Breast cancer is an endocrine-dependent tumor and the long-term stimulation of estrogen plays an important role in the development of breast cancer. oophorectomy was used more than 100 years ago to treat advanced breast cancer, and the clinical application of the anti-estrogen drug DD triamcinolone (tamoxifen) in the 1970s ushered in a new era of endocrine therapy for breast cancer. Endocrine therapy is less toxic and convenient for patients to take, and the clinical effect is similar to chemotherapy. 1 Brief history of endocrine therapy Guo Zhifeng, Department of Medical Oncology, Chifeng Hospital In 1895, Beatson used ovariectomy to control tumors in three cases of advanced and recurrent breast cancer, which pioneered endocrine therapy for breast cancer; in the 1950s and 1960s, people still more often applied surgical resection of endocrine organs (ovaries, adrenal glands, pituitary gland) or radiation methods to treat advanced breast cancer. However, these endocrine therapies have many toxic side effects, and only 1/3 of patients are clinically effective. Due to the emergence of some new endocrine therapies, the status of endocrine treatment through surgery and radiotherapy methods in breast cancer has gradually declined and is now rarely used. Endocrine drugs began to be used in breast cancer treatment in the 1930s and 1940s, and by the 1960s and 1970s, the discovery and isolation of estrogen receptors and the application of triamcinolone pushed the process of using endocrine drugs in breast cancer treatment. With the in-depth research on the mechanism of estrogen receptor complex in breast cancer cells, the application of endocrine drugs has become increasingly mature. At present, the available endocrine drugs include anti-estrogen agents, progesterone agents, aromatase inhibitors, luteinizing hormone-releasing hormone analogs, progesterone agents and androgens. Endocrine therapy can be used for the treatment of all stages of breast cancer and even for the prevention of breast cancer in certain high-risk groups. 2 Efficacy of endocrine therapy The efficacy of endocrine therapy is not related to the endocrine function status, but to the differentiation of tumor cells and hormone receptor status. The higher the content of hormone receptors in the cytoplasm and nucleus of cancer cells, the better the effect of endocrine therapy. Through endocrine therapy, the efficacy is not worse than chemotherapy as long as the cases are properly selected; and the toxicity and side effects of endocrine therapy are significantly reduced compared with chemotherapy, which is conducive to consolidation therapy; the patients’ survival quality is high. Endocrine therapy can reduce the postoperative recurrence rate and mortality of non-metastatic breast cancer, which has certain advantages over chemotherapy. The results of the Early Breast Cancer Clinical Trials Collaborative Group meta-analysis showed that adjuvant chemotherapy reduced the annual recurrence rate by 24% and the annual mortality rate by 15% overall. In patients with estrogen receptor-positive breast cancer, the effect of 5 years of postoperative adjuvant triamcinolone acetonide was quite significant, reducing the overall annual risk of recurrence by 47% and the annual risk of death by 26%, respectively. 54% and 52% of the risk of recurrence and death, respectively, were reduced in women under 40 years of age, no less than in any age group. Triamcinolone is equally effective regardless of the presence of axillary lymph node metastases. Endocrine therapy also has an advantage in the treatment of advanced metastatic breast cancer. It was found that 20%-30% of unselected metastatic breast cancer cases were effective in endocrine therapy, 50%-60% of ER-positive cases were effective in endocrine therapy, and the efficiency of endocrine therapy for both ER and PR-positive cases was more than 75%. For those with positive ER and PR, the efficiency of endocrine therapy can be more than 75%. For those with negative ER and PR, the efficiency is about 10%. The toxic side effects of endocrine therapy are significantly less than those of chemotherapy. For patients with advanced breast cancer, endocrine therapy does not reduce their quality of life due to treatment, and the efficacy is maintained for a longer period of time, and after resistance to one endocrine therapy drug is developed, other drugs can still be effective. Traditionally, endocrine therapy drugs are considered to be “growth-inhibiting drugs”, i.e. they keep cancer cells in a “dormant phase”, but research has found that endocrine therapy can induce cancer cell suicide and DD cancer cell apoptosis. This may be due to the fact that these drugs change the internal environment of cells. 