Endocrine therapy of breast cancer
I. The rationale of endocrine therapy for breast cancer and its target audience
Endocrine therapy for breast cancer began in 1896 when Beatson used ovariectomy to treat advanced breast cancer, and has a history of more than a hundred years since then. Endocrine therapy for breast cancer is the most mature and effective endocrine therapy for tumors.
Pathologically elevated levels of estrogen in the body are the main factor stimulating the proliferation of breast cancer cells. Estrogen is mainly secreted by the ovaries of women before menopause and by the adrenal glands and some adipose tissues after menopause. Estrogen and progesterone receptors are present in breast cells, and these receptors allow breast tissue to proliferate in response to hormone levels.
Studies have shown that about 2/3 of breast cancer cells contain some amount of estrogen receptor (ER), which is called ER estrogen receptor positive breast cancer; 40-50% of breast cancers contain progesterone receptor (PR), which is called PR progesterone receptor positive breast cancer. ER estrogen receptor or PR progesterone receptor positive breast cancers are sensitive to hormone therapy.
Currently, it is believed that endocrine therapy is indicated for patients with ER or PR progesterone receptor positive breast cancer, slow tumor growth, long disease-free survival after surgery, with or without bone and soft tissue metastases, asymptomatic visceral metastases and breast cancer with previous effective endocrine therapy.
II. Mechanism of endocrine therapy for breast cancer
Clinical methods to block estrogen action or reduce estrogen level are mainly classified as follows according to their mechanisms.
Estrogen antagonist therapy Estrogen antagonist has no effect on hormone level, it blocks the effect of estrogen by binding or blocking the ER estrogen receptor in cancer cells. This therapy is suitable for patients with ER estrogen receptor-positive breast cancer whose cancer has been removed. Although no lumps are detected, breast cancer cells may spread to other parts of the body and continue to grow and become life-threatening. Therefore, these patients often need adjuvant therapy to kill the cancer cells that have spread. For patients with ER estrogen receptor positive breast cancer, endocrine therapy is often used alone or in combination with chemotherapy as adjuvant treatment.
2.Estrogen level reduction therapy is mainly used to reduce estrogen production through surgical or non-surgical methods, thus reducing estrogen levels. This kind of therapy is suitable for patients with residual cancer after surgery or cancer patients with recurrence months or years after surgery.
1.Tamoxifen (triamcinolone acetonide)
Tamoxifen is one of the earliest and most used estrogen antagonists. It competes with estradiol to form Tam-receptor complexes to reduce the activity of cancer cells, stagnate tumor cells in G1 phase, reduce the proportion of S phase, and promote the production of interleukin 2 to enhance the cytotoxic effect of natural killer cells and macrophages. Tamoxifen, often applied for 5 years after surgery, reduces the recurrence rate of ER estrogen receptor-positive breast cancer (31% reduction reported in recent literature), and can also be used in breast cancer patients who have developed metastases. Tamoxifen has stable efficacy, low toxicity, and 25%-30% efficacy after failure with other drugs, so it is often used as the first-line drug. Tamoxifen can increase the incidence of endometrial cancer, which is often detected early and partially cured by surgical excision; it can also increase the incidence of uterine sarcoma, and patients should be examined immediately if they experience abnormal vaginal bleeding while taking tamoxifen; other side effects include blood clotting, increased body mass, facial flushing, mood swings, and occasionally early cataracts. For most breast cancer patients, the advantages of taking tamoxifen far outweigh the disadvantages.
2.Toremifene (Faradone)
The mechanism of action and efficacy are similar to tamoxifen, and the probability of causing endometrial cancer is very small. It is suitable for the treatment of metastatic breast cancer in postmenopausal women with unknown estrogen receptor positivity (or). Common adverse reactions are facial flushing, excessive sweating, uterine bleeding, leukorrhea, fatigue, nausea, rash, pruritus, dizziness, and depression. These adverse reactions are generally mild, mainly because of the hormone-like effects of toremifene.
3, fulvestrant (fulvestrant)
Fulvestrant is a new drug that blocks the action of estrogen by reducing the number of estrogen receptors. It is still effective for breast cancer patients whose tamoxifen treatment is ineffective. It is injected intramuscularly once a month. Adverse effects are facial flushing, mild nausea and fatigue.
4.Raloxifene (raloxifene, evista)
Raloxifene is a new drug that is being hotly researched and it is a selective estrogen receptor modulator. It is also used to treat osteoporosis because it has estrogen-like bone enhancing effects. According to the STAR trial of NSABP, the use of raloxifene in postmenopausal patients with lobular carcinoma in situ reduces the risk of invasive cancer.
