What Are Aromatase Inhibitors?

Aromatase inhibitors can specifically cause aromatase inactivation, block the aromatization reaction, inhibit estrogen production, and reduce the level of estrogen in the blood to achieve the purpose of treating breast cancer. Mostly used in patients with advanced postmenopausal breast cancer who have failed antiestrogen (tamoxifen) treatment. Common aromatase inhibitors: Exemestane, Letrozole, Anastrozole.

Aromatase inhibitors can specifically cause aromatase inactivation, block the aromatization reaction, inhibit estrogen production, and reduce the level of estrogen in the blood to achieve the purpose of treating breast cancer. Mostly used in patients with advanced postmenopausal breast cancer who have failed antiestrogen (tamoxifen) treatment. Common aromatase inhibitors: Exemestane, Letrozole, Anastrozole.

Aromatase (AR) (also known as estrogen synthetase) is a complex enzyme of microsomal cytochrome P450, which is composed of hemoglobin P450 _{a rom} and reduced coenzyme NADPH. In fat, breast and breast cancer cells, it is a key enzyme and rate-limiting enzyme that catalyzes the conversion of androgens to estrogen in the body.It can aromatize the A ring of androgens, remove the carbon atom at position 19 and convert the carbonyl group at position 1 Hydroxyl, which catalyzes the conversion of androgens such as androstenedione and testosterone to estrone and estradiol, the latter two being the main source of estrogen in postmenopausal women. Estrogen is related to tumor progression, and aromatase plays the ultimate rate-limiting catalytic role in estrogen biosynthesis.

Aromatase inhibitor (AI) can specifically cause aromatase inactivation, block the aromatization reaction, inhibit estrogen production, and reduce the level of estrogen in the blood to achieve the purpose of treating breast cancer. Mostly used in patients with advanced postmenopausal breast cancer who have failed antiestrogen (tamoxifen) treatment. Common aromatase inhibitors: Exemestane, Letrozole, Anastrozole. ^[1]

1. Aromatase inhibitors 1. Distribution and regulation of aromatase

Estrogens are synthesized in various tissues in men and women. Postmenopausal women's circulating estrogen levels are mainly maintained by estrogen synthesized by adipose tissue. However, it has been found that estradiol levels in breast tissue of postmenopausal women are 10 times higher than in plasma. It has been reported that aromatase activity and aromatase mRNA are present in normal breast tissue and breast tumors. Some clinical observations show that aromatization in tumors is related to tumor response to suppression of estrogen synthesis after aromatase inhibitor treatment, and local estrogen production may also have important effects on tumor proliferation. However, the aromatase activity measured in human breast cancer tissue homogenate is relatively low, and it is not enough to catalyze the formation of a sufficient amount of estrogen to activate the estrogen receptor. Other studies have shown that local estrogen concentrations are sufficient to stimulate tumor growth. At the same time, tissue culture found that some tumors stimulated by estrogen can also accelerate proliferation through testosterone, and the stimulation can be blocked by aromatase inhibitors. It is suggested that testosterone is aromatized to produce estrogen. It can be seen that the aromatase in tumors is of great significance to stimulate the production of estrogen in tumor proliferation.

2. Aromatase inhibitors 2. Classification of aromatase inhibitors

Studies show that two-thirds of breast cancers are estrogen-dependent, and they resolve after estrogen decreases. In 1973, Schwarsel first proposed that aromatase inhibitors can specifically cause the inactivation of target enzymes, block the aromatization reaction, inhibit the production of estrogen, and reduce the level of estrogen in the blood to achieve the purpose of treating breast cancer, and have successively reported A series of compounds that inhibit AR activity. Aromatase inhibitors have attracted the attention of related scholars as a new idea for breast cancer treatment. After nearly 30 years of efforts, three generations of AR inhibitors have been developed and marketed as second- or third-line drugs for breast cancer. , Japan, etc. have been widely used in clinical. AR inhibitors can be divided into steroids and non-steroids according to their structure. The specific classification is shown in Table 1, and the specific structure is shown in Figure 1.

2.1 Steroid aromatase inhibitors

2.1.1 Exemestane (Aromasin)

In 1988, the Italian company Pharmaela & Upjoin successfully researched and developed a new generation of anti-aromatase drug exemestane, which belongs to the third generation of aromatase inhibitors and was approved by Europe and the United States and other countries at the end of 1999.It is mainly used to treat the advanced breast of postmenopausal women cancer.

