Endocrine therapy for breast cancer
Endocrine therapy for breast cancer has a history of more than 100 years, much longer than the use of chemotherapy drugs. As early as 1896, Beatson first reported in The Lancet that removal of the ovaries could cause breast cancer to regress. In the 1970s, the introduction of triamcinolone acetonide became a new milestone in endocrine drug therapy for breast cancer, and the introduction of third-generation aromatase inhibitors in the 1990s brought a new era of endocrine therapy for breast cancer.
Advantages: easy administration, few adverse effects, and long-lasting efficacy.
Methods.
Surgery: There are three traditional surgeries: oophorectomy, adrenalectomy and pituitary resection. In recent years, in addition to oophorectomy, the other two are rarely used.
Advantages and disadvantages of oophorectomy.
Advantages: Immediate decrease in estrogen levels can be obtained, with an efficiency of 76% in ER-positive cases, and should be used in premenopausal patients.
Disadvantages: It causes irreversible menopause in 1/3 of ineffective premenopausal cases.
Radiotherapy instead of oophorectomy is slow to work and may sometimes be incompletely suppressed.
2. Drug therapy: anti-estrogens, aromatase inhibitors (AI), luteinizing hormone-releasing hormone analogs (LHRHa), estrogen/androgen analogs and progestins.
Three drugs are highlighted: TAM, AI, and Zoladex.
(1) TAM, which binds to the estrogen receptor (ER) and blocks the action of estrogen on the receptor. It can be used for the relief treatment of recurrent metastatic breast cancer, postoperative adjuvant therapy and breast cancer prevention in high-risk healthy women.
(2) AI, by inhibiting the activity of aromatase, blocking the conversion of androstenedione and testosterone to estrogen via aromatization in tissues other than the ovary, to achieve the purpose of inhibiting the growth of breast cancer cells and treating tumors.
a. Non-steroidal drugs: the first generation of aminoglutethimide (AG), the second generation of fadrozole (fadrozole), the third generation of anastrozole and letrozole. Mechanism of action: reversible inhibition of enzyme activity by binding to iron atoms in ferrous heme, and endogenous substrate race to the active site of aromatase.
b, Steroids: Testosterone in the first generation, Fomestane in the second generation, and exemestane in the third generation. Mechanism of action: structurally similar to the endogenous action substrates of aromatase, androstenedione and testosterone, they can compete as pseudo-substrates to occupy the active site of the enzyme and irreversibly bind to it in the form of covalent bonds to form intermediate products, causing permanent enzyme inactivation, thus inhibiting estrogen synthesis.
(3) Zoladex: It acts on the hypothalamus through negative feedback to inhibit the production of gonadotropin-releasing hormone (GnRH/LH-RH) by the hypothalamus; it also competes with GnRH receptors or LH-RH receptors on the pituitary cell membrane to prevent the pituitary from producing FSH and LH, thus reducing estrogen secretion by the ovaries. It can replace oophorectomy for the treatment of premenopausal recurrent metastatic breast cancer.
Basic consensus on the use of triamcinolone acetonide in the adjuvant treatment of breast cancer.
(1) The determining factor of adjuvant endocrine therapy is the hormone receptor status, and the best results are obtained with ER positive.
(2) The appropriate duration of drug administration is 5 years.
(3) The efficacy is not related to age.
(4) Taking triamcinolone acetonide reduces the incidence of contralateral breast cancer, but significantly increases the risk of endometrial cancer.
(5), The addition of triamcinolone acetonide after chemotherapy in ER-positive patients is more effective than chemotherapy alone and triamcinolone acetonide alone.
(6), sequential triamcinolone acetonide after chemotherapy is more effective.
The latest research results of the third generation AI
ATAC trial – adjuvant endocrine therapy
METHODS: A total of 9366 cases were enrolled to compare the efficacy of anastrozole and TAM for adjuvant treatment of breast cancer with a follow-up of 68 months (median time).
RESULTS: Anastrozole group significantly prolonged disease-free survival (P=0,01) and recurrence time (P=0,05), and significantly reduced distant metastasis (P=0,O4) and contralateral breast cancer (P=0,O1), the
MA17 – Follow-up intensive adjuvant therapy for early breast cancer
Methods: 5187 women with early postmenopausal breast cancer were enrolled, all patients had completed 5 years of TAM treatment before enrollment and were randomized to 2 groups after enrollment, placebo group and letrozole group. The mean follow-up was 2 and 5 years.
RESULTS: The number of breast cancer events in the two groups was 75 and 132, respectively, with 4-year survival rates of 93% and 87%, respectively (P < 0, 01). This result suggests that 5 years of standard TAM treatment followed by 5 years of letrozole can further improve the efficacy.
BIG1-98 trial – adjuvant treatment for early postmenopausal breast cancer
Methods: 8028 patients were enrolled and randomly divided into 4 groups: TAM in the first group, letrozole in the second group, TAM for 2 years followed by letrozole for 3 years in the third group, and letrozole for 2 years followed by TAM for 3 years in the fourth group. Follow-up was 26 months.
RESULTS: The risk of disease-free survival was 19% lower in the letrozole group than in the TAM group.
IES 031 trial
METHODS: 4742 patients were enrolled and started with TAM for 2-3 years after surgery and randomized into 2 groups, one group (2362 patients) was switched to exemestane and the other group (2380 patients) continued with TAM for 2-3 years. Follow-up was 30 and 6 months.
