The incidence of breast cancer continues to rise, and the combination of current surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular targeted therapy can still only cure about 50% of patients, and those 50% of patients with recurrence and metastasis will undoubtedly enter the incurable stage of advanced rescue treatment. In order to achieve the treatment goal of prolonging survival and improving quality of life, not only do clinicians need to have comprehensive techniques of breast cancer treatment, but also need the flexible art of clinicians. From our experience of treating nearly 5000 cases of advanced breast cancer in the Department of Breast Cancer Medicine, we would like to discuss our experience of treating advanced breast cancer in our unit in combination with the current NCCN guideline recommendations for the treatment of advanced breast cancer.
I. Comprehensive evaluation of recurrent metastatic breast cancer
As soon as possible, we should clarify whether the patient really has recurrent metastasis of breast cancer, and if there is recurrent metastasis, then the extent of recurrent metastasis should be the most important starting point for formulating treatment strategy and implementing relief treatment. This is like marching to war, when you do not know how many troops the enemy has, how the troops are distributed, and what the strength of the troops is, it is impossible and impossible to make a correct battle plan.
1.Scope definition of recurrent metastatic breast cancer
Usually multi-site ultrasound, chest X-ray or CT, whole-body bone scan and necessary head CT or MRI should be indispensable imaging examinations. With the more widespread use of PET/CT, it can be recommended if economic conditions allow, which is also a clear indication for PET/CT in Europe and the United States. The sensitivity and specificity of this technique for the diagnosis of recurrent breast cancer metastasis are higher than 90%.
It can be used as a screening test for recurrent metastases at an early stage, and it can also avoid the duplication of costs for multi-site ultrasound, CT, MRI, and bone scan.
Special emphasis should be placed here on the confirmation of bone metastasis diagnosis.
1. Almost all bone metastases of breast cancer are osteolytic bone metastases. Among 354 cases of bone metastases from breast cancer summarized by our department, 353 cases were osteolytic and 1 case was mixed type, and the possibility of osteogenic repair after osteolytic treatment cannot be excluded;
2. The previous effective treatment has often transformed osteolytic metastases into mixed type or osteogenic images;
3. For the diagnosis of bone metastases with only 1 or 2 osteogenic or mixed bone abnormalities throughout the body and abnormal bone scan or MRI or CT bone imaging, caution must be exercised. Because, bone trauma, bone proliferation or degenerative degeneration can show similar images. This is when necessary bone tissue aspiration biopsy should become recommended. This is already routine at MD Aderson Cancer Center in the United States.
In addition, the correlation between abnormally elevated breast cancer tumor biomarkers and tumor recurrence and metastasis is a concern for both doctors and patients. Comprehensive data show that the correlation between elevated breast cancer tumor biomarker CA153 and breast cancer recurrence and metastasis is about 70%, and our clinical practice also shows that elevated breast cancer tumor cell biologic CA153 can predict recurrence and metastasis in some breast cancer patients. The current academic consensus is that the persistent elevation of breast cancer tumor biomarker CA153 suggests that further confirmatory examination of tumor recurrence and metastasis should be performed, but it is not used as evidence to change the current treatment.
2.Pathological confirmation of recurrent metastatic breast cancer
After adequate tumor imaging examination and clarification of the metastatic range of the tumor, pathological puncture biopsy of the suspected site is usually necessary. This takes into account several factors: (1) identification of repeat cancer; (2) the most authoritative evidence of metastatic events; and (3) the need to clarify ER/PR status and Her-2 status for either endocrine therapy or molecular targeted therapy.
The transformation of ER/PR status and Her-2 status during treatment has been demonstrated by numerous studies. The issue of needle tract metastasis from puncture is often a concern for physicians and patients. Analysis suggests that for punctures without metastases, punctures leading to metastases would not have existed, and for punctures at true metastatic sites, there is indeed a risk of needle tract metastasis, but it has little impact on the reality that the patient has metastasized, and treatment after a clear diagnosis can further reduce this risk, and the many tumor information provided by puncture pathology is often decisive for the patient’s subsequent treatment.