Exemestane features: The combination with aromatase in the body is irreversible, it is an aromatase inactivator. Exemestane is a pseudo substrate of aromatase, and its structure is similar to that of natural enzyme substrates androstenedione and testosterone, which can be inactivated by irreversibly binding to the active site of the enzyme (this effect also (Called "self-destructive inhibition"), which significantly reduces the level of estrogen in the blood circulation of postmenopausal women. No "rebound" on the inactivation of aromatase. In vitro experiments found that the aromatase in JEG-3 cells in the exemestane group was still inhibited when exemestane, aminohypnotic, and anastrozole were separately removed from the cell culture fluid, and the latter two groups The aromatase activity of JEG-3 cells was increased. The increase in enzyme activity caused by the use of aromatase inhibitors may impair the long-term efficacy of aromatase inhibitors, and exemestane has the property of continuously inhibiting aromatase activity without increasing the level of aromatase protein. Helps reduce this risk. The substrate is highly selective and has no significant effect on the biosynthesis of steroids and aldosterone in the adrenal cortex. Exemestane has no significant effect on other enzymes in the steroid production pathway even when it is 600 times higher than its concentration that inhibits aromatase.

In May 2002, various international collaboration groups cooperated to select postmenopausal breast cancer patients and conducted 42 exemestane clinical trials, which involved the prevention of breast cancer, postoperative adjuvant treatment, neoadjuvant treatment, and metastatic breast cancer. In terms of treatment, we hope to obtain sufficient evidence-based medicine.

2.1.2 Formestane

Formestane is an aromatase inhibitor in human placental microsomes, rat ovarian microsomes, human breast cancer cells and breast cancer biopsy samples, and belongs to the second generation of aromatase inhibitors. Xu Jien's research shows that formestane can cause rapid inhibition of rat ovaries and human placental microsomes, and the activity inhibition can reach 50% within 3-20 minutes after administration. Formestane 50mg / (kg · d) was used to measure the inhibition rate of conversion of androstenedione to estrogen by isotope tracer after 90%.

Studies by Dowsett M and others showed that after administration of formestane 500 mg in postmenopausal women, the average plasma estrogen level decreased by 40% within 24 hours, and it decreased by 80% after 7 days of administration; 250 mg injection every 2 weeks inhibited females within 8 weeks The hormone level is about 60%; its maximum effective oral dose is 250 mg / d. Since premenopausal women's estrogen production is mainly controlled by gonadotropin released by the pituitary gland and is not reduced by aromatase inhibition, premenopausal women's use of formestane alone has no significant effect on estradiol levels. Appears to produce an antagonistic effect.

Brodie AM et al. Used dimethylbenzoanthracene (DMBA) to induce breast cancer in rats. Formamestane was given 50 mg / kg, im, bid. After 4 weeks of administration, about 90% of the tumors in the rats shrank. > 50%, 4% of rat tumors completely resolved. Studies by Chander SK and others show that Formestane 12.5 mg / kg + 5% lemon (limonene) is effective for carcinogen N-nitrosourea (NMU) -induced breast tumors in rats, with an inhibition rate of 83.3%, which is better than Formest Stein is used alone. Dowsett M et al found that Formestane had no effect on serum androstanediol, testosterone, or 5-dihydrotestosterone levels when administered by all routes of oral / parenteral absorption; Formestane 250 mg / d , Po, After 4 doses, 34% of patients experienced a decrease in sex hormone binding globulin (SHBG) levels. The gastro-mass spectrometry (GC-MS) analysis was used to determine the serum estrone level of parenteral absorption The inhibition is about 40%. Formestane's inhibition of estrogen biosynthesis did not change estrogen precursor content in postmenopausal women.

New uses and uses of formestane have gradually been discovered, such as the treatment of early endometrial cancer, the inhibition of Candida, the use of trastuzumab in combination with breast cancer, and the combination of quasione to suppress aroma Enzymes, enhance the inhibitory effect of specific antibodies on tumor cells, reduce the adverse reactions of a single drug.

2. 2 non-steroidal aromatase inhibitors

2.2.1 Aminoglutethimide, AG, Aminoglutethimide, Aminoglutethimide, Amiphenidone

Aminutamide is a steroid biosynthesis inhibitor. Although aminutamide is a potent inhibitor of aromatase, it also inhibits the carbon chain lyase that converts steroids into pregnenolone, reduces the in vivo synthesis of corticosteroids, and often causes skin rashes, ataxia and dysentery. Sleep, the incidence rate is as high as 60%, and it should be used with hydrocortisone. Occasionally leukopenia, thrombocytopenia, and hypothyroidism can occur. Non-steroidal aromatase inhibitors contain heteroatoms (usually with N-containing heterocyclic moieties). It usually interferes with the steroidal glycosylation process by combining with heme iron of cytochrome P 450. Like most steroid inhibitors, these compounds are reversible aromatase inhibitors. In general, most reversible non-steroidal aromatase inhibitors have low specificity, and will inhibit the hydroxylation of steroid synthesis involved in other cytochrome P 450 to varying degrees. In addition to ammonia lumitide, other non-steroidal aromatase inhibitors are highly selective for aromatase.

