Aromatase activity in primary and metastatic human breast cancer

Aromatase activity was measured in 104 primary and 24 metastatic breast cancer patients. The assay employed quantitates the production of 3H water release from 1 beta-[3H]androstenedione after aromatization. Of 104 human primary breast tumors studied, 64 contained measurable aromatase activity, ranging from 5-70.5 pmol estrone formed/g protein/hour. In primary breast cancers there was no difference in levels of aromatase activity when analyzed by menstrual status or age by decade. Aromatase activity was similar in small and large primary tumors. The median aromatase activity of primary breast tumors (8.6 pmol/g/h) was similar to that found in metastatic breast cancer deposits (12.0 pmol/g/h). Aromatase activity did not correlate with either estrogen (ER) or progesterone (PR) receptor concentration in the tissues assayed. In this regard there were 33 ER- PR- tumor biopsies. Twelve of these 33 tumors contained aromatase activity greater than 10 pmol/g/hour.     

Aromatase gene expression and its modifying factors in breast tumor tissue

Aromatase (CYP 19) gene expression was studied in 70 breast tumors. When RNA-dot-blot or rt-polymerase chain reaction were used expression frequency was 60.4 and 91.7%, respectively. An analysis of individual variants of non-coding exon of aromatase gene confirmed that, unlike normal mammary tissue, tumor switched from activation of exon I.4 ("sensitive" to glucocorticoids) to exons II ("sensitive" to cAMP) or I.3. This difference was relatively somewhat more pronounced in the Russian material. Direct correlation between aromatase enzymatic activity and expression of exons II and I.3 in tumor tissue appeared more significant than that of aromatase gene coding site. An evaluation of the expression of adenylate cyclase G-protein alpha-subunit genes established an inverse correlation between expression of Gi2a and exon I.3. Breast tumors with elevated basal aromatase activity were more sensitive to aromatase inhibitors (letrozole, 4-OHA) in vitro although no relationship between use of CYP19 (aromatase) 5' exon variant and in vitro inhibition of aromatase was detected. A correlation was observed between expression of aromatase gene and variants of its 5' exon, on the one hand, and age, tumor grade, steroid receptor presence and tumor lymphocytic infiltration, on the other. To summarize, local estrogen production in breast tumor tissue is regulated by a wide range of factors expression both aromatase gene influencing and its enzymatic activity, thus providing leverage on both.     

Aromatase and breast cancer

Aromatase activity may be detected using in vitro and in vivo techniques in most breast cancers and mammary adipose tissue. This activity makes a variable contribution to endogenous estrogens within the breast and in many cases represents the major source of these hormones. Such local biosynthesis may maintain the growth of some hormone-dependent tumors. The factors which regulate aromatase activity within the breast are not defined but are likely to include growth factors and cytokines which may be produced by breast tissues so that autocrine and paracrine loops may exist. Estrogen biosynthesis within the breast, like other peripheral systems, appears sensitive to classical aromatase inhibitors and the new generation of drugs are capable of profoundly blocking the activity and markedly reducing endogenous estrogen levels; in turn these endocrine effects are translated in dramatic anti-tumor influences in hormone-dependent breast cancer.     

Aromatase inhibitors in breast cancer therapy

Estrogens are involved in numerous physiological processes and have crucial roles in certain disease states, such as mammary carcinomas. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in breast tissue and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitors, such as aminoglutethimide, has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors, such as 4-hydroxyandrostenedione and exemestane produce potent aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole and exemestane, are approved for clinical use as first-line endocrine therapy in postmenopausal women with metastatic hormone-dependent breast cancer and as second-line endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies.     

Aromatase inhibitors in breast cancer therapy

Recent advances have been made in the hormonal treatment of breast cancer with the advent of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane). These newer agents have substantial antitumor activity and appear to be as effective as tamoxifen, with fewer adverse effects. Recent reports indicate that anastrozole is more effective than tamoxifen as adjuvant endocrine therapy in postmenopausal women with breast cancer. This report provides an overview of the clinical trials conducted to date with the aromatase inhibitors as first- and second-line therapies, with an emphasis on recently updated analyses comparing anastrozole with tamoxifen in the adjuvant setting.     

Aromatase inhibitors in breast cancer therapy

Estrogens are involved in numerous physiological processes and have crucial roles in certain disease states, such as mammary carcinomas. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in breast tissue and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitors, such as aminoglutethimide, has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors, such as 4-hydroxyandrostenedione and exemestane produce potent aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole and exemestane, are approved for clinical use as first-line endocrine therapy in postmenopausal women with metastatic hormone-dependent breast cancer and as second-line endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies.     

芳香化酶抑制剂在乳腺癌治疗中的运用

芳香化酶是绝经后雌激素合成过程中的一个限速酶,而且在乳腺癌组织中为高表达,因此芳香化酶抑制剂(AI)可通过对其抑制作用而控制绝经后乳腺癌的发展.现综述AI的分类、发展、在乳腺癌治疗中的作用机制以及在各期乳腺癌治疗中的应用,并着重介绍第3代AI.     

