and led to lower recurrence rates, especially in receptor-positive women (26% reduction). The side-effect profile was different than that for tamoxifen, with fewer hot flushes, gynecologic symptoms, endometrial cancers, strokes and thromboembolic events; however, an increased incidence of fractures, joint symptoms and carpal tunnel syndrome was observed. Future analyses will determine whether benefits and fracture rates persist after stopping treatment, and the extent to which currently marginal benefits on late end points, such as distant recurrence and death after recurrence, are sustained or improved.
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PMID:The ATAC trial: the vanguard trial for use of aromatase inhibitors in early breast cancer. 1802 17

Tamoxifen significantly reduces the risk of developing breast cancer in women at increased-risk. The usefulness of tamoxifen has been limited by its side effect profile, especially its propensity to worsen vasomotor symptoms. Hormone therapy (HT) has long been utilized to reduce vasomotor symptoms in peri- and post-menopausal women. The aim of this study was to compare the incidence of hot flashes, weight gain and other side effects associated with taking tamoxifen alone versus tamoxifen in combination with HT in high-risk women. One hundred eighty high-risk women were enrolled into one of two parallel study cohorts to receive tamoxifen alone (93 women) or tamoxifen with HT (87 women). Women were monitored at baseline, 3 months and then yearly for assessments of menopausal symptoms and toxicities associated with tamoxifen alone versus tamoxifen plus HT. We also assessed for differences in menopausal symptoms and toxicities by type of HT (estrogen vs. estrogen and progestin combination). Hot flash scores increased at 3 months and at 1 year compared with baseline in women on tamoxifen alone as well as for women on HT. Women on tamoxifen with estrogen only replacement had the greatest increase in hot flash scores, although this was not significantly different than the increase seen with tamoxifen alone. About 47% of participants on tamoxifen gained weight and there was a strong trend towards less weight gain in women on the combination of tamoxifen and HT, most pronounced for those on tamoxifen with estrogen alone replacement therapy. The addition of HT to tamoxifen therapy does not ameliorate tamoxifen-induced vasomotor symptoms. Tamoxifen associated weight gain, however, may be lessened by the addition of HT.
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PMID:The addition of hormone therapy to tamoxifen does not prevent hot flashes in women at high risk for developing breast cancer. 1920 76

The study aimed to improve understanding of the natural history and impact of hot flushes after breast cancer. Data were collected from women participating in an RCT of relaxation to reduce the incidence of flushes from breast cancer follow-up clinics from two hospitals in South-East England. Repondents were 150 women experiencing hot flushes following completion of primary treatment for breast cancer. This study utilized a flush diary, the Hot Flushes and Night Sweats Questionnaire (HFNSQ), Functional Assessment of Cancer Therapy with Endocrine Subscale (FACT-ES) and Spielberger State/Trait Anxiety Index (STAI) as the main outcome measures. The study found that in this sample, 51 (34%) women experienced flushes more than five years after diagnosis and 75 (50%) more than 5 years after menopause. Sleep disruption occurred in 90 women (72% of those that returned diaries), affecting half of the nights they recorded. The mean problem rating on the HFNSQ was 4.85 out of 10. A peak incidence of flushes was apparent around 10 a.m. in women taking tamoxifen. It was concluded that hot flushes after breast cancer may be long-lasting and cause sleeping difficulties for many women. Tamoxifen may affect the diurnal pattern of flushes. After breast cancer, the duration of flushes, potential distress and disruption to women's lives should not be underestimated and appropriate interventions should be offered.
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PMID:Menopausal hot flushes after breast cancer. 1926 29

To undertake a systematic review of three first-line treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR+, i.e. ER+ and/or PgR+) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-to-progression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (Q-Twist difference = 1.5; P < 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with post-menopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with appropriate caution. Head-to-head comparisons between letrozole, anastrozole and exemestane in the first-line MBC setting are warranted.
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PMID:Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer. 2053 42

Tamoxifen has a key role in the management of women with hormone receptor (HR) positive breast cancer. It is the endocrine treatment of choice in premenopausal women with HR positive breast cancer and is also clinically indicated in significant numbers of post-menopausal women who have relative contraindications to aromatase inhibitors. Tamoxifen is a pro-drug that is metabolised to its active metabolites by the cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A, CYP2B6, and CYP2C19. The CYP genes are polymorphic resulting in variable enzyme activity. Retrospective clinical data suggests that specific single nucleotide polymorphisms (SNPs) of CYP2D6 can lead to null or reduced enzyme activity resulting in worse outcomes for those individuals when treated with tamoxifen for HR positive breast cancer. There is however a lack of robust prospective clinical data on this subject. Commercial tests are now available for the genotyping of CYP2D6 with the aim of individualisation of tamoxifen therapy for patients with HR positive breast cancer. Selective serotonin reuptake inhibitor antidepressant drugs such as paroxetine and fluoxetine have also been used to manage tamoxifen induced hot flushes. These drugs potently inhibit the metabolism of tamoxifen by CYP2D6 and thus potentially may lessen the efficacy of tamoxifen. The genetic variations in other enzymes involved in tamoxifen metabolism (CYP3A, CYP2B6, CYP2C19) do not appear to cause any meaningful difference in the efficacy of tamoxifen. This review article will summarize the available published breast cancer data on the interaction between the relevant SNPs for CYP2D6, CYP3A, CYP2B6, and CYP2C19 and the efficacy of tamoxifen, their role in individualisation of hormonal therapy and the role of the commercially available genotyping kits.
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PMID:Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. 2118 24

Tamoxifen is used as an adjuvant therapy to reduce breast cancer recurrence among women with estrogen receptor positive tumors. Antidepressants are also commonly used in such women, to treat depression or to manage hot flushes, a frequent tamoxifen secondary effect. Some antidepressants could potentially inhibit cytochrome P450 2D6, required to activate tamoxifen, interfering with its action. Although there is not a clear cut directive on the subject, it is nowadays recommended to treat women with antidepressants with the lower cytochrome P450 2D6 inhibition potential to avoid a possible antagonism that may reduce tamoxifen s prevention of breast cancer recurrence at least in some patients with CYP2D6 genetic variation. The recommended antidepressants are desvenlafaxine, milnacipran, venlafaxin, escitalopram and citalopram.
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PMID:[Antagonism of tamoxifen and antidepressants among women with breast cancer]. 2152 23

Tamoxifen, an oestrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole.
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PMID:Tamoxifen and CYP 2D6 inhibitors: caution. 2175 53


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