2.2.2 letrozole

Letrozole is a highly selective, third-generation aromatase inhibitor. Its superiority in efficacy, safety and economics has been confirmed by many clinical studies. Letrozole, as a reversibly bound aromatase inhibitor, effectively reduces plasma estrogen levels by inhibiting aromatase in the periphery and tumor tissues, thereby removing stimuli to hormone-sensitive tumors. About one-third of breast cancers continue to develop depending on estrogen stimulation. The pre-menopausal women's estrogen mainly comes from the ovaries, while the post-menopausal women's estrogen is mainly derived from the androgen produced by the adrenal glands, fat, muscle and liver through aromatase. Therefore, for postmenopausal women, by inhibiting aromatase, estrogen production in the body can be reduced, thereby achieving the purpose of treating breast cancer. The aromatization of steroid molecules is the last step in the process of estrogen biosynthesis.Selective aromatase inhibitors are endocrine therapeutic drugs that can act in the final stage of estrogen biosynthesis and do not interfere with the synthesis of other steroid hormones. Better target, better selectivity in effect and efficacy.

First-line treatment for postmenopausal advanced breast cancer: PO25 is a multicenter, randomized, double-blind, double-simulation controlled trial designed to compare third-generation aromatase inhibitors and tamoxifen as first-line treatment for postmenopausal breast cancer feasibility. This study involved 10 medical research institutions in 29 countries. A total of 916 postmenopausal women with advanced breast cancer were included in the trial. The median follow-up period was 32 months. Results The efficacy of the letrozole group was better than that of the tamoxifen group.

Second-line rescue treatment: Comparison of letrozole with the first-generation aromatase inhibitor amino-hypnotic (AG): Second-line study enrolled 555 patients who failed tamoxifen, taking letrozole 2.5 mg and 0.5 mg daily And AG 250 mg, the effective rates of the three groups were 19.5%, 16.7%, and 12.4%, respectively, and the effective and stable durations were 21 months, 18 months, and 14 months, respectively. Letrozole 2.5 mg group had significantly better tumor progression time (TTP), treatment failure time TTF, and overall survival than the AG group, and slightly better than the 0.5 mg group.

Neoadjuvant therapy: Studies have shown that patients treated with tamoxifen have a lower chance of developing contralateral breast cancer than the control group. It was found that tamoxifen can prevent breast cancer. However, it only blocks the effect of estrogen and cannot reduce its synthesis, so it cannot remove the potential carcinogenic effect of estrogen metabolites, that is, cause the side effects of endometrial canceration, and the third-generation aromatase inhibitor can inhibit the estrogen's Synthesis, to make up for the shortcomings of tamoxifen, theoretically better prevention. A multi-center phase III clinical study of letrozole in postmenopausal, ER (estrogen receptor) and / or PR (progesterone receptor) -positive primary breast cancer patients, 162 were treated with trazozole 2.5 mg per day. 175 cases of tamoxifen 20 mg per day were 4 months. The results showed that in each study endpoint, the letrozole group was significantly better than the tamoxifen group. More patients were eligible for BCS, and 45% of patients benefited from breast preservation. The objective response rate (ORR) of the letrozole group was significantly higher than that of the tamoxifen group (55% vs 36%, P <0.001). Compared with tamoxifen, more than 50% of patients obtained after treatment with letrozole beneficial.

Through the synthesis of many large-scale clinical trials, it is confirmed that letrozole is in various stages of postmenopausal breast cancer treatment, that is, first-line treatment of advanced breast cancer, neoadjuvant treatment of primary breast cancer, and subsequent enhancement of early breast cancer. In the treatment, they all have excellent clinical effects, with less side effects and high patient compliance. Its role in adjuvant treatment of early breast cancer will be concluded in ongoing clinical trials. Some studies at the gene level will reveal the clinical application value and application characteristics of trzozole, so as to better guide the clinical application of letrozole and benefit more patients. Letrozole has a strong inhibitory effect on estrogen, which also laid the foundation for it to open up other cancer treatment fields related to female hormone levels.

2.2.3 Anastrozole

Anastrozole is a third-generation aromatase inhibitor and was approved by the US Food and Drug Administration (FDA) in 1995 for the treatment of metastatic breast cancer. In China, pre-import clinical validation studies were conducted from September 1997 to June 1998. Monotherapy for patients with postmenopausal advanced breast cancer achieved an effective rate of 25.0%, and was approved by the China National Drug Administration in 1999 ( (CFDA) approved to be officially listed in China.