5.Aromatase inhibitors
The mechanism of action of aromatase inhibitors is that more than 70% of estrogen in postmenopausal women is produced by androgen precursors produced by adrenal glands through the action of aromatase, and the activity of aromatase in tumor tissues of about 70% of patients is higher than that of surrounding tissues. These drugs are mainly used in postmenopausal patients with positive estrogen receptors. The latest National Comprehensive Cancer Network 2007 guidelines emphasize that these drugs should not be used in patients whose ovaries are still functional. The 1st and 2nd generation aromatase inhibitors have been used for their side effects and poor efficacy. 3rd generation drugs such as letrozole (Flon), anastrozole (Renindezvous) and exemestane are now mainly used. Many recent studies have shown that aromatase inhibitors present a strong challenge to the traditional status of tamoxifen. Aromatase inhibitors rarely cause endometrial cancer and uterine sarcoma, but there is an increased incidence of osteoporosis and fractures. Therefore, calcium and vitamins and appropriate physical activity are recommended for patients on long-term use of such drugs.
6.Progestin
The mechanism of action of progesterone is to inhibit hypothalamic gonadotropin-releasing hormone, thus inhibiting follicle stimulating hormone and luteinizing hormone secretion as well as inducing hepatic alpha-reductase to accelerate androgen degradation in the body, thus reducing estrogen synthesis. It competes with the PR progesterone receptor to inhibit the interaction of estradiol with the ER estrogen receptor. The main progestin drugs are megestrol and megestrol. Progestins are indicated for the postmenopausal population, for the palliative treatment of recurrent metastatic breast cancer, and remain effective in patients who have failed tamoxifen therapy. For patients with predominantly bone metastases who have poor general condition, weakness or loss of appetite, progestins can be used as first-line drugs. The main progestogen side effects are obesity, fluid retention, hyperglycemia and hypertension.
7.Gonadotropin-releasing hormone analogues
Gonadotropin-releasing hormone analogues include goserelin and leuprolide, which are used in estrogen receptor-positive premenopausal patients, and their efficacy can be increased when combined with tamoxifen. The main side effects are facial hot flashes, headache, decreased libido, vaginal dryness, and decreased bone salt density.
No single endocrine therapy is effective for all patients with estrogen receptor positive or progesterone receptor positive breast cancer, so it is extremely important to choose the most appropriate endocrine therapy for the patient. The choice is based on the patient’s gender, menstrual status (menopausal or not), age, physical status (other co-morbidities or not), history of endocrine therapy (and hormone resistance or not), degree of tumor differentiation, and the level of expression of specific proteins and genes in breast cancer.
A recent study by Canadian scholars found that letrozole, an aromatase inhibitor, is highly effective in male breast cancer, especially in progressive breast cancer. It can also be used to treat male breast cancer by orchiectomy.
While tamoxifen remains the first choice for premenopausal receptor-positive women, a new view suggests that the preferred regimen for postmenopausal receptor-positive women is to use tamoxifen for 2-3
years before switching to an aromatase inhibitor to complete 5 years of endocrine therapy, or 5 years with an aromatase inhibitor alone. Studies have shown that tamoxifen is preferred in female patients >75 years of age with estrogen receptor positivity, while female patients >85 years of age have limited efficacy with all endocrine therapies. Breast cancer that recurs after tamoxifen treatment is best treated with an aromatase inhibitor or fulvestrant.
The 2007 National Comprehensive Cancer Network guidelines for endocrine therapy in advanced recurrent metastatic breast cancer have no new changes from the past; while for endocrine therapy in receptor-positive early breast cancer, 3rd generation aromatase inhibitors have become one of the first-line options for postmenopausal breast cancer.
The current research on the effects of hormone resistance, which refers to the insensitivity of some breast cancers to one or more hormone treatments, has become a hot topic. Studies have elucidated that high expression of estrogen receptor-alpha (estrogen receptor has both alpha and beta isoforms) or AIB1 protein (ER estrogen receptor-alpha enforcer protein) or HER2/neu (an oncogene) in breast cancer tissues is closely associated with tamoxifen and fulvestrant resistance, and tamoxifen-based drugs should be avoided in such breast cancer patients.
Overcoming the effects of hormone resistance by blocking selective growth factor receptor signaling is being investigated and offers hope for the use of tamoxifen analogs in this group of patients.
Although studies such as the letrozole (P024) study have demonstrated the effectiveness of letrozole in patients with HER2 overexpressed breast cancer, most experts believe that it is not yet appropriate to apply HER2 status to guide the design of endocrine therapy regimens.
In conclusion, the selection of an appropriate endocrine therapy regimen for a patient requires a combination of many factors to determine, which is a new direction of current research, and physicians’ recommendations will change over time with the results of subsequent studies.
(1) Oophorectomy (debulking)
The growth of breast cancer is related to the endocrine function of the ovaries. Therefore, elimination of bilateral ovarian function is an important endocrine therapy in the treatment of advanced or recurrent breast cancer that is premenopausal or about 1 year postmenopausal. The effectiveness of oophorectomy depends on whether the breast cancer is estrogen-dependent or not. Only estrogen-dependent breast cancer is an indication for oophorectomy, otherwise the efficacy will not be obvious, and clinically it is usually considered as estrogen-dependent when the breast cancer has metastasis in the axillary lymph nodes or when the breast is obviously swollen and painful during menstruation. Postmenopausal and young patients are not suitable for prophylactic oophorectomy.
