Breast cancer is a common malignant tumor in women, with the highest incidence rate in Europe and America. With the gradual improvement of people’s living standard and changes in environment and dietary structure, the incidence of breast cancer in China is on the rise year by year. According to the National Cancer Center and the Bureau of Disease Prevention and Control of the National Health and Family Planning Commission 2013 Annual Report of China Tumor Registry, the incidence rate of breast cancer in urban areas of the national tumor registry was 47.79/100,000 in 2010 and 27.72/100,000 in rural areas.One of the major changes in the cancer spectrum in the 2013 Annual Report of China Tumor Registry compared with 2012 is that the incidence rate of female cancers has increased significantly. Breast cancer ranked the 1st malignant tumor in women.
Endocrine therapy is one of the important tools for the treatment of advanced breast cancer. The major domestic and international guidelines recommend that endocrine therapy is the preferred treatment option for hormone receptor positive metastatic breast cancer unless the disease needs to be controlled rapidly or endocrine therapy is resistant. The current status and development of endocrine therapy in hormone-receptor-positive metastatic breast cancer are summarized here.
I. Milestones in the development of endocrine therapy
The application of tamoxifen in 1977 made the endocrine therapy for breast cancer really come to the clinic. Subsequently, the first generation aromatase inhibitor (AI) amiloride was used in the treatment of breast cancer in postmenopausal women with good efficacy. In the late 1990s, the second-generation AI was gradually replaced by the third-generation aromatase inhibitors (such as the steroidal exemestane and the nonsteroidal anastrozole and letrozole) with better efficacy and selectivity and lower toxic effects. The second-generation AI is gradually replaced by third-generation aromatase inhibitors (such as the steroidal exemestane and the non-steroidal anastrozole) with better efficacy and selectivity and lower toxicity.
The results of intensive clinical studies have shown that tamoxifen, as a selective estrogen receptor (ER) modulator, has estrogen-like effects, and its long-term use may increase the risk of endometrial cancer, etc. There is a need for continuous clinical development of safer drugs. A new drug, fulvestrant, was introduced, which inactivates both transcriptionally active region 1 (AF1) and transcriptionally active region 2 (AF2) on the hormone receptor and accelerates the degradation of ER.
In contrast to triamcinolone, which blocks only AF2, fulvestrant exerts a purely anti-estrogenic effect and has no ER agonistic effect. At the 2014 San Antonio Breast Cancer Conference, the final survival results of a randomized phase II clinical trial of fulvestrant 500 mg and anastrozole in first-line treatment of ER-positive breast cancer were reported, and the median survival time of patients in the fulvestrant group was prolonged by 5.7 months compared with the anastrozole-treated group (P=0.041). If this result is confirmed by the phase III clinical trial, it will fundamentally change the treatment of hormone receptor-positive metastatic breast cancer.
Comparison of endocrine therapy and chemotherapy for hormone receptor-positive metastatic breast cancer
Chemotherapy has definite efficacy in hormone receptor positive metastatic breast cancer, but it is more toxic than endocrine therapy, and its resulting safety problems affect its position in the first-line treatment.
In terms of efficacy, although chemotherapy has a higher remission rate than endocrine therapy, the difference in overall patient survival is not statistically significant. 92 patients with locally recurrent or metastatic breast cancer were randomized into 2 groups and treated with endocrine therapy and cytotoxic agents, respectively. the results showed that cytotoxic agents had a higher remission rate than endocrine therapy, but the duration of remission was comparable and the difference in overall survival was not The difference in overall survival was not statistically significant.
In Taylor et al. study, 181 elderly patients with recurrent or metastatic breast cancer were divided into endocrine therapy and combination chemotherapy groups, and the results showed that the difference in treatment efficacy between endocrine therapy and combination chemotherapy was not statistically significant, while the better safety and quality of life made endocrine therapy the first-line treatment option for elderly patients with stage IV breast cancer. In the ANZBCTG study, similar results were obtained by comparing the remission rates in advanced postmenopausal breast cancer by crossover between endocrine and chemotherapy, as well as the combination of both.
In terms of safety, endocrine therapy is significantly less toxic than chemotherapy, and toxicities can directly affect patient satisfaction with treatment.Taylor et al. raised the issue of greater chemotherapy toxicities in their study, observing that toxicities were more severe in the CMF (cyclophosphamide + methotrexate + fluorouracil) group than in the tamoxifen group; 10% of patients in the CMF group withdrew early because they could not tolerate the toxicities Six patients experienced life-threatening toxicity, while no patients in the initial tamoxifen group experienced serious side effects.
