The relationship between the occurrence and progression of breast cancer and estrogen has long been a concern. Endocrine therapy for breast cancer has undergone more than 100 years of evolution and has become an important part of the comprehensive treatment for breast cancer. This article will review the progress of endocrine therapy for breast cancer in recent years.
1. The principle of endocrine therapy for breast cancer
The normal development and growth of the breast depends on the coordinated action of various hormones. Normal breast epithelial cells contain many hormone receptors, such as estrogen receptor (ER), progesterone receptor (PR) and androgen receptor. After breast cancer, some breast cancer tissues can retain all or some of the hormone receptors and are functional, and their growth and development are influenced by the hormonal environment, which is a hormone-dependent tumor. On the contrary, breast tissues with little or no receptor retention during the cancerous process and whose growth is no longer controlled and regulated by hormones are considered non-hormone-dependent tumors. The main hormone that promotes the growth of hormone-dependent breast cancer is estradiol (E2), followed by estrone (E1). Estrogen primarily contributes to cancer cell proliferation through ER-mediated gene transcription, and indirectly affects breast cancer growth by influencing the secretion of peptide hormones or other factors from the pituitary and other endocrine organs. In addition, estrogen can also promote the secretion of various growth factors such as insulin-like growth factor (IGF) and epidermal growth factor (EGF) through the autocrine and paracrine mechanisms of cancer cells, which further promote the proliferation of cancer cells (including non-hormone-dependent cancer cells) and play an important role in the maintenance of the malignant phenotype of breast cancer. The mechanism of endocrine therapy for breast cancer is to alter the endocrine microenvironment required for hormone-dependent tumor growth, so that tumor cell proliferation stops in G0/G1 phase and thus tumor remission is obtained. The aim of the existing endocrine therapies is to inhibit, remove or interfere with the effect of estrogen, so as to prolong the remission time and maintain a better quality of life.
2.Endocrine therapy for pre-menopausal breast cancer
There are more premenopausal breast cancer patients in China. As the ovaries are still functioning, estrogen mainly comes from the ovaries. For patients with ER or PR positive, eliminating the source of estrogen is crucial for the treatment of breast cancer.
(1) Commonly used drugs
a. Anti-estrogen drugs
Anti-estrogen drugs, represented by triamcinolone acetonide (TAM), are the most commonly used drugs for endocrine treatment of breast cancer. TAM competes with estradiol for estrogen receptors on the cell surface, causing breast cancer cells to stagnate in the G1 phase and inhibiting tumor growth, but also has estrogen-like effects.
b. Gonadotropin-releasing hormone (LHRH) analogs
LHRH analogs are structurally similar to the hypothalamic gonadotropin-releasing hormone and bind competitively to the corresponding receptors on the pituitary cell membranes. The affinity and antidegradation ability of LHRH are stronger than those of endogenous LHRH, so the release of gonadotropin luteinizing hormone and follicle-stimulating hormone from the pituitary gland is reduced, resulting in a decrease in estrogen secretion in the body. The use of LHRH analogs in premenopausal patients can reduce estrogen levels to postmenopausal levels, but this process is reversible and can be restored by stopping the drug. Commonly used LHRH analogs include Goserelin. Clinical trials have shown that for premenopausal, ER-positive breast cancer, the objective efficiency and survival time of goserelin are not lower than those of ovariectomy or chemotherapy, regardless of the early or late stage of the tumor.
c. Progesterone analogues
Progesterone analogues mainly inhibit the secretion of follicle-stimulating hormone and luteinizing hormone through negative feedback, reducing the production of ovarian estrogen; reduce the production of estrogen in the adrenal cortex by inhibiting the secretion of adrenocorticotropic hormone; and competitively inhibit the binding of estradiol to ER after binding to progesterone receptor (PR), blocking the effect of estrogen on breast cancer cells. Commonly used drugs include megestrol and megestrol.
(2) Treatment strategy
Currently, the treatment options for premenopausal patients are: ① 2~3 years with triamcinolone, and if they enter menopause, they can switch to aromatase inhibitors; ② if they are still not menopausal after 2~3 years of triamcinolone, they can continue to use triamcinolone up to 5 years, and if they enter menopause after 5 years, they can use aromatase inhibitors for another 5 years as follow-up intensive treatment; ③ for some premenopausal patients who are not suitable for treatment with triamcinolone, or have high risk of recurrence For some premenopausal patients who are not suitable for treatment with triamcinolone or have high risk of recurrence and metastatic factors, the use of aromatase inhibitors as adjuvant therapy after ovarian denervation can be considered.
