Since the first successful application of ovariectomy debulking by Dr. Beatson in England in 1893 to treat advanced breast cancer, more than 100 years of development of endocrine therapy for breast cancer, we have had many choices of endocrine therapy for breast cancer such as ovariectomy debulking, norethind drug debulking, triamcinolone acetonide (TAM), progestin analogs, aromatase inhibitors, and fluviscitron.
Especially in recent years, with the successive successful development of third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane, and the completion of several prospective, randomized controlled clinical studies of third-generation aromatase inhibitors with triamcinolone, third-generation aromatase inhibitors have increasingly become an important treatment option for hormone receptor-positive breast cancer patients. However, in clinical practice, clinicians often face confusion on how to interpret the literature scientifically and how to apply the findings of clinical studies rationally. In the clinical practice of breast cancer, we always adhere to the scientific concept of “adjuvant therapy follows other people’s articles, and salvage therapy follows one’s own efficacy”, and strive to achieve the main goal of “maximizing the patient’s benefit”.
I. Adjuvant endocrine therapy for early-stage breast cancer
”Adjuvant treatment follows the article of others” means that since adjuvant treatment is carried out after surgical removal of visible tumor, it is impossible to evaluate the clinical efficacy according to the change of the size of specific lesions. Physicians can only select adjuvant regimens based on the results of relevant prospective, randomized controlled studies that have been completed, which means that we follow the evidence of evidence-based medicine to determine our adjuvant therapy. The main drugs currently available for adjuvant endocrine therapy for breast cancer are TAM and third generation AIs.
1.TAM
TAM is almost the only choice for premenopausal patients with early postoperative breast cancer who do not undergo ovarian removal or ovarian function suppression. However, regarding the length of time for TAM application, the results of NSABP B14 study had shown that extending TAM to 10 years in lymph node negative breast cancer patients did not show an advantage of disease-free survival and overall survival compared with taking the drug for 5 years, but also led to an increased occurrence of endometrial cancer and cardiovascular disease. However, the results of the new ATLAS trial show a different result.
A total of 11,500 patients with early-stage breast cancer were enrolled in the trial, and after completing 5 years of adjuvant TAM therapy, they were then randomized into two groups: continuation of TAM therapy and blank control. The results of the 10-year study found that the recurrence rate in the 10-year TAM therapy group was significantly lower than that in the control group, and this advantage was not affected by ER(+) or unknown, age, or the presence or absence of lymph node metastasis. The study also found that this advantage persisted between 5-9 years and 10-14 years after TAM. While the difference in mortality between the two groups was not significant, the 10-year TAM group had a lower mortality rate. The results of this study have not been conclusively concluded, but at least suggest that prolonging the duration of TAM may still be a treatment option for patients with lymph node metastases.
2.Third generation AIs
For adjuvant endocrine therapy options for postmenopausal breast cancer patients, third-generation AIs have become an important treatment option, but they have multiple options in terms of timing of application for different patient populations, and these recommendations have been included in the 2008 edition of the NCCN Breast Cancer Treatment Guidelines because they are all supported by evidence-based medicine. They can be divided into the following three approaches.
(1) Application of AIs from the beginning for a total of 5 years. This recommendation is derived from the findings of the ATAC, BIG-198 trial. The latest ATAC results with 100 months of follow-up showed that anastrozole improved disease-free survival by 4.8% compared to TAM, while the BIG-198 results with 51 months of follow-up also showed a 2.9% disease-free survival advantage of letrozole over TAM. However, neither anastrozole nor letrozole showed superior overall survival to TAM in the above two studies.
Therefore, we believe that since the toxic reactions of AIs and TAM are different, the choice should be made after a thorough weighing of each patient’s condition and organismal status. For low-risk and intermediate-risk patients, TAM can still be a treatment option if the patient has AIs-related side effects diseases such as osteoporosis and osteoarthrosis, since the absolute benefit of AIs is not significant.
(2) Switching to AIs for 3~2 years after 2~3 years of triamcinolone acetonide application. Current clinical studies supporting the above recommendation include the IES031 trial for switching to exemestane, the ITA trial for switching to anastrozole, and the ARNO95 trial.