II. Treatment strategies for advanced recurrent metastatic breast cancer
After the comprehensive diagnosis of the extent of breast cancer metastasis, pathological confirmation of metastatic site, and the collection of tumor cell biomarkers ER/PR and Her-2, how to design the strategy of rescue treatment plan and how to execute the developed strategy are the urgent problems faced by clinicians.
1.Treatment ideas for recurrent metastatic breast cancer
To formulate a treatment strategy for advanced recurrent metastatic breast cancer, we must always keep in mind the objective reality that “breast cancer is a systemic disease and breast cancer cells have been disseminated throughout the body of patients with recurrent metastasis”. Only when we are clear about the current situation of systemic breast cancer dissemination and metastasis, can our clinicians properly deal with the relationship between systemic and local treatment, and use systemic chemotherapy, endocrine therapy, molecular targeted therapy, surgery, radiotherapy and interventional therapy.
First of all, we would like to remind you that there is a group of patients who have a chance to be cured despite the so-called “recurrence and metastasis”, because strictly speaking, this group of patients should belong to the “local or regional recurrence”, specifically including post-breast-conserving surgery In this group of patients, there were intra-mammary recurrence, recurrence of lymph node metastasis in the axillary area, recurrence of lymph node metastasis in the supraclavicular area, and even local recurrence of metastasis in the chest wall, intercostal area, and ribs in some patients.
We believe that the recurrent metastases in this group of patients are still limited to the regional lymph node metastases of the primary tumor, and the severity of the disease does not significantly exceed that of the initial diagnosis, so systemic treatment should be the primary treatment for this group of patients, and through comprehensive treatment again, it is entirely possible to obtain a cure, which is essentially different from systemic bone and visceral multiple metastases. We have many such patients who have again achieved long-term survival and even ultimate cure.
Therefore, when breast cancer patients have recurrent metastases and have completed comprehensive imaging, histopathology, tumor biomarkers and other examinations, we should synthesize the degree of recurrent metastases of each patient, and for those patients who may have the possibility of being cured again, we should be more aggressive in the design of retreatment plan, treatment intensity, treatment time frame and other plans;
For patients with extensive visceral metastasis, especially extensive brain and liver metastasis, we must implement mostly single-drug sequential and toxic tolerable drug therapy under the premise of maintaining a better quality of life, in order to prolong patients’ survival and maintain a high quality of survival as much as possible, and avoid overtreatment.
2.Treatment implementation of recurrent metastatic breast cancer
Systemic relief treatment means include several treatment means of chemotherapy, endocrine therapy and molecular targeted therapy. We have been insisting on the clinical practice of advanced breast cancer that “relief treatment follows its own efficacy”. The objective existence of tumor lesions provides us with the conditions to accurately evaluate the efficacy of each treatment option.
In the design of treatment regimens for initiating systemic therapy, we follow the principle of “preferring previously unused regimens or previously effective regimens that are not discontinued by tumor progression factors, secondly choosing previously used regimens with unevaluated efficacy, and excluding previously ineffective regimens.” . For example, for patients with recurrent metastases after previous anthracycline adjuvant therapy, paclitaxel, norviben and even Kinzel, Siroda, three third-generation aromatase inhibitors, and Herceptin for Her-2 positivity can be used as the first choice, and all of them can be used as the so-called first-line therapy, with one or more of them The other drugs are naturally relegated to the second, third, fourth, and fifth lines of treatment.
Because not one drug is 100% effective, a clinical remission rate of 20-50% is possible for each patient with three outcomes: effective, stable, and progressive. It does not matter which drug is chosen at the beginning, because the patient will have to use almost all of these drugs during the long course of relief therapy. What is important is that if a drug is chosen, it must be used well, with adequate dosage, adequate time frame for treatment, and scientific, timely and accurate evaluation of efficacy and side effects. Here we should emphasize the understanding of “SD”, many data have shown that SD of breast cancer ≥ 6 months is equivalent to the contribution of CR and PR to patient survival.