Aromatase inhibitors in postmenopausal breast cancer patients

Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.     

Aromatase inhibitors in the management of early breast cancer

The adjuvant treatment of patients with endocrine-sensitive breast cancer has been dominated for several decades by the gold-standard tamoxifen. Promising results on the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to the development of these agents in the treatment of early breast cancer. Recent results consistently show the superiority of these agents over tamoxifen, and the therapeutic strategies of AIs in the adjuvant setting are still being discussed. Various approaches have been evaluated, including the following:

1.

upfront 5-year use of an AI instead of tamoxifen for newly diagnosed patients,     

Aromatase inhibitors and male breast cancer

Abstract The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.     

Aromatase inhibitors in adjuvant setting in breast cancer

For more than twenty years, tamoxifen represents the gold standard treatment in adjuvant setting for breast cancer patients. However, the tamoxifen activity remains complex, with its agonist effects, sometimes a poor tolerance and a certain number of patients become refractory to treatment. The aromatase inhibitors, such as progestatifs, were developed to challenge tamoxifen efficacy, along with improved tolerability. The third generation of aromatase inhibitors seems to provide significant gains in efficacy over tamoxifen for postmenopausal patients with hormone receptor positive breast cancer and they have already been approved in patients with metastatic disease. We review, in this article, the rationale for using IA in patients with breast cancer and, across the different clinical trials results already published, their current major role they are playing in adjuvant setting for menopausal hormonal receptor-positive breast cancer patient. One of the main issues using the third generation of IA is their long-term side effects, especially bone turnover and lipid metabolism.     

Aromatase inhibitors in breast cancer: an overview

We examined published reports on the use of aromatase inhibitors in postmenopausal patients with hormone receptor-positive breast cancer. Our data were obtained through a MEDLINE search of literature published in English. Current data indicate that aromatase inhibitors are equivalent or superior to tamoxifen as first-line therapy for metastatic breast cancer and as neoadjuvant treatment for primary breast cancer. In addition, randomized studies have shown that aromatase inhibitors can be administered instead of tamoxifen as a single agent for 5 years or sequentially with tamoxifen for 5 or 10 years. These choices should be discussed with the patient, considering the estimated risk for recurrence and other associated comorbid conditions such as osteoporosis and thromboembolism.     

Aromatase inhibitors for breast cancer in postmenopausal women

Third-generation aromatase inhibitors are potent inhibitors of the aromatase enzyme, which catalyzes the last step in estrogen biosynthesis. These agents are active against breast cancer in hormone-na?ve postmenopausal women and in women who have experienced failure of tamoxifen or failure of tamoxifen plus other hormonal therapy. There are two types of aromatase inhibitors, irreversible steroidal activators (e.g., exemestane) and reversible nonsteroidal imidazole-based inhibitors (e.g., anastrozole, letrozole). Recent data suggest that some women who experience failure of one type of aromatase inhibitor can subsequently derive benefit from the other type. The reason for this lack of cross-resistance is unknown. This finding of non-cross-resistance between steroidal aromatase activators and nonsteroidal aromatase inhibitors offers the opportunity to increase the number of lines of hormone therapy before making the inevitable switch to more toxic chemotherapy, thus potentially improving quality of life for postmenopausal women with advanced disease. Data from postmenopausal women with advanced disease suggest that steroidal and nonsteroidal aromatase inhibitors have similar tolerability profiles; however, emerging data suggest that there may be differences in their effects on end organs, which may become evident with longer term use, such as in the adjuvant or prevention settings. Steroidal agents appear to have beneficial effects on lipid and bone metabolism, whereas nonsteroidal agents may have neutral or unfavorable effects. These differences may be attributed to the androgenic effects of steroidal agents; clinical trials are currently under way to confirm these suspicions.     

Aromatase inhibitors as adjuvant therapy in breast cancer

The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormone-responsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen's benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor-positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.     

Aromatase activity and its gene expression in tumor tissue of smokers and non-smokers with breast cancer

Tissue was sampled from 121 tumors of the breast. The activity of aromatase (estrogen synthetase) was assessed by radiobiochemical means in 61 cases; gene expression was evaluated with the aid of polymerase chain reaction in 14 and the same--by the dot-blot procedure in 46 patients. Inveterate smokers (15 years and more) made up 16.5%. The smokers revealed a distinct tendency towards aromatase activity decreasing in tumor tissue (chiefly in menopausal patients) as well as lower intensity of aromatase gene expression assessed in terms of polymerase chain reaction. Alongside with other evidence, our finding point to long-term-smoking-related sensitivity of intratissular estrogen synthesis being higher than in general circulation. It also demonstrated local aromatization inhibition in tumor tissue, the latter being a possible mechanism which causes tumor tissue hormone sensitivity to change in smokers and affects course of disease.