In 2014, the American Society ofClinicalOncology (ASCO) updated its guidelines for adjuvant endocrine therapy in HR(+) breast cancer. In 2015, the St. Gallen Consensus Conference discussed the treatment decision of early-stage breast cancer in more depth, and more and more attention was focused on “from individualized treatment to precision medicine”, and all parties paid more attention to the endocrine treatment of breast cancer. However, the results of studies designed in different periods are different or even contradictory, which makes clinical decision-making difficult.
I. Adjuvant endocrine therapy for premenopausal HR(+) breast cancer
(A) Standard treatment for premenopausal, low-risk HR(+) patients: 5 years of tamoxifen (TAM) therapy
Since TAM has been used in the endocrine treatment of HR(+) breast cancer, several clinical studies have focused on its duration and efficacy, and the results have established 5 years of TAM as the standard adjuvant therapy [3]. A subgroup analysis in the SOFT study showed that low-risk, chemotherapy-free patients had a recurrence-free breast cancer rate of more than 95% after 5 years of TAM therapy alone [5]. It is evident that adjuvant endocrine therapy with TAM alone has good efficacy in some low-risk, chemotherapy-naïve patients.
[Hot question 1] Which patients can benefit from an extended course of TAM therapy?
In 2013, the results of two large randomized controlled studies, ATLAS and aTTom, were published regarding the need to extend the course of treatment to 10 years. 6846 patients with HR(+) breast cancer were included in the ATLAS study, and 10 years of TAM treatment further reduced the recurrence rate and death rate of breast cancer compared with 5 years of TAM treatment. The ATLAS and aTTom studies together demonstrated a reduction in breast cancer recurrence rates with 10 years of TAM therapy compared to 5 years of TAM therapy, with the benefit occurring mainly after 7 years of treatment.
However, the previous NSABP B-14 study showed otherwise: for estrogen receptor-positive, lymph node negative breast cancer patients, the group receiving 5 years of TAM after surgery (570 patients) did not show an advantage in terms of survival over the 10-year TAM treatment group (583 patients). Therefore, the question of which patients could benefit from an extended course of TAM treatment has been further explored, and it has been suggested that patient age (<40 years) and lymph node status could be used as a basis for assessing whether to extend the course of treatment [8]. However, overall, existing assessment systems built on immunohistochemical markers, multi-genotyping have only been proven to be useful for screening patients who may benefit from adjuvant endocrine therapy, chemotherapy, and assessing the risk of relapse. There is no reliable assessment system to screen patients who may benefit from an extended course of endocrine therapy.
We suggest that for patients with risk factors for postoperative recurrence (age <40 years, positive lymph nodes, cytologic grade 3) who require chemotherapy and who are not menopausal after 5 years of TAM therapy, an extended course of TAM therapy up to 10 years may be considered.
【Hot question 2】 How to choose endocrine drugs for patients who cannot be judged to be menopausal after 5 years of TAM treatment?
Patients who are not menopausal (pre-menopausal or perimenopausal) at the time of diagnosis should consider extending endocrine therapy after completing the initial 5 years of TAM treatment. At this point, the patient’s menstrual status should be determined, and if the patient is still pre-menopausal, TAM therapy should be extended to 10 years; if the patient is post-menopausal, aromatase inhibitor (AI) therapy for 5 years is an option, based on the results of current studies.
However, the current criteria for judging menopause are based on the relevant expert consensus [9]. And the results of some studies have shown that TAM may lead to pharmacological amenorrhea and significantly affect the sex hormone levels of perimenopausal breast cancer patients, and it is difficult to determine the menopausal status of patients in clinical practice [10].
Therefore, combining clinical practice experience, the pharmacokinetic characteristics of TAM and the physiological rules of the hypothalamic-pituitary-ovarian axis, it is recommended to discontinue TAM for 3-6 months after 5 years of TAM treatment, and to continue TAM if not menopausal; for patients whose menstruation does not resume after discontinuation, especially those aged >45 years, by sex hormone levels at the time of discontinuation, 3 months and/or 6 months after discontinuation, combined with ultrasonography and other Make a comprehensive judgment and start AI treatment if confirmed to be in menopausal status.