However, in the clinical process, we often face patients’ dissatisfaction with “SD”. In addition to detailed explanation, first of all, we clinicians should correct the perception of “SD”. Following the above clinical thinking, “effective prescriptions should not be changed, ineffective prescriptions should be changed” should be our guiding principle in formulating and changing protocols. We believe that there are only the following three cases to consider changing the treatment plan. First, tumor progression; second, intolerable drug toxicity, including those who have reached the maximum tolerated dose of anthracycline-containing chemotherapy regimen; and third, economic unsustainability. Otherwise, any change in treatment regimen is questionable.
The 2008 edition of the NCCN guidelines has given the basic idea of treatment for advanced recurrent metastatic breast cancer. Specifically, systemic chemotherapy is currently used for patients with ER/PR-negative, progressive visceral metastases and endocrine therapy-resistant recurrent metastases; endocrine therapy is used for patients with ER/PR-positive, asymptomatic visceral metastases, bone or soft tissue or lymph node recurrent metastases, even for patients with ER/PR-negative or endocrine therapy-resistant recurrent metastases, and may be considered for participation in endocrine therapy trials. The molecularly targeted drugs Herceptin and Lapatinib are mainly used for patients with Her-2 positive disease. Obviously the above NCCN guideline recommendations are still line type, only a basic outline, the actual clinical practice to be far more relapsed. For example, is the relief chemotherapy regimen a combination or sequential single agent? How to reasonably switch between endocrine therapy and chemotherapy? How to synergize the combination of molecular targeted drugs with chemotherapy and endocrine drugs?
For patients with recurrent metastatic breast cancer with symptomatic progressive visceral metastases, two-drug combination chemotherapy is generally the preferred regimen if the patient is young or in good physical condition. Because, two-drug combination regimens paclitaxel + platinum, norviben + platinum, Kenzyme + platinum, paclitaxel + Kenzyme, paclitaxel + Siroda, norviben + Siroda, etc. have about 50% clinical efficiency and 30% SD, so symptom and tumor control can usually be obtained in most patients.
However, all of these regimens have difficulties in sustaining treatment in the long term, and patients usually fail to adhere to them after completing 4-6 cycles of treatment. Our treatment strategy is to disassemble the above combination drugs into single drug applications again. The disassembled single drug paclitaxel, Noviben, Kenzyme, and Siroda can mostly maintain the efficacy of combination chemotherapy for the maximum possible time. For patients with hormone receptor-negative bone metastases, we also mostly choose the monotherapy strategy of Herodar, Kinzel, and paclitaxel to facilitate long-term dosing and maintenance.
For patients with ER/PR positive, asymptomatic visceral metastases, bone or soft tissue or lymph node recurrent metastatic breast cancer, endocrine therapy is mostly the first-line option. Since most patients in this group have already used tamoxifen, the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are mostly the main choices. In premenopausal patients, removal or suppression of ovarian function is also an issue often discussed by both physicians and patients.
Our opinion is that bilateral ovarian removal should be the basic treatment option for this group of patients if they are not particularly well-off, because the 3-5 endocrine treatment options that patients may experience will all require removal of ovarian function. And since this was first applied by Dr. Beaton in 1893 to treat advanced breast cancer, bilateral ovarian resection debulking has been an important treatment option for patients with hormone receptor-positive advanced breast cancer. In addition, fulvestrant, progestin, estrogen, and testosterone propionate are also optional options for endocrine therapy.
The increasing prominence of molecularly targeted drugs in the treatment of advanced breast cancer and the nearly doubled pathological complete remission rate of Herceptin in combination with chemotherapy versus chemotherapy alone tell us that the era of molecularly targeted drugs for the relief treatment of breast cancer has arrived. The findings that bevacizumab Avastin in combination with paclitaxel is significantly better than chemotherapy alone also show us the importance of Avastin in the treatment of advanced breast cancer. Our combined application of Herceptin, Lapatinib, Avastin and chemotherapy has also yielded a number of wonderful therapeutic results in the clinic so far.