3 Commonly used endocrine therapeutic drugs 3.1 Estrogen receptor modulators Early on, these drugs were called anti-estrogen drugs or estrogen receptor inhibitors. The mechanism of action is that the drug binds to the estrogen receptor (ER) so that estrogen cannot bind to the ER and acts, i.e., competitive inhibition. Recent studies have found that it is an estrogen receptor modulator that acts as an inhibitor in some parts of the body (such as the breast) and behaves like estrogen in others. Commonly used drugs include triamcinolone (tamoxifen, TAM), toremifene (cardinal, phalloctone), and raloxifene (LY139481). The application of triamcinolone in the treatment of breast cancer began in the 1970s, with an efficiency of about 60% in ER-positive patients. The efficacy of adjuvant triamcinolone for 5 years after surgery for estrogen receptor-positive breast cancer patients is very significant, with an overall reduction in recurrence rate of 47% and mortality rate of 26%, respectively. Adjuvant postoperative chemotherapy followed by 5 years of sequential triamcinolone acetonide further reduced mortality and recurrence rates compared with one treatment. Triamcinolone is a first-line endocrine drug with low toxicity and has a good therapeutic effect on premenopausal and postmenopausal women, and it is generally not recommended to be used in combination with other endocrine therapeutic agents. The recommended dose of triamcinolone acetonide is 20 mg/d. Increasing the dose does not increase the efficacy but greatly increases the toxicity. Large-scale clinical trials have shown that the optimal course of triamcinolone acetonide application is 5 years of postoperative dosing, and prolonging its use does not increase the efficacy significantly, while the toxic side effects increase significantly. In addition, triamcinolone may reduce the incidence of contralateral breast cancer as well as reduce the risk of breast cancer in women at high risk of developing it. The more common adverse reactions to triamcinolone include hot flashes (10% to 20%), nausea, vomiting (10%), increased vaginal discharge, vaginal dryness, vulvar pruritus, irregular vaginal bleeding, vision loss due to retinopathy, and hepatic impairment (e.g., elevated transaminases, fatty liver), amenorrhea, and vascular thrombosis and phlebitis. A more serious adverse effect is the increased risk of endometrial cancer, which increases 3 to 4 times for those who have taken it for 5 years. Regular gynecological examination or uterine ultrasound can play a preventive role. Toremifene is an analogue of triamcinolone, which has similar estrogenic and anti-estrogenic activities with triamcinolone. Phase III clinical trials have confirmed that in the first-line treatment of metastatic breast cancer, the efficiency of toremifene and triamcinolone groups are similar, but toremifene has less toxic side effects. In the adjuvant treatment of non-metastatic breast cancer, the efficacy of the toremifene and triamcinolone groups is similar. Toremifene can be considered when the application of triamcinolone has more toxic side effects. Raloxifene is a type of selective estrogen receptor modulator (SERM), which means that anti-estrogen drugs act as ER blockers in some sites (e.g. tumors) and ER stimulators in others (e.g. bone, cardiovascular). Raloxifene has a high affinity for ER and has anti-estrogen-like effects on breast and uterus, while showing estrogen-like effects on skeletal and vascular endothelial smooth muscle cells, so it was often used in the past to prevent osteoporosis and lower serum cholesterol in older women. Clinical results have shown that raloxifene reduces the recurrence rate of ER-positive breast cancer, while the incidence of endometrial cancer does not increase, but rather has a mild decrease. Raloxifene has no significant toxic side effects and has no effect on liver function. 