(B) Young, premenopausal HR(+) breast cancer patients can be considered for combined ovarian function suppress (OFS) therapy, and TAM or AI can be added according to risk factors. However, none of them included the standard treatment group of TAM after chemotherapy as a control, so no clear conclusion has been obtained. Until 2014, the results of the SOFT study were published: the 5-year disease-free survival rate for all patients increased from 84.7% to 86.6% (P=0.1) in the post-chemotherapy TAM treatment compared with the OFS+TAM group. This result led to the discussion of several questions as follows.
[Hot question 3] Which patients need combination OFS treatment?
In the SOFT study, the benefit of OFS treatment in the age <35 years subgroup was very clear: the 5-year breast cancer recurrence-free rate was 78.9% in the OFS+TAM group and 67.7% in the TAM group, with an absolute benefit of 11.2%; and age was an important factor influencing the choice of OFS treatment. The results of the previous INT0101 study showed that chemotherapy combined with OFS + TAM (5 years) in the age <40 years group improved tumor-free survival (72% versus 54%) compared with chemotherapy alone in patients with lymph node positive HR(+) breast cancer [11].The results of a 2007 Meta-analysis showed that age was an important factor influencing the selection of luteinizing hormone-releasing hormone analogs ( luteinizing hormone-releasing hormone a (LHRHa); the combination of LHRHa with chemotherapy and/or TAM reduced the risk of recurrence by 25.2% and the risk of recurrent death by 28.3% in the age <40 years subgroup, whereas this benefit was only 3.9% and 7.5% in the age >40 years subgroup; further stratified analysis of age found that the <35 years group had the greatest benefit (HR=0.66), followed by the 35-39 years group (HR=0.77), and >40 years had no significant benefit [12].
Also, the results of studies such as INT0101 and SOFT showed that high-risk patients can benefit from OFS treatment, which seems to suggest the role of risk factors such as positive lymph nodes in the choice of OFS treatment. However, in clinical practice, for some patients who are close to perimenopause, have a low risk of recurrence, and are still premenopausal after adjuvant chemotherapy, but may be expected to enter menopause after 2-3 years of treatment, their adjuvant endocrine therapy can be selected as TAM therapy first, and the subsequent 5-year AI therapy may be more reasonable after menopause.
The physiological function of normal female ovaries is most closely related to age, and age should be the primary consideration when considering whether a breast cancer patient needs to undergo OFS treatment.
【Hot question 4】OFS treatment combined with TAM or AI?
Combined analysis of the results of the TEXT and SOFT studies showed that OFS+AI (exemestane) significantly improved disease-free survival, time to breast cancer recurrence and time to distant recurrence compared to OFS+TAM; subgroup analysis showed that patients with high-risk factors such as positive lymph nodes and maximum tumor diameter >2 cm (by chemotherapy subgroup), OFS+AI was more effective than OFS+TAM (5 years) in terms of no The absolute benefit in time to breast cancer recurrence was 5.5% and 3.9% in the two studies, respectively; while the difference in absolute benefit between OFS+TAM and OFS+AI groups was smaller in patients with lower risk clinicopathological characteristics (no chemotherapy subgroup) [13]. In a similar clinical study, the ABCSG-12 study, which selected patients with lower-risk breast cancer (median age 45 years, 75% of patients with stage T1, 66% of patients with negative lymph nodes, and 75% of G1/2) with a median follow-up of 62 months, OFS+TAM had similar disease-free and overall survival rates (HR 1.08 and 1.75, respectively) to OFS+AI (anastrozole). The latter may be worse [14]. It is evident that high-risk patients are more able to benefit from OFS combined with AI therapy, while low-risk patients benefit less. In the 2015 St. Gallen consensus, most experts supported the inclusion of ≥4 lymph node involvement, age <35 years, grade 3, and poor results of polygenic testing as influencing factors for selecting OFS combined with AI therapy, but polygenic testing is not widely available in China [15].