(3) Switch and extend the application of AIs for 5 years after 5 years of triamcinolone acetonide application. Current clinical trials that support switching and extending the application of AIs after 5 years of TAM include the MA17 trial, which supports switching and extending the application of letrozole for another 5 years, and the NSABP B33 trial, which supports switching and extending the application of exemestane for another 5 years. This takes into account two patient populations, one of which is patients who have been currently taking TAM for 2-3 years or have been on TAM for 5 years. The second is that the patient has already entered perimenopause, and after 2-3 years of TAM, the patient is likely to enter menopause, at which point switching to AIs would be logical. As for which of the three third-generation aromatase inhibitors is better, there is a lack of randomized controlled comparative study results. The ongoing MA27 trial of anastrozole compared with exemestane and the FACE trial of anastrozole compared with letrozole will give the expected answers.
II. Endocrine treatment strategy for advanced recurrent metastatic breast cancer
We have been insisting on the idea of “relief treatment based on clinical efficacy evaluation” in the clinical practice of advanced breast cancer. Because the objective tumor lesions provide us with the conditions to accurately evaluate the efficacy of treatment, no trial results can surpass the evidence of realistic efficacy. The guiding principle for the development and modification of treatment protocols is “no change in prescription if it is effective and no change if it is not effective”. For the relief of endocrine therapy, we believe that only the following three conditions can be considered to change the treatment plan. Firstly, tumor progression; secondly, intolerable drug toxicity; and thirdly, economic unsustainability.
Currently, the recommended endocrine therapies for advanced breast cancer patients include
(1) estrogen receptor antagonists triamcinolone acetonide and toremifene.
(2) non-steroidal aromatase inhibitors anastrozole and letrozole.
(3) Steroidal aromatase inactivators, exemestane.
(4) estrogen receptor modulator fulvestrant
(5) Progestins such as megestrol and megestrol.
(6) Other drugs: fluorometholone, testosterone propionate. According to the latest 2008 NCCN guidelines, the principles of endocrine therapy for advanced recurrent metastatic breast cancer are recommended as follows. A number of studies have also been reported on the comparative efficacy between these endocrine therapeutic agents. The clinical benefit rate of first-line relief anastro
56.2-59% for anastrozole, 50% for letrozole, 67% for exemestane, and 38-55.5% for triamcinolone acetonide.
I. ER/PR positive with bone/soft tissue metastases only or asymptomatic visceral metastases
1. For patients who have received adjuvant anti-estrogen therapy within one year, AIs or progestin-based or other endocrine drugs may be chosen until tumor progression or intolerable toxicity occurs. If the tumor progresses further and receives 3 endocrine relief regimens with no further clinical benefit or symptomatic visceral metastases, you may consider switching to systemic chemotherapy on the one hand, or a new clinical trial of endocrine therapy on the other.
2. For patients who have not received prior adjuvant anti-estrogen therapy or whose adjuvant anti-estrogen therapy has been administered for more than one year. If the patient is postmenopausal, AIs or anti-estrogen drug therapy can be considered; if the patient is not postmenopausal, bilateral oophorectomy or ovarian function suppression should be performed first, and then AIs or anti-estrogen therapy should be selected according to postmenopausal principles. If the tumor progresses further and receives 3 endocrine relief regimens with no further clinical benefit or symptomatic visceral metastases, switching to systemic chemotherapy can be considered on the one hand, and a new clinical trial of endocrine therapy can be considered on the other.
ER/PR-negative or endocrine therapy-resistant
Patients who are hormone receptor negative, or positive but resistant to endocrine therapy, may also be considered for clinical studies of endocrine therapy if they have only bone or soft tissue or asymptomatic visceral metastases. In our clinical course, we often select progestin analogs for 1-2 months of relief therapy for patients who are hormone receptor negative, ineffective with chemotherapy treatment, or unable to tolerate chemotherapy toxicity.
This is because in cases where the patient’s other treatments are ineffective or cannot be continued, strictly monitored treatment with progestin analogs is feasible, even if the ineffective progestin analogs’ effects of improving appetite and increasing weight can improve the patient’s organism condition and provide conditions for further treatment. In addition, for patients with recurrent metastases or stage IV with bone metastases, bisphosphonates should become the routine basic treatment.
Third, the definition of menopause
As the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane, the prerequisite for their application must be menopause or complete suppression of ovarian function. However, the current criteria for defining menopause are still somewhat flawed The 2008 Breast Cancer NCCN guideline recommendations on criteria for menopause still extend the 2007 version of the definition.
The details are as follows.
1, bilateral oophorectomy.
2, age ≥ 60 years.
3, if age 20 pmol/L and normal gonadotropins, it is recommended to choose triamcinolone, or triamcinolone combined with ovarian function depot, or AIs combined with ovarian function depot.