Endocrine therapy is one of the main systemic treatments for breast cancer. As early as the end of the 19th century, bilateral oophorectomy has been used to treat advanced premenopausal breast cancer. In the 1970s, the introduction of triamcinolone acetonide became a new milestone in endocrine drug therapy for breast cancer, and in the 1990s, the introduction of third-generation aromatase inhibitors brought a new era of endocrine therapy for breast cancer. Endocrine therapy plays a very important role in hormone-dependent recurrent metastatic breast cancer and post-operative adjuvant treatment of early stage breast cancer, and can even be used to prevent the occurrence of breast cancer in high-risk healthy women.
1.The basic drugs of endocrine therapy for breast cancer
The drugs used in endocrine therapy for breast cancer are anti-estrogens, aromatase inhibitors (AI), luteinizing hormone-releasing hormone analogs (LHRHa), estrogen/androgen analogs and progestins.
1.1 Anti-estrogens, which bind to the estrogen receptor (ER) and block the action of estrogen on the receptor. The most commonly used is triamcinolone acetonide (TAM), which can be used for the palliative treatment of recurrent metastatic breast cancer, postoperative adjuvant therapy, and breast cancer prevention in high-risk healthy women.
1.2 Aromatase inhibitors, by inhibiting the activity of aromatase, block the conversion of androstenedione and testosterone to estrogen via aromatization in tissues other than the ovary, to inhibit the growth of breast cancer cells and treat tumors. Aromatase inhibitors are suitable for post-menopause and are divided into two categories according to different mechanisms of action: ① Non-steroidal drugs, which reversibly inhibit enzyme activity by binding to iron atoms in ferrous hemoglobin and competing with endogenous substrates for the active site of aromatase. There are first-generation aminoconductant (AG), second-generation fadrozole, third-generation rinindel (anastrozole), and feron (letrozole). Steroids, similar in structure to the endogenous substrates of aromatase, androstenedione and testosterone, can compete as pseudo-substrates to occupy the active site of the enzyme and irreversibly bind to them in the form of covalent bonds to form intermediates, causing permanent enzyme inactivation and thus inhibiting estrogen synthesis. (exemestane).
1.3 LH C RH analogues, through negative feedback action on the hypothalamus, inhibit the hypothalamus from producing gonadotropin-releasing hormone (GnRH/LH C RH); they also compete with GnRH receptors or LHRH receptors on the pituitary cell membrane to prevent the pituitary from producing FSH and LH, thus reducing estrogen production by the ovaries. The representative drug is Zoladex (Noradex), which can replace ovariectomy for the treatment of premenopausal recurrent metastatic breast cancer.
1.4 Androgens and estrogens. Therapeutic doses of androgens and estrogens can change the human endocrine environment and inhibit the growth of tumor cells, but they also show significant adverse effects, and are currently less commonly used in clinical practice.
1.5 Progestins, through altering the body’s endocrine environment, inhibit the production of LH and ACTH by the pituitary gland through negative feedback, or act on breast cancer cells through progesterone receptors. The commonly used ones are methyl progesterone (MPA) and megestrol (MA).
2.Endocrine therapy for metastatic breast cancer
The purpose of treatment for recurrent metastatic breast cancer is to improve the quality of life and prolong the survival of patients. Whether to choose endocrine therapy for recurrent metastatic breast cancer depends on the hormone receptor status (ER/PgR) of the patient’s tumor tissue, age, menstrual status and the degree of disease progression. In principle, chemotherapy should be preferred for patients with rapidly progressing recurrent metastatic disease, while endocrine responsive breast cancer, which used to be called hormone-dependent breast cancer, can be preferred for slowly progressing hormone-responsive breast cancer.
Characteristics of slowly progressing recurrent metastatic breast cancer: (i) hormone receptor (ER and/or PR) positive; (ii) longer disease-free survival after surgery; (iii) only soft tissue and bone metastases, or no significant visceral metastases, such as non-diffuse pulmonary metastases and liver metastases, and other visceral metastases with small tumor load that are not life-threatening. The hormone-responsive breast cancer concept, which defines which patients are suitable for endocrine therapy in terms of their potential benefit from endocrine therapy, considers that patients who meet one or more of the following conditions may benefit from endocrine therapy: (i) positive ER and/or PR at the primary site and/or recurrent metastases; (ii) elderly patients; (iii) long disease-free postoperative interval; and (iv) previous benefit from previous endocrine therapy.
Basic principles of endocrine therapy for recurrent metastatic breast cancer: ①The principle of treatment for recurrent metastatic breast cancer 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 treatment with 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 be maintained for as long as possible with continuous therapeutic use to prolong the duration of disease control with the aim of prolonging overall survival.