We advocate a comprehensive assessment of risk factors for recurrence in premenopausal patients at the postoperative stage, and then a comprehensive consideration of chemotherapy and endocrine therapy options. If there are positive lymph nodes, grade 3, etc., adjuvant chemotherapy is followed by OFS combined with AI therapy.
[Hot question 5] Is it necessary to monitor hormone levels in pharmacological OFS treatment?
For young, planned OFS combined with AI or TAM treatment as described earlier in this article, chemotherapy-induced changes in menstrual status may occur if pharmacologic OFS treatment is administered, and cause barriers to the selection of subsequent endocrine treatment options. In the SOFT study, it was required that patients enrolled in the study who were scheduled for chemotherapy be confirmed to reach premenopausal levels by estradiol levels within 8 months after chemotherapy before they could be enrolled for randomization, however, this could not be followed in clinical practice. Our recommendation is that patients should be determined to be menopausal before chemotherapy is initiated and an endocrine regimen should be selected; for patients requiring pharmacologic OFS therapy, monitoring of hormone levels during pharmacologic OFS therapy is not required.
This is because: (1) for this group of young patients suitable for OFS treatment, most of the effects of chemotherapy on menstruation are reversible, and most patients can resume menstruation 4-6 months after stopping chemotherapy. If repeated testing of hormone levels is performed after chemotherapy to determine whether they are in premenopausal status and thus decide whether to proceed with OFS treatment is both unreliable and delays subsequent treatment, therefore, before the start of chemotherapy It is therefore more reasonable to determine the patient’s menstrual status before the start of chemotherapy. (2) For patients requiring OFS treatment, the TEXT study used an approach that simply waited for the onset of OFS treatment without repeatedly testing hormone levels, i.e., pharmacologic OFS treatment with LHRHa, which suppresses estrogen to postmenopausal levels in 2 to 3 weeks [16]. (3) Estrogen levels fluctuate with the natural physiological cycle, and the combination of other endocrine drugs on top of OFS treatment can also affect estrogen levels, and the test results of hormone levels cannot directly represent the patient’s menopausal status. Therefore, it is not recommended to routinely monitor sex hormone levels during clinical use of LHRHa.
【Hot question 6】Which patients receiving TAM therapy need to monitor endometrial thickness?
TAM has partial estrogen receptor activation and can affect the endometrium, with possible pathological changes including endometrial polypoid hyperplasia, endometrial polyps, endometrial atypical hyperplasia, and endometrial cancer [17]. patients with long TAM use, postmenopause, and irregular vaginal bleeding are at increased risk of endometrial lesions, and the above 3 aspects need to be referred to during TAM treatment to develop monitoring principles [18].
Gynecologic examination, including ultrasound to check endometrial thickness, should be performed before the start of endocrine therapy, except for pre-treatment lesions. Gynecologic examinations should be performed at least every 12 months during TAM treatment if the uterus is still preserved. The American Congress of Obstetricians and Gynecologists recommends that gynecologic surveillance be increased for postmenopausal patients treated with TAM, especially when symptoms associated with irregular vaginal bleeding occur; endometrial biopsy is recommended if endometrial thickening (thickness >8 mm) is detected, and hysteroscopic biopsy can improve the accuracy of sampling; when endometrial thickness is 5-8 mm, a comprehensive analysis should be performed in conjunction with other risk factors to determine whether to perform endometrial biopsy [19].
As for premenopausal patients, there are normal physiological changes in endometrial thickness during normal menstrual cycles, and patients with amenorrhea during chemotherapy may experience endometrial thickening after chemotherapy due to the imminent resumption of menstruation, and measurement of endometrial thickness is not helpful in determining the patient’s menstrual status. Therefore, for patients who are not menopausal after chemotherapy, there is no need to increase the frequency of monitoring if there are no other high-risk factors. In clinical practice, some physicians recommend endometrial thickness monitoring to young patients with normal or temporary amenorrhea after chemotherapy, resulting in confusion between physicians and patients and unnecessary gynecological operations such as diagnostic scraping. We suggest following and strictly grasping the above indications to avoid excessive examination and invasive operations.