The ANZBCTG study also concluded that endocrine therapy is less toxic and that initial endocrine therapy is a more appropriate treatment option for postmenopausal patients with metastatic breast cancer. A study conducted from the patient’s perspective also showed that in patients with human epidermal growth factor receptor 2 (HER2)-negative hormone receptor-positive metastatic breast cancer, endocrine therapy was associated with better quality of survival and treatment efficacy and lower rates of adverse events compared with chemotherapy.
With the accumulation of clinical evidence, scholars gradually formed a consensus in the early 21st century that endocrine therapy is the treatment of choice for hormone receptor-positive metastatic breast cancer. However, with the emergence of new chemotherapeutic and endocrine agents in the past 20 years, the choice between endocrine and chemotherapy will again be challenging. There are more studies on paclitaxel drugs, especially some derivatives such as doxorubicin or albumin-bound paclitaxel.
The latest phase I and II clinical trials have evaluated the therapeutic efficacy of paclitaxel in combination with other chemotherapeutic agents or bevacizumab, etc. The latest study by Dranitsaris et al. in Chinese patients showed that albumin-bound paclitaxel, a new type of paclitaxel for the treatment of breast cancer, could significantly reduce the toxic side effects of paclitaxel while ensuring therapeutic efficacy.
In the 2013 annual meeting of the Chinese Society of Clinical Oncology (CSCO), a prospective study of advanced breast cancer involving 47 research centers sponsored by CSCO was presented. 200 patients with hormone receptor-positive, HER2-negative breast cancer were enrolled. 200 patients received chemotherapy or endocrine therapy in a 1:1 ratio. The objective remission rate (ORR) was 63% and 22%, the clinical benefit rate (CBR) was 67% and 69%, the time to disease progression (TTP) was 52 weeks and 48 weeks, and the time to treatment failure (TTF) was 20 weeks and 48 weeks in the chemotherapy and endocrine treatment groups, respectively; the ORR of patients in the chemotherapy group was significantly higher than that in the endocrine treatment group (P<0.001), but the CBR and TTP of patients in the chemotherapy and endocrine treatment groups were different. The differences in CBR and TTP of patients were not statistically significant (P=0.333 and P=0.589), and the TTF of patients in the endocrine therapy group was significantly longer than that in the chemotherapy group (P=0.025).
III. New development of endocrine therapy
In recent years, with the improvement of diagnostic level and the deepening of basic medical research, a series of drugs with new mechanisms of action have been applied to the clinic.
HER2 protein is highly expressed in about 10% of breast cancer patients, and clinical guidelines recommend the addition of anti-HER2 therapy (trastuzumab, patuximab, etc.) for HER2-positive advanced breast cancer patients; and for hormone receptor-positive/HER2-positive breast cancer patients can choose the treatment strategy of anti-HER2 combined with endocrine therapy or chemotherapy drugs.
In addition, patients with advanced breast cancer in remission from endocrine therapy will eventually progress with resistance to endocrine therapy. Analysis of the reasons for this may be related to mechanisms such as tumor hypersensitivity to estrogen, ER alteration and activation of ER-related signaling pathways. Currently, a large number of novel therapeutic agents and endocrine therapy are used in combination in clinical trials for endocrine-refractory advanced breast cancer.
A phase II clinical study on Ganitumab, a monoclonal IgG1 antibody to insulin-like growth factor 1 receptor (IGF-1R), showed that Ganitumab in combination with fulvestrant did not provide clinical benefit in patients with hormone receptor-positive advanced breast cancer who failed endocrine therapy. the BOLERO-2 study showed that the mTOR inhibitor everolimus in combination with exemestane significantly improved progression-free survival (PFS) compared with exemestane alone in hormone-receptor-positive/HER2-negative breast cancer patients with disease progression after treatment with nonsteroidal AIs, but had no significant effect on overall survival (OS).
The toxicities of everolimus need to be focused on, and the cost-effectiveness ratio also needs to be considered. In addition, the combination of palbociclib, a cell cycle protein-dependent kinase 4/6 inhibitor, with letrozole significantly improved PFS in patients with progressive hormone receptor-positive/HER2-negative breast cancer in a phase II clinical study, and a phase III clinical study of palbociclib in combination with letrozole for the first-line treatment of metastatic breast cancer is currently underway.
In addition, fulvestrant-based combination therapy is being actively explored, with results from the FERGI study showing that the PI3K kinase inhibitor pictilisib in combination with fulvestrant did not significantly prolong PFS in patients with AI-resistant, postmenopausal ER-positive advanced or metastatic breast cancer. however, results from an exploratory analysis showed that in the ER and progesterone receptor double-positive patient subgroup, pictilisib combined with fulvestrant resulted in a 1-fold prolongation of PFS in patients.