For postmenopausal recurrent metastatic breast cancer, the first choice of first-line endocrine therapy is third-generation aromatase inhibitors, including anastrozole, letrozole, and exemestane. International multicenter clinical studies have demonstrated that third-generation aromatase inhibitors are more effective than megestrol in the second-line treatment of recurrent metastatic breast cancer that has failed triamcinolone therapy. In first-line endocrine therapy for recurrent metastatic breast cancer, third-generation aromatase inhibitors are significantly more effective than triamcinolone. Chemotherapy may be preferred for premenopausal patients with recurrent metastatic breast cancer. If chemotherapy fails, or if the disease is suitable or requires endocrine therapy, pharmacologic ovarian debulking combined with aromatase inhibitors may be indicated.
There are several clear definitions for the determination of menopause in the 2006 NCCN Breast Cancer Treatment Guidelines: (1) after bilateral oophorectomy (or effective radiation debulking); (2) age 60 years or older; (3) age 60 years or younger, not receiving chemotherapy, triamcinolone acetonide, toremifene, or ovarian function suppression therapy, with more than 12 months of spontaneous menopause and blood E2 and FSH reaching postmenopausal levels; (4) age Under 60 years old, treated with triamcinolone acetonide and toremifene, and blood E2 and FSH reach postmenopausal level; ⑤ Patients who are receiving LH-RH analogues or agonists cannot determine whether they are menopausal; ⑥ Premenopausal women who are receiving adjuvant chemotherapy, menopause cannot be used as a basis for determining menopause.
After the failure of the preferred aromatase inhibitor treatment for recurrent metastatic breast cancer, chemotherapy can be considered; when it is suitable to continue with endocrine therapy, progestin, estrogen receptor modulator Fasolodex, and other aromatase inhibitors can be used. And based on the lack of evidence from current clinical studies that there is no cross-resistance between third-generation aromatase inhibitors (inactivating) agents, caution should be exercised when choosing another third-generation aromatase inhibitor after the failure of a particular aromatase inhibitor therapy.
With the exception of LH-Rha combined with AI in premenopausal patients, combinations between different classes of endocrine agents are not currently advocated because there is no evidence from clinical trials that surface combinations are better than single agents.
Whether the combination of endocrine therapy and chemotherapy is synergistic is inconclusive, although there are reports of experimental and small sample clinical studies of triamcinolone acetonide and toremifene combined with chemotherapy that may reverse chemoresistance, and clinical reports of progestin combined with chemotherapy to increase efficacy and mitigate adverse effects of chemotherapy. The combination of endocrine drugs and chemotherapeutic drugs is not advocated at present, especially since there is no successful experience of combining third-generation aromatase inhibitors with chemotherapy. However, progesterone can improve the general condition of patients with advanced metastatic breast cancer, and the combination with chemotherapy can increase the tolerance of patients to chemotherapy.
3.Neoadjuvant endocrine therapy
Preoperative neoadjuvant endocrine therapy can be another option for preoperative treatment of postmenopausal hormone receptor positive patients, especially for those elderly patients who are not suitable for chemotherapy, and can be considered for surgical resection after shrinking the tumor through 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 treatment of postmenopausal patients, improving efficiency and increasing the chance of breast conservation.
The concept of preoperative neoadjuvant endocrine therapy has been increasingly accepted, but there are currently greater difficulties in its clinical application. The reason is that those locally advanced patients who need preoperative treatment can be started with neoadjuvant therapy if only a clear pathological diagnosis is required, and the efficiency of first-line combination chemotherapy is higher. In contrast, preoperative neoadjuvant endocrine therapy requires waiting for hormone receptor test results of tumor tissues, while the hormone receptor positivity rate of Chinese women is about 50%, and receptor negative patients are not suitable for endocrine therapy; even premenopausal patients with positive receptors can choose chemotherapy. However, with the further popularization of China’s population aging and medical insurance to more elderly patients, coupled with the continuous updating of endocrine therapy concept by both doctors and patients, the clinical application of preoperative neoadjuvant endocrine therapy will become more widespread.
4.Post-operative adjuvant endocrine therapy for breast cancer
Triamcinolone is the most commonly used endocrine therapy drug for postoperative adjuvant treatment of early stage breast cancer. The basic consensus on the application of triamcinolone in adjuvant treatment of breast cancer are: (1) the determining factor of adjuvant endocrine therapy is hormone receptor (ER/PR) status, ER positive has the best effect, and some ER negative PR positive patients can also use triamcinolone; (2) the appropriate duration of triamcinolone is 5 years, and then (3) The efficacy of triamcinolone is not related to the patient’s age and can be used before and after menopause; (4) Triamcinolone can significantly reduce the occurrence of contralateral breast cancer, but can only prevent the occurrence of estrogen receptor-positive breast cancer; (5) Long-term use of triamcinolone will increase the risk of endometrial cancer; (6) Adding triamcinolone after chemotherapy for ER-positive patients is better than both chemotherapy alone and triamcinolone alone. The effect of adding triamcinolone after chemotherapy is better than both chemotherapy and triamcinolone alone, and the effect of sequential combination of triamcinolone after chemotherapy is better than simultaneous combination. As a representative drug for endocrine treatment of breast cancer, triamcinolone acetonide has significantly less adverse effects than chemotherapy, and most patients and healthy women can tolerate continuous treatment for 5 years or more. However, given that triamcinolone acetonide has been widely used in the clinic and is available as a prophylactic drug for healthy women, it is still important to be alert to the possible adverse effects of long-term drug use. Such as malaise, facial flushing, rash, vaginal dryness, vaginal bleeding, and, less commonly, dyspepsia, nausea, diarrhea, sweating, weight gain, and venous thrombosis.