Adjuvant endocrine therapy for postmenopausal HR(+) breast cancer
(I) Initial endocrine therapy
【Hot question 7】How to choose the initial endocrine therapy for postmenopausal patients with HR(+) breast cancer?
After the introduction of the 3rd generation AI, it has been gradually applied to the adjuvant treatment of postmenopausal breast cancer patients.The results of the ATAC study showed that after 10 years of follow-up, 5-year AI treatment significantly improved disease-free survival and reduced the risk of recurrence compared with 5-year TAM treatment, establishing AI as the standard regimen for the adjuvant treatment of early postmenopausal breast cancer patients [20].In 2015, the EBCTCG conducted a study of 30,000 patients who received 5-year TAM treatment in previous studies. Meta-analysis of 30,000 patients treated with 5 years of TAM or AI confirmed that a 5-year treatment regimen containing AI was superior to a 5-year TAM regimen alone [21].The results of the BIG1-98 study, in addition to validating these results, showed no significant difference in efficacy between TAM and AI switching regimens over 5 years of adjuvant treatment compared to 5 years of AI treatment [22].
Although further analysis of patients in different risk strata in this study showed that the 5-year disease-free survival rates in the letrozole group, letrozole-for-TAM group, TAM-for-letrozole group, and TAM group in high-risk patients were 80%, 76%, 74%, and 69%, respectively, with the letrozole group having a greater advantage in terms of efficacy; however, given the superior efficacy of 5-year AI treatment over 5-year TAM treatment, neither switching regimen However, given the superior efficacy of 5-year AI therapy over 5-year TAM therapy, neither of the two switching regimens further improved the overall efficacy of 5-year AI therapy, and the switching regimen was more appropriate for patients who could not tolerate the original regimen.
Therefore, for tolerated postmenopausal patients with HR(+) breast cancer, 5-year AI therapy is an appropriate initial option. And theoretically, patients who can benefit from initial TAM therapy are a sensitive group for endocrine therapy and are more likely to benefit from subsequent intensive endocrine therapy. Based on the results related to TAM switching to AI therapy in the BIG1-98 and TEAM studies, and the results related to intensive endocrine therapy reducing the risk of breast cancer recurrence in studies such as MA17, patients who were initially treated with TAM after menopause can all switch to 5-year AI therapy during the treatment period.
(B) Postmenopausal, HR(+) breast cancer patients who have completed 5 years of AI therapy
【Hot question 8】Postmenopausal patients with HR(+) who have completed 5 years of AI therapy: continue with AI, switch to TAM, or stop?
HR(+) patients are at risk of recurrence up to 15 years after diagnosis. Results have been shown to reduce the risk of delayed relapse more with 10 years of TAM therapy compared to 5 years of TAM therapy and 5 years of TAM therapy followed by 5 years of AI therapy compared to 5 years of TAM therapy; therefore, for patients at high risk of relapse, extended therapy with 5 years of AI therapy may provide greater benefit. In the 2015 St. Gallen Consensus, panelists recommended that TAM therapy or AI therapy (for 3 to 5 years) can be continued or discontinued for patients who have received 5 years of AI therapy when choosing an option to extend endocrine therapy.
No study results have been reported regarding the effectiveness and regimen of follow-up endocrine therapy for patients who have received 5 years of AI therapy. Although several studies of AI extension therapy are ongoing, it is difficult to provide relevant results comparing the efficacy of 5-year AI therapy and 5-year AI therapy with subsequent TAM therapy, due to study design limitations. Therefore, based on the currently available evidence that (1) patients can tolerate the 5-year endocrine therapy they have received as endocrine-dependent patients; (2) overall, the efficacy of 10-year endocrine therapy is better than 5-year for screened patients; and (3) the regimen of 5-year TAM therapy followed by 5-year AI therapy is superior to 5-year TAM therapy alone; we believe that for postmenopausal, postmenopausal patients who have completed 5-year AI therapy HR(+) patients can be considered to switch to 5-year TAM therapy.