3.Endocrine therapy for postmenopausal breast cancer
(1) Commonly used drugs
a.Triamcinolone acetonide
Since 1986, triamcinolone acetonide has become the first choice of adjuvant endocrine therapy for early breast cancer patients. According to the data, the tumor recurrence rate and mortality rate of postmenopausal breast cancer patients treated with triamcinolone for 5 consecutive years were significantly reduced. In the three age groups of 50-59 years old, 60-69 years old and 70 years old or above, the corresponding recurrence risk rate was reduced by 34%, 44% and 51%, and the corresponding death risk rate was reduced by 24%, 35% and 37%, respectively. Patients treated with triamcinolone for 5 consecutive years had significantly higher efficacy than those treated for a short period of time, but the effect of continuous triamcinolone treatment for more than 5 years on DFS was not significant. Long-term continuous treatment has shown that triamcinolone has a low rate of tumor recurrence and mortality after the end of 5 years of regular treatment, but it has also been shown to have side effects with the risk of endometrial cancer, uterine polyps, deep vein thrombosis and thromboembolism.
b. Aromatase inhibitors
Postmenopausal women derive their estrogen mainly from the conversion of cholesterol secreted by the adrenal glands, and aromatase is the rate-limiting enzyme for this conversion process. Aromatase inhibitors reduce estrogen synthesis by inhibiting the action of aromatase, and also inhibit tumor cell growth by inhibiting aromatase activity in tumor cells. The 1st generation aromatase inhibitors are non-selective, represented by the non-steroidal amiloride; the 2nd generation aromatase inhibitors include the non-steroidal Fadrozole and the steroidal formestane; the 3rd generation highly selective aromatase inhibitors include the non-steroidal anastrozole, letrozole and the steroidal aromatase inactivator exemestane. Among them, anastrozole and letrozole are type II non-steroidal aromatase inhibitors, while exemestane is a type I steroidal aromatase inhibitor. These drugs are mainly indicated for ER-positive, postmenopausal or premenopausal breast cancer patients after ovarian denervation therapy. In recent years AIs have become the treatment of choice for postmenopausal estrogen receptor-positive, metastatic breast cancer patients. Compared with triamcinolone therapy, AIs clearly have more advantages in prolonging the treatment time. Although there are no experimental results showing that AIs have significantly improved survival, they have many advantages over triamcinolone, such as reversing the endometrial hyperplasia induced by triamcinolone therapy, etc. Although in vitro trials and clinical trials in progressive breast cancer have confirmed the existence of the 3 AIs in reducing estrogen levels Although in vitro trials and clinical trials in progressive breast cancer have demonstrated differences in estrogen level reduction among the three AI, there are no significant differences in clinical benefit or overall survival, and the adverse effects are essentially the same.
Letrozole
Letrozole is a third-generation aromatase inhibitor that is 150-250 times more active than aminoglutethimide in vivo and 10,000 times more active in vitro. The effectiveness and safety of letrozole as a second-line drug after failure of TAM treatment for postmenopausal, ER-positive breast cancer have been reported. Compared with megestrol, letrozole is better than the former in terms of clinical efficiency, duration of disease remission and survival, and the incidence of side effects such as fluid retention and weight gain is also lower than the former. At the San Antonio Breast Cancer Conference, the International Breast Organization released the results of a recent multicenter study: postoperative use of letrozole, a third-generation aromatase inhibitor that blocks estrogen synthesis, in early-stage breast cancer patients significantly reduced the risk of death from breast cancer by 19%, the risk of overall breast cancer recurrence by 19%, and the risk of distant metastasis from breast cancer compared to previous use of the estrogen receptor antagonist triamcinolone. by 19%.
Exemestane
Exemestane irreversibly binds to the substrate binding site of aromatase, causing aromatase inactivation, and is a steroidal aromatase inactivator. Exemestane can reduce plasma estradiol level by 52% to 72%. Exemestane has no cross-resistance with non-steroidal aromatase inhibitors. The International Exemestane Study Group (IES) randomized 3224 postmenopausal, ER-positive female breast cancer patients who had been taking oral TAM for 2 to 3 years to continue adjuvant TAM therapy until 5 years in one group and to continue exemestane for 2 to 3 years in the other group; after a median follow-up of 36 months, it was found that the risk of recurrence was reduced by 32% in the exemestane group, with an absolute 4.7% lower absolute value (P=0.00005); thrombosis was more common in the TAM group (P=0.007) and fracture was more frequent in the exemestane group. Follow-up ≥3 years revealed a better DFS in the exemestane group (HR=0.76,P=0.0001) and a statistically significant difference in survival benefit (HR=0.83,P=0.05).
Anastrozole
Anastrozole is a potent and selective triazole aromatase inhibitor that inhibits cytochrome P-450-dependent aromatase, thereby blocking the biosynthesis of estrogen, a major stimulus to breast cancer cell growth. 9366 postmenopausal, receptor-positive or unknown patients were enrolled in the ATAC study. The study enrolled all post-surgical breast cancer patients and randomized them to compare the effects of adjuvant therapy with anastrozole versus TAM. The results of 6241 cases with a median follow-up of 68 months showed that anastrozole was superior to TAM in terms of PFS, with PFS of 85% and 81.7% in the two groups, respectively; tumor-related death was reduced by 3.3%; and HR=0.87 (p=0.001).
c. New anti-estrogenic drugs
Fulvestrant, the first simple anti-estrogenic drug to complete phase III clinical trials, is a new steroidal estrogen receptor antagonist with selective downregulation of estrogen receptor levels. Fulvestrant has a chemical structure similar to that of natural-type estrogens and has a high affinity for ER, with an affinity 100 times stronger than that of TAM.