3.2 Aromatase inhibitors or inactivators Postmenopausal women’s body estrogen is mainly derived from the conversion of extra-ovarian androgens to estrogen, and this conversion requires the action of aromatase, which is mainly done in the adrenal glands. Aromatase inhibitors or inactivators can block the source of estrogen in postmenopausal women. Therefore, they can be used in postmenopausal women with breast cancer. Clinically used aromatase inhibitors include aminoglutethimide (amiloride, AG), lantalum (formestane), letrozole (Fury, Flon, letrazole), and ryanodine (anastrozole), etc. Aromatase inactivators include exemestane. AG is a first-generation aromatase inhibitor that blocks the conversion of androstenedione to estrone secreted by the adrenal glands and is mainly used in the treatment of advanced postmenopausal breast cancer. The main toxic effects of AG are fatigue, irritability and dizziness. This drug is now nearly eliminated. Lantalum is a non-competitive aromatase inhibitor, which belongs to the second generation of aromatase inhibitors. Lantalum is administered intramuscularly and has weak androgenic activity. It is generally used as a second- or third-line treatment. In patients who failed AG therapy, the remission rates were 10% and 21%, respectively, when switching to lantarone. Letrozole and anastrozole are third-generation aromatase inhibitors with high selectivity and do not affect the function of glucocorticoids, salt corticoids and thyroid, so the application of letrozole does not require the addition of adrenocorticosteroids. Letrozole is better than megestrol or AG in the treatment of advanced postmenopausal breast cancer, and has less toxic side effects. It is more effective than triamcinolone in the adjuvant treatment of postmenopausal women with breast cancer, so it has been used as the first-line drug for postmenopausal women with positive receptors. The common dose is 2.5 mg/d. The duration of postoperative adjuvant use is usually 2-5 years. Common toxic side effects include skin flushing, vaginal dryness, gastrointestinal dysfunction (anorexia, nausea, vomiting, diarrhea), malaise, arthralgia or tonicity, drowsiness, headache, and rash, which are usually easily tolerated by patients. Exemestane is an aromatase inactivator and is mainly used in postmenopausal, receptor-positive women, recurrent and metastatic breast cancer that has failed treatment with other aromatase inhibitors and postoperative adjuvant therapy. 3.3 Luteinizing hormone-releasing hormone analogs (LHRH-a) Ovarian secretion of estrogen and progesterone is regulated by gonadotropins (follicle-stimulating hormone and luteinizing hormone) secreted by the pituitary gland. The action of luteinizing hormone-releasing hormone analogs is equivalent to pharmacological pituitary resection. the mechanism of action of LHRH-a is to bind to the receptors of pituitary gonadotropin-releasing hormone and suppress the secretion of gonadotropins to achieve selective pharmacological pituitary resection and total suppression of ovarian function, so that estrogen in pre-menopausal women reaches the level of estrogen in post-menopausal women and the patient stops menstruating after the drug is administered. The current drugs are Goserelin (Noradex, Zoladex, Goserrlin) and Leuprorelin (Inhibiton). The “double dose” therapy is a monthly intramuscular injection of Noradex followed by Renintex, mainly used for premenopausal patients at high risk and patients with recurrent or metastatic breast cancer. The main adverse effect of LHRH-a is menopause syndrome (i.e. menopause syndrome), which is characterized by irritability, hot and cold, agitation, insomnia, etc. 3.4 Progesterone drugs The main effect of progesterone drugs is to antagonize estrogen and counteract the effect of estrogen on the breast and endometrium. It inhibits the secretion of prolactin from the anterior pituitary gland, exerting an anti-breast cancer effect. In addition, progesterone can promote protein synthesis and improve appetite, and is suitable for patients in advanced stages, especially those with malignant fluid. Progesterone is more effective in postmenopausal hormone receptor-positive patients. Generally, the longer the years of menopause, the better the efficacy, and the effective rate of those who have been amenorrheic for more than 10 years is 43%, while the effective rate of those who have been amenorrheic for less than 5 years is only 20%. Progesterone has an efficiency of 26% for those who have failed triamcinolone treatment, while triamcinolone has an efficiency of 0.5% for those who have failed progesterone treatment, so progesterone is often used as the second-line endocrine therapy drug. The commonly used drugs are medroxyprogesterone (Meclizine, Elysium, MA) and meprogesterone (Mamphestone, Bene, MPA). It is generally believed that megestrol and megestrol as endocrine therapeutic drugs can achieve the same efficacy as triamcinolone, but due to more toxic side effects, they are mainly used clinically for the treatment of progressive, recurrent and metastatic breast cancer. 