IV. Status of endocrine therapy for hormone receptor-positive metastatic breast cancer
1. Guidelines recommend endocrine therapy as the preferred option.
Both domestic and international guidelines recommend endocrine therapy as the first-line treatment option for patients with hormone receptor-positive advanced breast cancer. in 2014, the American Society of Clinical Oncology (ASCO) guidelines were updated to recommend that for patients with hormone receptor-positive/HER2-negative progressive breast cancer, except for rapidly life-threatening disease or concerns about endocrine therapy resistance, endocrine therapy should be used as their standard first-line treatment, rather not chemotherapy.
In 2014, the European College of Oncology-European Society of Medical Oncology International Consensus on Advanced Breast Cancer, version 2, recommended that for patients with hormone receptor-positive/HER2-negative advanced breast cancer, endocrine therapy should be chosen as first line, even if visceral metastases occur, except for patients with endocrine therapy resistance or those who need rapid onset of action; for patients with hormone receptor-positive/HER2-positive disease, endocrine therapy + anti HER2 therapy or chemotherapy + anti-HER2 therapy, or if anti-HER2 drug therapy is not tolerated, endocrine therapy alone can be used.
The recommendations of our guidelines are consistent with international guidelines, that is, endocrine therapy can be used in the first line for recurrent or metastatic breast cancer with ER-positive and/or progesterone receptor-positive; in addition, endocrine therapy can also be tried in patients with unknown ER and progesterone receptors or negative receptors, if the clinical course of the disease is slow.
For patients with disease progression or recurrence after first-line endocrine therapy, the above guidelines also recommend switching to different therapeutic agents for second-line, third-line or even multi-line endocrine therapy.
2. Current status of the use of endocrine therapy at home and abroad.
In actual treatment, most patients with advanced breast cancer in the United States and Europe have accepted the recommended regimens of ASCO and ESMO guidelines. A survey of hormone receptor-positive/HER2-negative metastatic breast cancer patients in the United States from 2004 to 2010 showed that the vast majority of patients were treated with endocrine therapy as first-line treatment.
A European study retrospectively analyzing the proportion of first-line treatment options for 355 hormone receptor-positive/HER2-negative advanced breast cancers in Belgium, France, Germany, Sweden, and the Netherlands showed that 69% of all newly diagnosed advanced breast cancer patients and advanced breast cancer patients who recurred more than 1 year after adjuvant therapy received first-line endocrine therapy, while chemotherapy was limited to patients who needed rapid symptom control .
The opposite is true for domestic treatment options. In a survey of advanced breast cancer patients in 17 provinces and cities nationwide, Lingbo Jiang et al. showed that 97.7% (589/603) of patients with hormone receptor-positive recurrent metastatic breast cancer received first-line chemotherapy, and only 1% received endocrine therapy, with a rather low proportion of patients receiving standard therapy.
The main reasons for the low proportion of domestic patients receiving first-line endocrine therapy are.
(1) Attending physicians do not fully understand the research progress and indications for endocrine therapy at home and abroad, and a considerable number of scholars still believe that for hormone receptor-positive recurrent metastatic breast cancer, endocrine therapy can only be used for some patients with slow disease progression and no visceral metastases. In fact, except for patients who have failed endocrine therapy and need rapid symptomatic relief, endocrine therapy remains appropriate for those with visceral metastases. Some clinical studies on endocrine therapy have been available even earlier, but these results are not widely known by clinicians.
(2) Clinicians have misconceptions about endocrine therapy, believing that endocrine therapy is too slow to work. In fact, if endocrine therapy is effective, its onset of action is similar to that of chemotherapy, which has been demonstrated in patients with bone metastases from advanced breast cancer.
(3) There are fewer clinical studies for Chinese patients and too little information to refer to, and clinicians will first use the chemotherapy regimen they think they are sure of.
To address the above reasons, a series of approaches should be taken to reverse the status quo of endocrine therapy in China. Firstly, the treatment concept of clinicians should be updated, the continuing education of clinicians should be strengthened, and the indications for endocrine therapy should be clarified.
The indications for endocrine therapy should be clarified. Secondly, more clinical studies should be conducted to compare the efficacy of endocrine therapy and chemotherapy, and to accumulate experience in the use of endocrine therapy in our population, so as to provide reference for clinicians. Again, endocrine therapy drugs should be promoted into hospitals and medical insurance to promote the popularity of endocrine therapy. Finally, patients can be promoted and served with a view to significantly improving their compliance with medication and satisfaction with treatment.
The vast majority of treatments for advanced metastatic breast cancer are palliative in nature, aiming to maintain or improve patients’ quality of life and prolong their survival time. Endocrine therapy, on the other hand, has become the treatment of choice for hormone receptor-positive metastatic breast cancer with the same therapeutic efficacy as chemotherapy and less toxic side effects, but it is relatively little used in China. On the other hand, whether the survival time and quality of life of patients with hormone receptor-positive metastatic breast cancer can be further improved by the combination of endocrine drugs and combined targeted therapy, etc. is a hot spot for future research.