(iii) If patients do not tolerate AI or TAM therapy, they should consider switching to another class of drugs
Adverse effects of TAM include facial flushing, vaginal bleeding, vaginal drainage, and, less frequently, more serious adverse effects including venous thrombosis, endometrial cancer, and ocular toxicity. Prolonged duration of endocrine therapy is a risk factor for increased risk of pulmonary embolism and endometrial cancer.
Adverse effects of AI are usually manifested as hypertension, dyslipidemia, joint pain, osteoporosis, and gynecological symptoms and facial flushing are less common than TAM. meta-analysis showed that the incidence of endometrial cancer was low in the AI-treated group (0.4% in the AI group and 0.2% in the TAM group), but the incidence of fracture was high (8.2% in the AI group and 5.5% in the TAM group).
Although ocular lesions in endocrine therapy are rare, they should be taken seriously. However, there are small studies of increased retinal hemorrhage with AI, which may be related to vascular lesions caused by decreased estrogen levels.
During the use of AI and TAM, patients should be properly instructed to cope with adverse drug reactions and monitored for the occurrence of serious adverse reactions. If patients cannot tolerate them, they can consider stopping the drug for a short period of time (2-4 weeks) to determine whether the reactions are drug-related, and then consider replacing them with another class of drugs, i.e., TAM with AI or AI with TAM.
III. Endocrine therapy for advanced breast cancer
HR(+), human epidermal growth factor receptor
2, HER2)-negative advanced breast cancer with lesions confined to the breast, bone, soft tissue or asymptomatic patients with visceral metastases with little tumor load are given priority for endocrine therapy.
(I) Endocrine therapy for premenopausal, HR(+) advanced breast cancer: After OFS treatment or ovarian debulking, follow the endocrine therapy protocol for postmenopausal advanced breast cancer. 1896, Beatson first reported ovariectomy for premenopausal metastatic breast cancer. Subsequently, it was demonstrated that single-agent LHRHa had similar overall survival to ovariectomy and could be used as an alternative to ovariectomy for advanced premenopausal breast cancer. Pharmacologic OFS therapy for premenopausal, HR(+) advanced breast cancer has an objective remission rate of approximately 30%. The results of a Meta-analysis for LHRHa for advanced breast cancer showed that a treatment regimen of LHRHa combined with TAM could be considered for patients with advanced breast cancer suitable for endocrine therapy, which significantly prolonged overall survival (22% reduction in risk of death) and progression-free survival [23]. With the advancement of standard treatment for breast cancer, the majority of patients with early premenopausal breast cancer receive postoperative TAM adjuvant endocrine therapy, and the results of corresponding studies have also confirmed the effectiveness of OFS+AI as first-line treatment for advanced premenopausal breast cancer, which can improve the rate of disease remission, disease control, and median time to disease progression of 8 months.
(B) Endocrine therapy for postmenopausal, HR(+) advanced breast cancer
[Hot Question 9] What is the first choice of endocrine therapy for recurrent metastatic breast cancer that fails after TAM treatment?
TAM used to be the first-line treatment drug for advanced endocrine therapy for breast cancer patients. The results of the North American trial of 3rd generation AI anastrozole, TARGET trial, confirmed that anastrozole extended the time to disease progression from 6 months to 10.7 months compared to TAM in first-line endocrine therapy for advanced breast cancer. Subsequent clinical trials of letrozole and exemestane in first-line endocrine therapy for advanced breast cancer have also confirmed their superiority over TAM in terms of time to disease progression and objective remission rates. The status of 3rd generation AI in the first-line endocrine therapy for postmenopausal patients with HR(+) advanced breast cancer is thus established.
