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

For the past 25 years, the estrogen antagonist tamoxifen has been considered the 'gold standard' for the treatment of breast cancer, despite certain tolerability issues and the risk of developing resistance. The aromatase inhibitors work by blocking the conversion of androgens to estrogen and were developed for use in patients where ovarian function had ceased (naturally, surgically or pharmacologically). Anastrozole, a third-generation nonsteroidal aromatase inhibitor that is a highly potent and selective inhibitor of the aromatase enzyme, has been shown to be superior to the gold standard tamoxifen for the first-line treatment of postmenopausal women with advanced breast cancer. As second-line therapy, anastrozole has shown superior survival compared with megestrol acetate and is also efficacious as neoadjuvant treatment in postmenopausal women and in combination with goserelin for the treatment of premenopausal women with advanced breast cancer. More recently, the results of the ATAC (anastrozole, tamoxifen, alone or in combination) trial, a large study in 9366 patients, demonstrated that anastrozole was significantly superior to tamoxifen for the treatment of postmenopausal women with early breast cancer, with regards to disease-free survival (p = 0.013) and incidence of contralateral breast cancer (p = 0.007). In addition, anastrozole was shown to be significantly better tolerated than tamoxifen with respect to endometrial cancer (p = 0.02), vaginal bleeding/discharge (p < 0.0001 for both), ischaemic cerebrovascular events (p = 0.0006), thromboembolic events (p = 0.0006) and hot flushes (p < 0.0001), while tamoxifen was associated with significantly less musculoskeletal disorders and fractures than anastrozole (p < 0.0001 for both). This review focuses on both the clinical pharmacology and the clinical data of anastrozole with emphasis on its future applications.
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PMID:Anastrozole (Arimidex) in clinical practice versus the old 'gold standard', tamoxifen. 1250 8

ATAC, a randomized, double-blind trial, compared tamoxifen (20 mg) with anastrozole ('Arimidex') (1 mg) alone, and the combination of anastrozole plus tamoxifen (combination), as adjuvant endocrine treatment for postmenopausal patients with early breast cancer. Patients with operable invasive breast cancer following completion of primary therapy, who were candidates to receive adjuvant endocrine therapy, were eligible for this study. Primary endpoints were disease-free survival (DFS) and tolerability. Other endpoints included time to recurrence (TTR: censoring non-breast cancer deaths before recurrence) and the incidence of contralateral breast cancer. A total of 9366 patients were included in this study (N=3125, 3116 and 3125 for anastrozole, tamoxifen and the combination, respectively). Median duration of therapy was 30.7 months and median follow-up was 33.3 months. The total numbers of events were 317, 379 and 383 for anastrozole, tamoxifen and the combination, respectively. DFS was significantly improved in the overall population for anastrozole versus tamoxifen (hazard ratio (HR)=0.81, 95% confidence interval (CI) (0.71-0.96), P=0.013). Anastrozole showed improved TTR compared with tamoxifen (HR=0.79, CI (0.67-0.94), P=0.008), which improved even further in the ER+ and/or PR+ subgroup (HR=0.73, CI (0.59-0.90), P=0.003). The incidences of hot flushes, thromboembolic events, ischaemic cerebrovascular events, vaginal bleeding/discharge and endometrial cancer were significantly reduced with anastrozole compared with tamoxifen (P<0.03 for all). Musculoskeletal disorders and fractures were significantly reduced in patients receiving tamoxifen compared with those on anastrozole (P<0.03 for both). No increase in hip fractures was seen for anastrozole versus tamoxifen (11 versus 13, respectively). Combination treatment was equivalent to tamoxifen in terms of both efficacy and tolerability. Anastrozole showed superior efficacy to tamoxifen for DFS, TTR and contralateral breast cancer. Early findings show anastrozole to be an effective and well-tolerated endocrine option for the treatment of postmenopausal patients with early breast cancer. For the first time a choice now exists for adjuvant endocrine treatment for postmenopausal women with hormone responsive tumours. Longer follow-up will further define the benefit/risk of anastrozole adjuvant therapy.
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PMID:'Arimidex' (anastrozole) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer--efficacy overview. 1462 37

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

Adjuvant endocrine treatment-related adverse effects have a strong impact on patients' quality of life and thereby limit therapy's risk benefit ratio resulting in morbidity and treatment discontinuation. Still, many AI adverse effects remain untreated given that they are unrecognized by conservative methods (e.g., proxy ratings). The ability of complementary patient-reported outcomes (PROs) to provide a more comprehensive assessment of side-effects is to be explored. A cross-sectional study sample of 280 postmenopausal, early stage breast cancer patients was subjected to a comprehensive PRO assessment (FACT-B/+ES) at their after-care appointment. Prevalence and severity of patient-reported physical side-effects and psychosocial burden related to adjuvant AI therapy were compared with prevalences derived from pivotal phase IV trials (ATAC 2005, BIG1-98 2005). Across all symptom categories, highest prevalence rates were found for joint pain (59.6%), hot flushes (52%), lost interest in sexual intercourse (51.4%), and lack of energy (40.3%). Overall, PROs resulted in significantly higher prevalence rates as compared to physician ratings for all symptoms published in pivotal clinical trials except vaginal bleeding and nausea. The treatment duration exerted no significant impact on symptom frequency (P > 0.05). Established prevalence rates of endocrine treatment-related toxicity seem to be underestimated. The incorporation of PRO data should be mandatory or at least highly recommended in clinical treatment planning to arrive at a more accurate assessment of a patient's actual symptom burden enabling improved individualized management of side-effects and mediating the preservation of treatment adherence.
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PMID:Is the toxicity of adjuvant aromatase inhibitor therapy underestimated? Complementary information from patient-reported outcomes (PROs). 2131 68