3.5 Estrogen The mechanism of action of estrogen in the treatment of breast cancer is to restrict the growth of cancer cells by altering the endocrine environment of the body. Estrogen is commonly used to treat patients who have been postmenopausal for more than 5 years, especially for those who have been effectively treated with depot treatment but have relapsed and worsened. The efficiency of estrogen receptor positive patients can reach 55% to 60%, and the efficiency of treatment of skin and soft tissue metastasis is higher, but the efficiency of visceral and bone metastasis is lower. The estrogen preparation currently in clinical use is hexestrol. Estrogens have more adverse effects, and some of them can also cause tumor development, so they are now less commonly used. 3.6 Androgens Androgens can inhibit the gonadotropic hormones of the pituitary gland, thus inhibiting follicle-stimulating hormone and luteinizing hormone, which in turn can cause breast tissue atrophy. Androgens are effective in advanced breast cancer, with an efficiency of 20% to 31% for postmenopausal breast cancer and 46% for receptor-positive patients. Androgen therapy is not restricted by age, and it is more effective in treating bone metastases, with an effective rate of 30%. The average survival of those with effective androgen therapy is 18-20 months, while those with ineffective treatment is 7-10 months. Commonly used androgen preparations include testosterone propionate, which is injected intramuscularly until a masculine tendency appears. Adverse reactions are mainly masculine symptoms, such as thickening of the voice and the appearance of beard, etc. Other still include high blood calcium and water-sodium retention, etc. Patients are often forced to stop the drug because of this, and most of the above toxic side effects can disappear on their own after stopping the drug. 4 How to choose endocrine therapy In the treatment of breast cancer, endocrine therapy is the oldest and one of the most commonly used methods among all other treatments except surgery. The mechanism of action of endocrine therapy is different from that of chemotherapy, and its side effects are less than chemotherapy, with longer maintenance time and better quality of life for patients. Breast cancer is a hormone-dependent tumor, regulated by estrogen and progesterone. The application of endocrine therapy has a better effect in cases with positive estrogen or progesterone receptors, while the effect is poor in ER and PR negative cases; therefore, endocrine therapy is generally not considered for those with negative hormone receptors. Likewise, if previous endocrine therapy is effective for tumor and the disease progresses again, the efficiency is still higher if the case is treated with other endocrine drugs instead. The selection of endocrine drugs is based on the patient’s age, lesion site, interval between surgery and recurrence, and receptor determination, in addition to the mechanism of action of different drugs and side effects. The following points can be chosen for reference in endocrine therapy: (1) Whether pre-menopausal or post-menopausal, triamcinolone acetonide is the preferred endocrine therapy drug because it is economical and effective, and the duration of medication is usually 5 years. 5 years later, if the person is menopausal, he can apply aromatase inhibitor for 2-5 years sequentially for better effect. (2) For postmenopausal families with good economic status, it is recommended that aromatase inhibitors be preferred and applied for at least 2-5 years. (3) Premenopausal high-risk patients, if the economic situation allows, can first choose “double German” therapy (i.e., the combination of Norad and Renindezvous), the effect is better than triamcinolone. (4) If the tumor recurs or metastasizes during the application of triamcinolone or other endocrine drugs, or if the disease progresses, another type of endocrine therapy can be used instead. (5) Progestins are used as second-line drugs, mainly for advanced breast cancer and other endocrine drugs have failed, especially for those with cachexia. (6) Endocrine therapy is usually administered sequentially after the completion of radiotherapy and chemotherapy, and usually not in combination with radiotherapy and chemotherapy. (7) Endocrine therapy alone can be considered for certain elderly recurrent and metastatic breast cancers.