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 therapy for early stage breast cancer, and can even be used to prevent the occurrence of breast cancer in healthy women at high risk.
Basic drugs for endocrine therapy of breast cancer
The drugs used in endocrine therapy for breast cancer are anti-estrogen drugs, aromatase inhibitors (AI), luteinizing hormone-releasing hormone analogs (LHRHa), estrogen/androgen analogs and progestins.
Anti-estrogen drugs, which bind to the estrogen receptor (ER), 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.
Aromatase inhibitors, by inhibiting the activity of aromatase, block the conversion of androstenedione and testosterone to estrogen via aromatization in tissues other than the ovaries, 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 heme and competing with endogenous substrates for the active site of aromatase. There are first-generation aminoglycone (AG), second-generation fadrozole, and third-generation rinindel (anastrozole) and flon (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 it in the form of covalent bonds to form intermediate products, causing permanent enzyme inactivation and thus inhibiting estrogen synthesis. (exemestane).
Luteinizing hormone-releasing hormone analogs (LHRHa) inhibit the production of gonadotropin-releasing hormone (GnRH/LHCRH) by the hypothalamus through negative feedback; 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 secretion by the ovaries. The representative drug is Zoladex (Norelide), which can replace oophorectomy for the treatment of premenopausal recurrent metastatic breast cancer.
Androgens and estrogens, therapeutic doses of which can alter the body’s endocrine environment and inhibit the growth of tumor cells, also show significant adverse effects and are currently less commonly used clinically.
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 meprogesterone (MPA) and medroxyprogesterone (MA).
Endocrine therapy for metastatic breast cancer
The aim of treatment for recurrent metastatic breast cancer is to improve patients’ quality of life and prolong survival. 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 therapy can be preferred for slowly progressing hormone-responsive breast cancer (Endocrineresponsive), which used to be called hormone-dependent breast cancer. The characteristics of slowly progressing recurrent metastatic breast cancer are.
①Hormone receptor (ER and/or PR) positive;
② Longer disease-free survival after surgery;
③ Only soft tissue and bone metastases, or no significant visceral metastases such as non-diffuse pulmonary and hepatic metastases, modest tumor load, and other visceral metastases 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.
① Positive ER and/or PR at the primary site and/or recurrent metastases;
(ii) Elderly patients;
(iii) Longer postoperative disease-free interval;
④ 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 the disease progression and improve the patient’s 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.
The 2006 US NCCN Breast Cancer Treatment Guidelines have several clear definitions regarding the determination of menopause.
①After bilateral oophorectomy (or effective radiation debulking);
②Age 60 years or older;
③Age 60 years or younger, without chemotherapy, triamcinolone acetonide, toremifene or ovarian function suppression therapy, with more than 12 months of spontaneous menopause and blood E2 and FSH at postmenopausal levels;
④Age 60 years or younger, treated with triamcinolone acetonide and toremifene, and blood E2 and FSH have reached postmenopausal levels;
⑤ Patients who are receiving LH-RH analogues or agonists cannot be determined to be menopausal;
(6) Premenopausal women who are receiving adjuvant chemotherapy, menopause cannot be used as a basis for determining menopause.
After the failure of the first choice of 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 drugs 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 agents 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 its combination with chemotherapy can increase the patient’s tolerance to chemotherapy.
Neoadjuvant endocrine therapy
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 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 positive rate of Chinese women is about 50%, and receptor negative patients are not suitable for endocrine therapy; even premenopausal patients who are receptor positive can choose chemotherapy. However, as China’s population ages and health insurance further spreads to more elderly patients, coupled with the continuous updating of the concept of endocrine therapy by both doctors and patients, the clinical application of preoperative neoadjuvant endocrine therapy will become more widespread.
Postoperative adjuvant endocrine therapy for breast cancer
Triamcinolone acetonide is the most commonly used endocrine therapeutic drug for adjuvant treatment after early breast cancer. The basic consensus on the application of triamcinolone acetonide in adjuvant treatment of breast cancer is as follows.
(1) The determining factor of adjuvant endocrine therapy is the hormone receptor (ER/PR) status, ER-positive has the best effect, and some ER-negative PR-positive patients can also use triamcinolone acetonide;
②The appropriate duration of triamcinolone acetonide is 5 years, and further extension of the duration of the drug cannot improve the efficacy;
(3) The efficacy of triamcinolone is not related to the patient’s age and can be used before and after menopause;
④Triamcinolone acetonide can significantly reduce the incidence of contralateral breast cancer, but can only prevent the incidence of estrogen receptor-positive breast cancer;
⑤ Long-term use of triamcinolone acetonide can increase the risk of endometrial cancer;
(6) The addition of triamcinolone acetonide after chemotherapy in ER-positive patients is more effective than both chemotherapy alone and triamcinolone acetonide alone, and the sequential combination of triamcinolone acetonide after chemotherapy is better than the 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 than 5 years of triamcinolone with fewer adverse effects 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.
The results of the IES-031 trial showed that 2-3 years of triamcinolone followed by 2-3 years of exemestane was significantly more effective than 5 years of triamcinolone as an adjuvant treatment after breast cancer surgery. The results demonstrated that adjuvant postoperative treatment of breast cancer with triamcinolone for 5 years followed by anastrozole for 5 years was significantly more effective than triamcinolone 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 the outcome regardless of whether there were lymph node metastases after surgery.
A clinical study published in Lancet in 2000 showed that post-chemotherapy amenorrhea significantly reduced the risk of recurrence and metastasis in ER-positive patients younger than 35 years of age, suggesting that adjuvant chemotherapy alone is not effective in these younger patients after breast cancer surgery 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 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, clinical trials have shown that pharmacological ovarian debulking is equivalent to CMF chemotherapy for premenopausal hormone receptor-positive patients. It is inconclusive whether the addition of ovarian denervation after 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 endocrine therapy for premenopausal breast cancer, 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.
①Anastrozole or letrozole for 5 years after surgery;
②Triamcinolone for 2-3 years followed by 2-3 years of sequential exemestane or anastrozole;
(iii) 5 years of triamcinolone followed by 5 years of intensive letrozole;
(iv) Patients who cannot tolerate aromatase inhibitors for various reasons remain on triamcinolone for 5 years.
In premenopausal hormone receptor-positive patients, postoperative adjuvant endocrine therapy can be chosen from.
(i) start with triamcinolone acetonide for 2-3 years and 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 then followed by 5 years of trimethoprim as a follow-up intensive therapy if they enter menopause after 5 years.
(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.