Regarding the switch between chemotherapy, endocrine therapy and molecular targeted drug therapy, our experience is that when patients’ bone marrow reserve and physical condition are reduced due to long-term chemotherapy, and the tumor is basically stable or controlled, switching to endocrine therapy with mild toxicity and “silent” can continue to effectively control the tumor while providing patients with rest and recuperation. At the same time, it can give the patient a chance to recuperate and provide the necessary physical and mental reserve for the possible reintroduction of systemic chemotherapy.
We often compare the switching of chemotherapy and endocrine therapy to the left and right hands carrying a heavy load, with the left hand being replaced by the right hand when the left hand is tired and the right hand by the left hand when the right hand is tired, so as to guard the long-term survival of patients. At present, the synergistic or sequential application of chemotherapy and molecular targeted drugs is also gradually practiced in the clinic, but molecular targeted drugs are mostly used as a basic drug, and the synergistic application of chemotherapy and molecular targeted drugs should be the standard treatment choice.
III. Local treatment of recurrent metastatic breast cancer
For patients with recurrent metastatic breast cancer, there is no doubt that systemic drug therapy is the main treatment option, then how to apply local surgery, radiotherapy and interventional therapy is also a concern for both doctors and patients. We believe that for recurrent metastatic breast cancer patients, although systemic drug therapy is very important, timely intervention of local therapeutic means is never excluded.
1. Is it reasonable to perform surgical resection or radiotherapy first when local recurrent metastases appear in the surgical area, chest wall or supraclavicular area? For recurrent metastasis in local area, we think it is not reasonable to choose local tumor resection or radiotherapy first.
We must take into account the potential systemic spread of metastasis of breast cancer and use the tumor lesion as the evaluation index of the effect of rescue treatment, so as to choose an effective systemic rescue treatment plan by using this tumor index to kill the potential systemic spread of tumor cells and reduce the risk of metastasis to other organs as much as possible. When the systemic rescue treatment is sufficient, that is, the local recurrent metastatic lesions are completely controlled or the maximum control effect of systemic tumor is obtained, then surgery or radiotherapy will be chosen to remove the local residual lesions. If the local tumor is removed by surgery or radiotherapy first, the opportunity to choose an effective systemic relief treatment plan is lost, and the subsequent consolidation treatment becomes a so-called “blind” treatment without evaluating the lesions.
2.What are the conditions of local treatment such as surgery, radiotherapy and interventional therapy? Surgery, radiotherapy and other local therapies are not only used for supplementary treatment after the systemic treatment is adequate, but also commonly used for the management of some tumor emergencies, such as palliative fixation of pathological fractures, surgical release of acute intestinal obstruction, palliative repair of local tumor ulcers, etc.
Radiotherapy is often used for symptom control of brain metastases, prevention of pathological fracture of bone metastases, control of local pain symptoms, etc. Especially for multiple brain metastases of breast cancer, radiotherapy almost becomes the main treatment choice, but radiotherapy of whole brain DT 40GY can not control breast cancer metastases at all, and tumor progression within six months after radiotherapy is almost inevitable, and stereotactic treatment of local lesions can sometimes control fewer and smaller However, we must admit that the treatment of brain metastases has become the short board of the “barrel effect” in breast cancer treatment.
For interventional treatment, especially for liver metastases of breast cancer, we must realize that 90% of the efficacy of this treatment on liver metastases comes from the low arterial blood supply to the tumor tissue due to hepatic artery embolization, not mainly from the infused chemotherapeutic drugs, therefore, interventional embolization is an important treatment option for liver metastases with poor chemotherapy effect.
IV. Conclusion
For advanced breast cancer with recurrent metastasis, clinical practice combining science and humanity, technology and art should be the realm that our clinicians pursue. In addition to improving our professionalism and enriching our treatment methods, the concept of “great medical practice” may be more precious than any panacea – “Medicine is not just medicine in a bottle! “