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Modern hormone therapy for breast cancer has developed significantly in recent years. Despite the different mechanisms of action of hormonal drugs, the main target of endocrine therapy is endogenous estrogens. The role of all known methods of hormone therapy is to reduce the proliferating effect of estradiol on breast cancer cells by blocking hormone receptors or by reducing the concentration of estradiol in serum and tissues.
Determination of estrogen receptors (ER) and progesterone (RP) in breast tumors allows one to reliably speak about the alleged sensitivity to hormone therapy. The presence of both types of receptors characterizes the highest efficiency of this method, reaching 80%. The response to hormone therapy in the presence of one type of receptor is reduced to 40%, but even in the presence of receptor-negative tumors, endocrine therapy can be successful in 10% of cases.
In the absence of information about the receptor status of the tumor, one can focus on indirect signs: postmenopausal age, a long disease-free interval between operations and metastatic manifestations, predominant damage to soft tissues, lymph nodes, and the skeletal system.
Until recently, antiestrogens, in particular tamoxifen, were considered the "gold standard" treatment for menopausal breast cancer patients with positive hormone receptors. Tamoxifen has been used in the first line of metastatic breast cancer, neoadjuvant and adjuvant hormone therapy.
New advances and prospects in endocrine therapy for breast cancer are associated with the emergence of third generation aromatase inhibitors. The main source of estrogen formation in menopausal women is androstenedione and testosterone. Their transformation occurs in adipose and muscle tissues, liver, adrenal glands and in the tumor tissue itself due to the aromatase enzyme, and aromatase is not involved in the synthesis of glucocorticoids and mineralocorticoids.
The aromatase reaction includes multiple hydroxylation of androgenic precursors with the participation of a specific cytochrome P-450 aromatase. Inhibition of the enzyme can be achieved in two main ways: competition with the natural substrate at the site of binding of androstenedione (type 1 inhibition) or interaction with the iron atom in the porphyrin of cytochrome P-450 (type 2 inhibition).
Type 1 inhibitors, such as exemestane, are analogs of androgen steroids. They are metabolized by aromatase into inactive intermediate substances, their connection with the aromatase molecule is irreversible, and the synthesis of a new enzyme molecule is required to restore estrogen synthesis. Therefore, steroid inhibitors are currently referred to as aromatase inactivators or suicidal inhibitors.
In contrast to aromatase inactivators, the effects of nonsteroidal inhibitors are usually reversible and depend on the continued presence of the drug. The synthesis of estrogens can resume after the cessation of the action of these inhibitors. Moreover, type 2 drugs directed against the iron atoms of cytochrome P-450, as well as other steroid hydroxylases, are not specific enough. This is especially true for the first generation of aromatase inhibitors such as aminoglutethimide. Recently developed new drugs from the group of aromatase inhibitors (anastrozole (Arimidex), letrazole) are selective for cytochrome P-450, which means they selectively inhibit the enzyme.
The main task for antiestrogens
So, the main task for antiestrogens and aromatase inhibitors is to suppress estrogenic effects on tumor growth, however, antiestrogens compete with estrogens for receptors, the complex with which reacts with DNA, from where transcriptional signals to tumors come from.
Aromatase inhibitors interfere with the synthesis of the basic estrogen - estrone, and as a result of their use there is no one to interact with the receptors.
The first non-steroidal inhibitor is aminoglutethimide, which in two comparative studies with tamoxifen did not reveal any advantages in therapeutic efficacy, and given its worse tolerance compared to tamoxifen and progestins, it took the third position in hormone therapy for advanced breast cancer.
The second generation of antiaromatase drugs (formestane, fadrozole) in randomized trials with tamoxifen also did not show significant benefits in therapeutic efficacy and tolerability.
The third generation of non-steroidal aromatase inhibitors (anastrozole, letrazole), already in the first comparative studies with megestrol acetate (II line of hormone therapy), demonstrated greater efficiency and a better spectrum of side effects. In a subsequent study in comparison with tamoxifen (I line of endocrine therapy), advantages in time to progression and a decrease in the frequency of side effects characteristic of tamoxifen were noted.
Recent research in adjuvant hormone therapy for breast cancer has shown that aromatase inhibitors are poised to take the lead, displacing the standard of adjuvant therapy, tamoxifen.
Anastrazole (Arimidex, pharmaceutical company AstraZeneca) is a third generation non-steroidal selective aromatase inhibitor. The drug is a triazole derivative of 2,2 {5 - (1H - 1,2,4 - triazole - 1 - ylmethyl) -1,3 - phenylene} bis (2 - methylpropion - nitrile). Arimidex is prescribed orally 1 time per day at a dose of 1 mg per day; at this dose, aromatization is suppressed by 96.7%, the plasma level of estradiol decreases by 86%, estrone by 87% and estrone sulfate by 93%.