In a randomized, double-blind, placebo-controlled phase II trial of 270 postmenopausal women, data showed that RAD 001 significantly improved the clinical outcomes of newly diagnosed estrogen receptor-positive breast cancer patients treated with letrozole. The overall clinical response rate was significantly higher with the combination of RAD 001 and letrozole than with letrozole alone (68% versus 59% P=0.062).
(2) Treatment strategy
The AI Overall Evaluation Group (AIOG) conducted a meta-analysis of the results of several large clinical studies comparing the efficacy of AI with TAM. The results showed that AI significantly reduced recurrence rates compared to TAM. the TEAM study focused on comparing the efficacy of exemestane with TAM initial adjuvant endocrine therapy, and at a median follow-up of 2.75 years, exemestane was slightly more effective than TAM, with a lower rate of distant metastases than the TAM group (P70 years old, patients with limited ability to tolerate surgery may be considered, and third-generation aromatase inhibitors may be preferred) . Preoperative neoadjuvant endocrine therapy can be another option for preoperative treatment of postmenopausal hormone receptor-positive patients, especially those elderly patients who are not suitable for chemotherapy, and can be considered for surgical resection after shrinking the tumor by neoadjuvant endocrine therapy. In patients with effective preoperative endocrine therapy, the same drugs can be used as postoperative adjuvant endocrine therapy after surgery. The results of the P024 clinical study on letrozole showed that letrozole, a third-generation aromatase inhibitor, was more effective than TAM in neoadjuvant therapy for postmenopausal patients, improving the efficiency and increasing the chance of breast conservation.
4.Endocrine therapy for metastatic breast cancer
The treatment of advanced metastatic breast cancer (MBC) is more difficult, and the main goal of treatment is to relieve symptoms and prolong high-quality survival. Endocrine drugs are particularly suitable for the treatment of MBC because they are easy to use, have precise efficacy and low toxicity. The efficacy of endocrine therapy is also influenced by factors such as the site of tumor metastasis and the duration of menopause. The appropriate endocrine therapy drug must be selected according to the patient’s menstrual status. Goserelin and leuprolide can be used for premenopausal patients; aromatase inhibitors for postmenopausal patients; and TAM and progestin can be used for patients of all ages. It is currently considered that endocrine drug therapy is preferred for patients >35 years of age, disease free survival >2 years after surgery, bone and soft tissue metastases without visceral metastases, and positive estrogen receptors or progesterone receptors, in the order of triamcinolone acetonide, progestin, and aromatase inhibitors.
The basic principles of endocrine therapy for recurrent metastatic breast cancer: ①The principle of treatment is to control disease progression and improve patients’ quality of life, so avoid unnecessary and intense chemotherapy as much as possible. ②For hormone receptor-positive recurrent metastatic breast cancer with slow progression, postmenopausal patients may prefer endocrine therapy; premenopausal patients may choose chemotherapy or may also consider using ovarian function inhibition combined with other endocrine drugs. (3) In hormone receptor positive patients, endocrine therapy should be given promptly in between treatments when chemotherapy is ineffective and the tumor is not controlled, or when the patient cannot tolerate continued chemotherapy for any reason. Patients with unknown hormone receptors or negative previous tests should also seek endocrine therapy opportunities by determining newly recurrent lesions or redetermining the receptor results of previous lesions. During the treatment phase, the criteria for evaluating the efficacy should be strict, based on the principle of “no change in the prescription if it is effective and no change if it is not effective”. After the failure of a certain treatment, the rational sequential use of chemotherapy and endocrine therapy is advocated. Different types of endocrine drugs can be applied sequentially in the relatively slow stage of disease development. ⑤ Long-term disease stabilization after treatment in patients with advanced disease is considered a clinical benefit, because clinical experience shows that the overall survival of patients with sustained stable disease for more than 6 months after treatment is the same as that of patients who achieve clinical remission (CR+PR), i.e., lesion reduction. Based on the fact that endocrine therapy is more suitable for long-term use, endocrine therapy should try to maintain continuous therapeutic use for as long as possible to extend the duration of disease control with the aim of prolonging overall survival.
5.Future direction of endocrine therapy research for breast cancer
The current hot spots of endocrine research on breast cancer are focused on the following aspects: (1) Continue to develop new endocrine therapeutic drugs, such as the development of selective estrogen receptor antagonists (SERM), highly selective aromatase inhibitors, growth hormone-releasing factor analogs, etc. (2) To study the combination of endocrine drugs with each other or with other anti-cancer drugs. (3) To explore the combined use of endocrine therapy with biological therapy. (4) To expand the scope of existing uses, such as chemoprevention of breast cancer, neoadjuvant endocrine therapy, and new endocrine drugs for adjuvant therapy. (5) To study in depth the mechanism of action of endocrine drugs and to prevent and reverse drug resistance. (6) To further clarify what is effective and what is not effective for endocrine therapy in hormone receptor positive patients through the study of new molecular sequences, risk factor stratification and prognostic models. With the development of medicine, congenital or acquired resistance to endocrine therapy will be further clarified to provide patients with individualized optimal endocrine therapy regimens.