For those with poor systemic conditions that make it difficult to tolerate surgery, radiation debulking can be used. The use of this method should first determine the anatomical position of the ovary based on its body projection. If the position of the uterus is normal, the body projection of the ovary is at the midpoint of the line connecting the umbilicus and the anterior superior spine to the midpoint of the pubic symphysis in a supine position: if the position of the uterus is abnormal, the position of the uterus can be adjusted accordingly. It is generally believed that the efficacy of the two types of denervation is comparable, but the surgical removal of the ovaries is more reliable and complete, and the effect time is faster; while the effect time of radiation denervation is delayed to 6-8 weeks, and if it is not effective after 8 weeks, it is considered as failure. The effect of radiation debulking can be judged by vaginal smear examination. The effect of radiation debulking to eliminate ovarian function is not permanent, about 1/3 of the patients still have menstruation after radiation debulking. Therefore, for patients with advanced breast cancer, unless they cannot tolerate surgery. Oophorectomy should be the first choice if debulking is needed.
In recent years, some researchers have used goserelin and other drugs to achieve similar effects as ovariectomy and have achieved good results. Goserelin is a decapeptide compound, which is similar to luteinizing hormone-releasing hormone (LHRH) analogue. It can bind to the receptors of pituitary luteinizing hormone-releasing hormone (LHRH) in the body, forming a reversible inhibition of LH and FSH secretion, which suppresses ovarian function and brings estrogen levels in premenopausal women to postmenopausal levels, thus inhibiting the promotion of estrogen on breast cancer growth. Goserelin has fewer side effects, mainly: dryness and heat, increased vaginal discharge, vaginitis, decreased or hyper sexual desire, and dizziness. Goserelin can now be considered as a safe, effective and reversible ovarian function suppressant for premenopausal breast cancer patients.
Whether surgical debulking, radiological debulking, or pharmacological debulking is taken, it can reduce the recurrence rate and mortality in menopausal patients with estrogen receptor-positive breast cancer.
(2) Adrenalectomy
The main source of estrogen in postmenopausal women is the precursors secreted by the adrenal glands. Removal of bilateral adrenal glands for advanced breast cancer is aimed at eliminating some of the hormones. In general, after bilateral oophorectomy, breast cancer patients may be in remission for several months to years, after which the blood levels of estrogen begin to rise again, with a small proportion of estradiol secreted by the adrenal glands and a large proportion of androstenedione, an androgen precursor secreted by the adrenal glands, which is converted to estrogen in the surrounding tissues by the action of aromatase. Therefore, in patients with effective ovariectomy, if bilateral adrenalectomy is performed at this time, the disease can be relieved for the second time, and the effective rate can be 40%-50%. In premenopausal women, bilateral oophorectomy must be done before adrenalectomy.
(3) Pituitary gland resection
The efficacy of pituitary resection for breast cancer is better for those with pleural, pulmonary and skeletal metastases, followed by those with soft tissue metastases, and less effective for patients with liver metastases, central nervous system metastases and diffuse lymphovascular infiltration in the lungs. Glucocorticoid, thyroxine and pituitary pressor hormone supplementation is required after pituitary gland resection. Patients who have undergone pituitary resection may not need to undergo adrenalectomy and vice versa. The results of adrenalectomy and pituitary resection are approximately the same.
(4) Orchiectomy
Male breast cancer is clinically rare and generally accounts for only 1% of the total number of breast cancers. The average age of onset of male breast cancer is higher than that of female. The treatment of male breast cancer is basically the same as that of female, i.e. radical mastectomy and postoperative comprehensive treatment including radiation therapy, chemotherapy, endocrine therapy, etc. should be done. Endocrine therapy is mainly used to eliminate hormones, and additional hormones and hormone combination chemotherapy are also used in advanced stages. Hormone elimination therapy includes bilateral orchiectomy, adrenalectomy and pituitary resection, among which bilateral orchiectomy has the best efficacy, with an efficiency of 60%-70% for patients with advanced gynecomastia. Estrogen and progesterone receptor measurements should be done on the resected specimens in order to guide the next step of treatment.
Which patients are suitable for endocrine therapy?
Currently, endocrine therapy is considered suitable for patients with ER or PR progesterone receptor positive tumor, slow growth, long disease-free survival, with or without bone and soft tissue metastases, asymptomatic visceral metastases, and patients with breast cancer for whom previous endocrine therapy is effective.
When is the right time for endocrine therapy?
For patients with receptor-positive breast cancer it is currently advocated that most patients require chemotherapy in combination with endocrine therapy. However, the timing of the two treatments has been controversial in the past. The results of a large clinical trial in recent years suggest that endocrine therapy should be started immediately after chemotherapy and radiotherapy to improve the survival of breast cancer patients on the one hand and to increase the effectiveness of chemotherapy on the other.
The duration of endocrine therapy varies from one endocrine regimen to another, and for the commonly used triamcinolone acetonide (tamoxifen) the duration of postoperative adjuvant therapy should be 5 years. Clinical trials have shown that 5 years of triamcinolone acetonide is better than 2 years, and 2 years is better than 1 year, but extending it to 10 years shows no difference in efficacy from 5 years, with an increased incidence of venous thrombosis and endometrial cancer. Therefore, the current recommendation is that triamcinolone should be taken continuously for 5 years.