Pharmokinetics
The pharmacokinetics of the drug has been thoroughly studied. Arimidex is rapidly and completely absorbed from the gastrointestinal tract, the maximum concentration is observed after 2 hours, the plateau is reached on the 7th day of treatment. The drug is metabolized in the liver, the half-life is 30-60 hours. Only 10% of the unchanged drug and 70% of metabolites are excreted in the urine. There is no need to adjust the dose of the drug in hepatic or renal failure.
Arimidex is well tolerated and rarely leads to a sensation of hot flashes and dryness of the vaginal mucosa, in addition, disorders of the gastrointestinal tract, drowsiness, asthenia, and headaches may occur. However, the cases of drug withdrawal due to side effects do not exceed 3%. The drug is not contraindicated in patients with a history of thromboembolic complications and hypertension.
Arimidex in the second line of hormone therapy for advanced breast cancer with progression after tamoxifen
The results of two multicenter studies in the USA and Europe comparing the efficacy and toxicity of Arimidex at doses of 1 and 10 mg per day and megestrol acetate at a dose of 160 mg per day during 2-line hormone therapy (after progression to tamoxifen) in 746 patients with advanced breast cancer ... There were no differences in the objective effect of treatment in the three groups (12.6%, 12.5% and 12.2%, respectively). However, in the group that received Arimidex at a dose of 1 mg per day, there was a significantly longer life expectancy compared with megestrol acetate (26.7 months versus 22.5 months). The two-year survival rate with Arimidex therapy was 56.1% and 46.3% with megestrol acetate.
When using Arimidex at a dose of 1 mg per day, there was no statistically significant difference in the 2-year survival rates in patients who achieved complete and partial regression or only stabilization (85% versus 86%). The 10 mg dose did not improve the results of Arimidex treatment.
A more striking result was obtained in a subgroup of patients with hepatic metastases. Clinical improvement (complete + partial regression + stabilization) with Arimidex 1 mg per day was observed in 26% of patients (n = 46) and in 17% (n = 41) with megestrol acetate. The duration of clinical improvement was 17.9 months for the groups, respectively. and 9.9 months.
The toxicity also differed in the group with the aromatase inhibitor and megestrol: weight gain, respectively, 1.5% and 11.9%; edema 7.3% and 13.8%; thromboembolic complications 3.4% and 4.7%; nausea, vomiting, diarrhea 29.4% and 21.3%; hot flashes 12.6% and 13.8%; dryness of the vaginal mucosa 1.9% and 0.8%.
Outcome
Thus, new aromatase inhibitors, in particular, Arimidex, have firmly taken the position of progestins in the second line of hormone therapy after antiestrogens in advanced breast cancer, not only due to their greater effectiveness, but also to lower toxicity. Today, it is considered unjustified to prescribe progestins after ineffective treatment with antiestrogens.
Arimidex in the first line of hormone therapy for advanced breast cancer.
Two randomized phase III trials were conducted comparing Arimidex 1 mg per day and tamoxifen 40 mg per day in the first line of hormone therapy in the treatment of 1021 women with locally advanced or metastatic breast cancer. Menopausal patients with ER + and / or PR + tumors, as well as with unknown receptor status, were included. The results are shown in Table 2.
In study No. 0030, Arimidex was superior to tamoxifen in terms of time to progression (11.1 months versus 5.6 months, p = 0.005) and in terms of objective effect (59.1% and 45.6%).
The second study found no significant differences in treatment effect between groups.
When analyzing the material, it turned out that in one study, receptor-positive tumors were found in 89% of patients, and in another - only in 45%. When the data from these studies were combined in the group with receptor-positive tumors, there was a significant difference in time to progression in favor of Arimidex (10.7 months versus 6.4 months, p = 0.022).
Antiaromatase therapy in patients who achieved clinical improvement (complete and partial regression + stabilization> 6 months) significantly increased the time to progression compared with tamoxifen (18 months versus 7 months) The toxicity of Arimidex was less, especially in relation to thromboembolic complications (3 , 6% and 6.5%, p <0.043).
Similar results were obtained by an independent group comparing the results of treatment with Arimidex 1 mg per day and tamoxifen 40 mg per day in 238 women with advanced breast cancer in the menopause. All patients had receptor-positive tumors and had not previously received adjuvant endocrine therapy (Table 3).
Thus, Arimidex has advantages in therapeutic activity and the frequency of side effects over tamoxifen in the first line of hormone therapy for metastatic and locally advanced breast cancer in menopausal women with a receptor-positive tumor.
Arimidex in adjuvant hormone therapy in patients with early stages of breast cancer in menopause
The international ATAC study (Arimidex, Tamoxifen Alone or in Combination - comparison of Arimidex and tamoxifen in monotherapy or in combination in the adjuvant therapy of early breast cancer) compares Arimidex, tamoxifen and their combination as a 5-year adjuvant therapy in postmenopausal women with early forms of cancer breast. The study involved 9366 patients from 381 centers in 21 countries.