Therefore, AI is the first choice for advanced first-line endocrine therapy in patients who have relapsed after TAM treatment. In addition, the results of a study confirmed that the efficacy of fulvestrant 250 mg in patients who failed anti-estrogen therapy was similar to that of AI: the results of the CONFIRM study confirmed that fulvestrant 500 mg was more effective than 250 mg in postmenopausal, HR(+) breast cancer patients who had received endocrine therapy (TAM or AI therapy), and the results of a phase II clinical trial (FIRST study) showed that fulvestrant 500 mg was more effective than 250 mg in postmenopausal, HR(+) breast cancer patients who had received endocrine therapy (TAM or AI therapy). The results of the phase II clinical trial (FIRST study) showed that fulvestrant 500 mg was more effective than AI and may be an alternative to TAM in the future after failure.
Hot issue 10] What are the treatment options for endocrine therapy in the “post-AI era”?
As mentioned above, AI has become the standard treatment for postmenopausal adjuvant endocrine therapy, and endocrine therapy for breast cancer has obviously entered the “post-AI era”. According to the available research results, patients with advanced breast cancer who have failed AI therapy can choose the following endocrine therapy options.
1. Option 1.
In terms of drug mechanism of action, fulvestrant can be an option for patients who have failed AI therapy, and both the global clinical CONFIRM study and the China CONFIRM study completed by Chinese researchers included patients who used AI in adjuvant therapy. In addition to reaffirming the superior efficacy of fulvestrant 500 mg compared to 250 mg, more meaningfully, in the AI-treated subgroup, the fulvestrant 500 mg group was more effective than the 250 mg group.
mg group (5.8 months versus 2.9 months, HR=0.65), confirming the clinical advantage of fulvestrant 500 mg for patients who failed AI therapy.
2. regimen II.
Exemestane in combination with everolimus. The results of the phase III clinical study BOLERO-2 confirmed that the use of exemestane combined with everolimus after failure of nonsteroidal AI therapy significantly improved the progression-free survival time of patients [24].
3, Option 3.
Endocrine therapy combined with CDK4/6 inhibitors. For patients who progress after receiving endocrine therapy (AI or TAM), including those who are on adjuvant therapy or progress within 12 months after adjuvant therapy, or who progress during endocrine therapy for advanced breast cancer, endocrine agents combined with targeted agents may be a new treatment option. 10% and 14% of patients in the two cohorts enrolled in the PALOMA1 study, respectively, received overtriazole during adjuvant therapy without systemic therapy for advanced disease; the results showed that letrozole combined with the CDK4/6 inhibitor palbociclib was significantly more effective than letrozole alone, significantly prolonging progression-free survival, leading to the approval of palbociclib as a pivotal study [25]. results of the PALOMA3 study showed that palbociclib combined with fulvestrant improved progression-free survival time compared with fulvestrant alone (9.2 months versus 3.8 months, HR=0.422), which was well tolerated, confirming that palbociclib combined with fulvestrant is an effective treatment option for breast cancer progression after endocrine therapy [26].
4. option IV.
Other endocrine agents. When AI becomes the standard of care for adjuvant endocrine therapy after postmenopausal breast cancer, TAM or progestin (methylhydroxyprogesterone or megestrol) is also an option for endocrine therapy after recurrent metastasis. Although there are no relevant clinical randomized controlled studies, in clinical practice, we have to think in terms of big data while accepting more and more new evidence-based medical data, reviewing the results of studies completed in different time periods, and choosing treatment options rationally by combining patients’ conditions and health insurance.
In conclusion, endocrine therapy for patients with advanced breast cancer should consider the type of drugs used in the patient’s previous endocrine therapy, the duration of treatment, and the interval to recurrence, comprehensively assess the patient’s sensitivity to endocrine therapy, weigh the efficacy against the adverse effects of the drugs, and reasonably make drug selection with a view to controlling tumor progression, relieving symptoms, and prolonging survival.