Anastrozole is suitable for advanced breast cancer in postmenopausal women who cannot be controlled by tamoxifen and other anti-estrogen therapies. For estrogen receptor negative patients, anastrozole can be used if it has a clinical response positive to tamoxifen. It can inhibit the conversion of androstenedione produced in the adrenal glands of patients after menopause to estrone, thereby significantly reducing the plasma estrogen level and inhibiting breast tumor growth. In addition, anastrozole did not significantly affect the production of adrenal corticosteroids or aldosterone.

Anastrozole for second-line rescue treatment: The results of large-scale clinical studies have shown that anastrozole can be used as a first-line drug instead of tamoxifen for the treatment of advanced breast cancer in postmenopausal women, and may be considered as the first-line treatment of choice. Anastrozole has a strong aromatase inhibitory effect, and can achieve nearly complete estrogen inhibition in both peripheral blood circulation and tumor tissues. In a multicenter phase III clinical trial completed in 1998, anastrozole was compared with megestrol in patients with previous tamoxifen failure. The two drugs achieved similar clinical benefit rates, with a median death time of 26.7 months in the anastrozole 1 mg group and 22.5 months in the megestrol group. The anastrozole treatment group was significantly better than the megestrol group in terms of survival rate. The results also show that anastrozole is better tolerated in patients with advanced breast cancer than megestrol. Therefore, anastrozole as a second-line rescue treatment can replace megestrol.

Anastrozole is used as an adjuvant therapy: Anastrozole data in first-line treatments show the role of anastrozole in early breast cancer treatment. Therefore, there is another study of anastrozole and tamoxifen alone and combined application (Anast rozole Tamox ifenAlone or Combination, ATAC test) .The purpose is to compare with tamoxifen in adjuvant therapy to confirm that it has the effect in patients with early breast cancer. The same effect.

Comparative study of anastrozole and other third-generation aromatase inhibitors in rescue therapy: the current representative third-generation aromatase inhibitors are mainly steroidal exemestane and non-steroidal Anastrozole, letrozole. A large study was conducted in 110 centers in 19 countries, comparing letrozole and anastrozole for second-line treatment of advanced postmenopausal breast cancer. A total of 713 patients were enrolled in the study. 356 patients in the letrozole group received 2.5 mg of letrozole daily; 357 patients in the anastrozole group received 1 mg of anastrozole orally. Both cases were those with positive hormone receptors or unknown receptors. Efficacy was evaluated every 3 months in the study. The results showed that the total response rate (OR) of the letrozole group was higher than that of the anastrozole group, which were 19.1% and 12.3%, respectively (P = 0.014). The clinical benefit rate of letrozole was higher than that of the anastrozole group, which were 27% and 23%, respectively, but there was no statistical difference (P = 0.218). There was no difference in TTP, time to treatment failure (TTF), response duration, and clinical benefit time between the two drugs. Studies have shown that the two drugs are well tolerated.

Anastrozole has shown good efficacy and tolerability.It has completely surpassed the traditional drug tamoxifen in the first-line and second-line treatment, adjuvant treatment and neoadjuvant treatment of breast cancer, and has become a possible alternative to tamoxifen Ideal drug.

3. Aromatase inhibitors 3. Chinese guidelines on the use of aromatase inhibitors

3.1 Tamoxifen, aromatase inhibitors or fulvestrant are all reasonable choices for patients who have not received anti-estrogen therapy or have a long postmenopausal relapse. The first choice of first-line endocrine therapy for third-generation aromatase inhibitors, including anastrozole, letrozole, and exemestane, for recurrent metastatic breast cancer after menopause. In second-line treatment of cancer, third-generation aromatase inhibitors are more effective than megestrol. In the first-line endocrine therapy of recurrent metastatic breast cancer, the third-generation aromatase inhibitor is significantly better than tamoxifen. Chemotherapy is preferred in patients with premenopausal recurrent metastatic breast cancer. If hormone receptor-positive patients are suitable or need endocrine therapy with aromatase inhibitors, bilateral oophorectomy is the first choice, followed by aromatase inhibitors. Drug-induced ovarian function inhibition in combination with aromatase inhibitors is also a possible option (but clinical evidence is lacking).

3.2 In postmenopausal patients, first-line endocrine therapy can choose aromatase inhibition, fulvestrant, tamoxifen or toremifene. Aromatase inhibitors are usually preferred, and there are contraindications to aromatase inhibitor therapy, aromatase inhibitor-assisted endocrine therapy, short disease-free survival, or those who cannot accept aromatase inhibitor therapy for economic reasons Patients may consider administering tamoxifen or toremifene.

3.3 Can be replaced with another type of aromatase inhibitor. If non-steroidal aromatase inhibitors (letrozole, anastrozole) fail to treat, you can consider switching to steroidal aromatase to inhibit exemestane treatment, and vice versa. ^[2]