With a median follow-up of 33 months. in the group receiving adjuvant therapy with Arimidex, the rate of tumor recurrence was statistically significantly reduced in comparison with tamoxifen (87% versus 89%). The decrease includes a decrease in the number of local relapses, distant metastases, and the number of cancers in the contralateral gland.
This absolute 2% decrease in tumor recurrence is adequate to a 17% decrease in the risk of tumor recurrence during adjuvant therapy with Arimidex.
At a median follow-up of 62 months, the aromatase inhibitor showed a further absolute reduction in tumor recurrence compared with tamoxifen.
In comparison with tamoxifen, Arimidex significantly reduces the risk of developing:
- local recurrence 21% (p = 0.0005);
- distant metastasis 14% (p = 0.04);
- cancer of the other breast 42% (p = 0.01)
Anastrazole was found to be more effective than tamoxifen in the adjuvant treatment of early breast cancer in postmenopausal women. Aromatase inhibitor therapy significantly reduced the risk of relapse and the incidence of complications such as endometrial cancer, thromboembolism, hot flashes, and uterine bleeding.
The data of the Austro-German study (ABCSG trial 8, ARNO95) confirmed the advantages of aromatase inhibitors in the adjuvant treatment of breast cancer when prescribed after 2-year use of tamoxifen.
3123 postmenopausal women were randomized after two years of adjuvant tamoxifen therapy to either Arimidex 1 mg / day or continued tamoxifen 20 mg / day.
With a median follow-up of 26 months, the risk of local recurrence, distant metastasis, and cancer in the other breast in patients treated with Arimidex was significantly lower than in the group with tamoxifen (the risk ratio for reducing recurrence in the Arimidex / tamoxifen groups was 0.59, p < 0.0018).
Similar results were obtained in a double-blind study (AES031) in the study of another aromazine inhibitor, aromazine, in the adjuvant therapy of operable stages of breast cancer. After 2–3 years of adjuvant tamoxifen therapy, patients were randomized to receive exemestane 25 mg daily or to continue therapy with tamoxifen 20 mg daily.
It was shown that in patients treated with aromazine, after three years, the risk of relapse was 32% lower than with tamoxifen treatment, and the disease-free period in absolute terms was 4.7% higher.
The results of these studies with a high degree of confidence (1st level) represent the advantage of aromatase inhibitors over tamoxifen in the adjuvant treatment of menopausal breast cancer patients with respect to local recurrence, metastasis, cancer of the other breast and the duration of the relapse-free period.
The introduction of aromatase inhibitors both in the treatment of advanced breast cancer and in adjuvant therapy continues. However, a number of unresolved problems remain. For example, a clear advantage of antiaromatase drugs over tamoxifen in terms of the incidence of thromboembolic complications, uterine bleeding and the development of endometrial cancer has been shown, but, on the other hand, a long-term decrease in estradiol levels against the background of aromatase inhibitors led to more frequent detection of bone pain, osteoporosis in these patients, fractures.
The optimal duration of adjuvant treatment with aromatase inhibitors and their sequence with tamoxifen has not been determined, the subgroups of patients who have an indisputable advantage from the introduction of aromatase inhibitors have not been characterized, and comparative studies of anastrazole, letrazole and exemestane have not been conducted.
There is a difference in the mechanism of action of the two types of therapy: antiestrogens and aromatase inhibitors. The great therapeutic efficacy of aromatase inhibitors presupposes the presence of a group of patients who are selectively sensitive to these drugs. In a comparative study of letrazole and tamoxifen, the objective effects of treatment, the receptor status of the tumor, and the expression of epidermal growth factor receptors were analyzed. Aromatase inhibitors have been shown to be highly effective in treating ER + tumors (regardless of HER – 1 or HER – 2 expression). In the treatment of ER + tumors with tamoxifen, the objective effect of HER – 1 and HER – 2 expression was minimal.
The ATAC adjuvant study analyzed the disease-free period during treatment with Arimidex and tamoxifen. The analysis was performed for receptor-positive tumors ER + PR + (74% of patients) and ER + PR– (17% of patients). In both groups, Arimidex was ahead of tamoxifen in terms of the disease-free period, but the greatest difference in favor of an aromatase inhibitor was observed in ER + PR– tumors [1,2,12]. It is known that the frequency of detecting the expression of HER – 1 or HER – 2 in ER + RP – tumors is higher than in the ER + RP + status. It is assumed that the greater effectiveness of aromatase inhibitors is associated with the ability to obtain a therapeutic effect when the tumor expresses epidermal growth factor receptors and a low level of estrogen receptors.
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In conclusion, it should be noted that the active introduction of aromatase inhibitors into clinical practice expands the possibilities of oncologists in the treatment of postmenopausal patients in both early and late stages of breast cancer.