The results of the ATAC trial showed that 5 years of anastrozole was more effective and had fewer adverse effects than 5 years of triamcinolone in the adjuvant treatment of early postmenopausal breast cancer, and the results of the BIG1-98 trial showed that 5 years of trimethoprim was more effective than 5 years of triamcinolone, and the results of the IES-031 trial showed that The results of the ITA and ARNO trials also showed that 2-3 years of triamcinolone followed by 2-3 years of anastrozole was significantly more effective than 5 years of triamcinolone, and the results of the MA-17 clinical trial demonstrated that postoperative adjuvant therapy for breast cancer trimethoprim followed by anastrozole for 5 years was significantly more effective than trimethoprim for 5 years.
In 1996, the Lancet published EBCTCG on the role of ovarian debulking in adjuvant therapy, which summarized the results of 12 trials with 3456 patients followed for 15 years and showed that ovarian debulking in premenopausal women improved outcomes regardless of postoperative lymph node metastasis. 2000 clinical study published in the Lancet A clinical study published in the Lancet in 2000 showed that post-chemotherapy amenorrhea significantly reduced the risk of recurrence and metastasis in ER-positive patients under 35 years of age, suggesting that adjuvant chemotherapy alone is not effective in these young patients, and that the addition of ovarian debulking may be more effective. Among the various ovarian debulking methods, ovariectomy has the advantage of complete blockage of ovarian-derived estrogen and the disadvantage of surgical trauma and irreversibility; radiotherapy ovarian debulking has the disadvantage of taking longer time, blocking ovarian function may be incomplete, and may also cause radiation damage to adjacent organs. Pharmacologic ovarian debulking, which has the same efficacy as surgical removal of the ovaries, has been used in the treatment of advanced premenopausal breast cancer in combination with aromatase inhibitors to achieve clear results. Pharmacologic debulking is safe and effective, overcoming the shortcomings of surgery and radiotherapy debulking, and is in line with the modern principles of breast cancer treatment that combines science and humanity to ensure efficacy and improve quality of life, and is more acceptable to many young patients. In the postoperative adjuvant treatment of early-stage breast cancer, there have been clinical trials showing that pharmacological ovarian debulking is equivalent to CMF chemotherapy for premenopausal hormone receptor-positive patients. It is inconclusive whether adding ovarian denervation to standard chemotherapy improves the efficacy.
So far, triamcinolone acetonide is still the basic drug for adjuvant endocrine therapy in breast cancer; the addition of third-generation aromatase inhibitors at different stages in postmenopausal patients has better efficacy than triamcinolone acetonide alone for 5 years; and pharmacological ovarian denervation combined with aromatase inhibitors may have better efficacy in premenopausal breast cancer endocrine therapy, but based on the fact that most breast cancer patients in Europe and the United States are postmenopausal, there are not many clinical studies in this field. Therefore, it is more necessary for our scholars to actively carry out multicenter clinical studies for the specific characteristics of more young patients with breast cancer in China, and explore treatment options that meet the characteristics of our population.
In summary, for postmenopausal hormone receptor positive patients, postoperative adjuvant endocrine therapy can be chosen from: (1) 5 years of postoperative anastrozole or letrozole; (2) 2-3 years of triamcinolone, followed by 2-3 years of sequential exemestane or anastrozole; (3) 5 years of triamcinolone, followed by 5 years of intensive letrozole; (4) 5 years of triamcinolone for patients who cannot tolerate aromatase inhibitors for various reasons. In premenopausal hormone receptor-positive patients, postoperative adjuvant endocrine therapy can be chosen: ①Triamcinolone acetonide for 2-3 years first, which can be switched to aromatase inhibitors if they enter postmenopause. ②If trimethoprim remains non-menopausal after 2-3 years, trimethoprim can be continued for up to 5 years, and if it enters menopause after 5 years, then trimethoprim can be used for 5 years as follow-up intensive therapy. (③For some premenopausal patients who are not suitable for triamcinolone therapy or have high-risk recurrence and metastasis factors, the use of aromatase inhibitors after ovarian denervation can be considered as adjuvant therapy.