RESULTS: The number of events in the exemestane and TAM groups was 183 and 266, respectively. the tumor-free survival rates in the two groups were 91, 5% and 86, 8%, respectively. The difference in overall survival was not significant. At 3 years after randomization, the risk of breast cancer recurrence in patients decreased by 32% in the exemestane group.
Study P025 – First-line treatment of advanced postmenopausal breast cancer
METHODS: 916 postmenopausal patients with advanced breast cancer were enrolled with a median follow-up period of 32 months, with Flon as the trial group and TAM set as the control.
RESULTS: Clinical efficacy of fluron was significantly better than TAM, with a TTP of 9,4 versus 6,0 and a median survival of 34 versus 30 months. Survival of patients not crossed over to the study was found to be 35 versus 20 months median survival.
Study P024 – neo-neo-adjuvant therapy
METHODS: 337 patients were randomized in a 1:1 ratio to the letrozole and triamcinolone groups and treated for 4 months.
RESULTS: Both letrozole groups were significantly better than the triamcinolone group.
Endocrine treatment strategy for advanced recurrent metastatic breast cancer
(1) The first-line endocrine therapy of choice is the third-generation AI, including anastrozole, letrozole and exemestane, which is superior to TAM in terms of efficacy.
(2) Second-line treatment for recurrent metastatic breast cancer that has failed triamcinolone therapy.
(3), Third-generation AI is more effective than megestrol.
(4), Chemotherapy can be preferred before menopause, and if chemotherapy fails, pharmacological ovarian debulking combined with AI can be taken.
Adjuvant endocrine therapy after early breast cancer surgery
Postmenopausal hormone receptor-positive patients
(1), Anastrozole or Letrozole 5 years after surgery.
(2), 2-3 years of TAM followed by 2-3 years of sequential exemestane or anastrozole.
(3), 5 years of triamcinolone followed by 5 years of intensive use of letrozole.
(4), Patients who cannot tolerate AI therapy for various reasons are still available for TAM for 5 years.
Premenopausal hormone receptor-positive patients
(1).TAM for 2-3 years first, and can be switched to AI if they enter menopause.
(2), If TAM is still not menopausal after 2-3 years, TAM can continue to be used for 5 years, and if it enters menopause after 5 years, then use trimethoprim for 5 years as follow-up intensive treatment.
(3) For some pre-menopausal patients who are not suitable for TAM treatment or have high risk of recurrence and metastasis factors, AI can be considered as an adjuvant therapy after ovarian debulking.
Issues to be noted in endocrine therapy for breast cancer
The definition of menopause is clearly defined in the 2006 NCCN guidelines. (1) Previously underwent bilateral oophorectomy. (2) Age ≥ 60 years. (3) If the patient is ≥60 years of age, the following two conditions must be present to define menopause. a, amenorrhea for 12 months without chemotherapy, TAM, toremifene treatment or ovarian suppression interventions; b, FSH and estrogen levels are in the menopausal range. (4) If a patient develops amenorrhea while on TAM or toremifene and is ≥ 60 years of age, amenorrhea can be defined only if FSH and estrogen levels are in the menopausal range.
2. the role of Her-2 in the choice of endocrine therapy. the Her-2 expression status guiding the choice of endocrine therapy is currently being explored. The results of two randomized controlled studies of neoadjuvant therapy suggest that AI results in higher clinical remission rates than TAM in postmenopausal patients with positive hormone receptors with Her-2 overexpression, but the relatively small sample sizes of these two studies affect the persuasiveness of the conclusions. The panel also highlighted that many clinicians still prefer to apply AI for postmenopausal patients with Her-2 over-expression.
3. The reasonable duration of AI adjuvant therapy. It is unclear whether applying AI for more than 5 years will result in greater patient benefit. Reassuringly, two trials have been proposed to evaluate the duration of treatment with AI. two randomized controlled study projects, NSABPB33 (exemestane) and MA-17 (letrozole), will continue the drug for 11-15 years after AI continues to be used for 6-10 years and will be compared with placebo to evaluate the reasonable duration of AI adjuvant application.
4. AI should not be used in receptor-negative breast cancer patients. no studies have been reported on AI adjuvant treatment of hormone receptor-negative postmenopausal breast cancer patients. The expert group believes that false negative results do exist due to the differences in hormone receptor testing techniques among different testing units.
5. TAM and megestrol are still important options for endocrine therapy. Although first-line relief or even postoperative adjuvant therapy has been used in the treatment phase of AI, it does not solve the problem of recurrence and metastasis of breast cancer, and TAM or megestrol is still the first choice after treatment failure.
6. Long-term AI patients should have bone density examination first. For patients with long-term AI application, 500-1000mg/d, 400-800IU/d of vitamin D, appropriate physical exercise and informing the risk of smoking should be recommended, regardless of the addition of zolay phosphate. Patients should be more routinely included if they are 65 years old, have a history of fractures, have lost more than 2 cm in height, have recently lost more than 5% of their body weight, have a fracture patient in their 1st degree immediate family, have late menarche, early menopause, have low calcium intake, vitamin D deficiency, smoke, have excessive alcohol intake, and are rarely active in general.
There are still many unexplained issues
1. Is sequential adjuvant medication after AI first-line or TAM the most effective option? If two drugs are sequential, when is the best time to switch from TAM to AI.
2. Do we know the long-term toxic effects of AI? Are there any solutions to address them?
3. Which patients will benefit most from AI therapy? How to screen the beneficiary population?
4. Which patients are at greatest risk of drug toxicity with adjuvant AI therapy?
5. What is a reasonable time frame for adjuvant AI therapy?
6. Can the adjuvant phase III AI be switched between each other and what are the differences in toxicity between them?