The aim of treatment for patients with recurrent metastatic breast cancer is to relieve symptoms, improve quality of life and prolong patient survival. The strategy to prolong the survival of patients with recurrent metastatic breast cancer is to reasonably select comprehensive treatment, choose the best first-line treatment as well as follow-up treatment, with systemic systemic treatment as the main treatment, combined with reasonable local treatment.
I. Disease assessment of recurrent metastatic breast cancer
First of all, patients with metastatic or recurrent breast cancer should be systematically evaluated to clarify the extent of the lesion. The assessment examination includes detailed history, comprehensive physical examination, blood and platelet counts, liver and kidney function tests, chest X-ray, bone scan and radiological examination of long or weight-bearing bones with pain or abnormal bone scan, abdominal CT or MRI scan can be considered. If possible, a biopsy of the recurrent lesion may be performed and the hormone receptor status (ER and PR) and HER-2 status may be determined again. PET or PET/CT scans provide a better understanding of the extent of systemic lesions. The panel does not routinely recommend the routine use of PET or PET/CT scans in the evaluation of patients with recurrence, but they should be considered when the results of other methods are ambiguous or clinically questionable. After systematic evaluation of the patient, it should be clarified whether it is simply a local recurrence or a systemic metastasis in order to adopt the appropriate treatment principles.
II. Rational adoption of local treatment
When appropriate, it is very important to choose reasonable local treatment for advanced breast cancer patients, as such local treatment can often rapidly relieve patients’ symptoms and improve their quality of life significantly.
For the presence of brain metastasis, soft meningeal metastasis, choroidal metastasis, pleural effusion, pericardial effusion, biliary tract obstruction, urinary tract obstruction, imminent pathological fracture, pathological fracture and spinal cord compression, local treatment should be preferred, including radiotherapy and effusion drainage, in order to control the disease and relieve symptoms. For patients with limited, painful bone metastases or soft tissue metastases and chest wall metastases, local treatment can also be considered.
III. Principles of drug use for categorical treatment
Patients with recurrent or metastatic breast cancer after systematic evaluation should be given bisphosphonates first if they are systemic lesions with clear bone metastases. For systemic drug therapy, a categorical treatment strategy should be adopted according to tumor hormone receptor and HER-2 status. Endocrine therapy is preferred if hormone receptor (ER and/or PR) positive, slow disease progression, no visceral metastases or asymptomatic visceral metastases. trastuzumab in combination with chemotherapy is preferred for HER-2-positive recurrent metastatic breast cancer. For other patients, such as hormone receptor negative, symptomatic visceral metastasis, or hormone receptor positive but ineffective to endocrine therapy treatment, chemotherapy-based combination therapy or chemotherapy alone should be considered first.
IV. Endocrine therapy
Patients with advanced breast cancer with systemic disease and positive hormone receptors (ER and/or PR), even if they have visceral metastasis, can be preferred to endocrine therapy if they are asymptomatic. patients with ER and PR negative status can also be selected for endocrine therapy under certain special circumstances, especially for patients with soft tissue metastasis and/or metastasis to bone. In addition, ER and PR status may be falsely negative in clinical practice, and in some patients the hormone receptor profile of the primary site may be different from that of the metastases. Therefore, a trial of endocrine therapy under strict efficacy evaluation and disease monitoring may be considered for patients with recurrent metastases with ER and PR negativity and only bone metastases or soft tissue metastases.
In postmenopausal patients who have received anti-estrogen therapy, aromatase inhibitors are the first-line treatment of choice for recurrent breast cancer. In premenopausal patients who have not received anti-estrogen therapy, initial treatment can be anti-estrogen monotherapy or effective ovarian suppression followed by aromatase inhibitors, which can be followed by surgical resection or luteinizing hormone-releasing hormone (LHRH) antagonists. The preferred second-line treatment option for patients who have failed premenopausal anti-estrogen therapy is ovarian function suppression combined with an aromatase inhibitor.
Endocrine therapy options for recurrent metastatic breast cancer include aromatase inhibitors (anastrozole, letrozole and exemestane), anti-estrogenic agents (tamoxifen, toremifene and fulvestrant) and progestational agents (megestrol acetate and methotrexate).
The principles of endocrine drug selection are mainly followed
1. No repeated use of drugs that have failed in the adjuvant phase of treatment;
2.Postmenopausal patients who have failed tamoxifen therapy should be treated with aromatase inhibitors;
3.For premenopausal breast cancer patients, the principle of endocrine therapy for postmenopausal patients can be followed on the basis of surgical resection or effective suppression of ovarian function treatment;
4.If aromatase inhibitors fail, progestin therapy or fulvestrant can be chosen;
5, non-steroidal aromatase inhibitors (anastrozole or letrozole) treatment failure can choose steroidal aromatase inhibitors (exemestane), progestin or fulvestrant; steroidal aromatase inhibitors treatment failure can choose non-steroidal aromatase inhibitors, progestin or fulvestrant.
6. Those who have not received anti-estrogen therapy before can still choose tamoxifen or toremifene.
The anti-estrogen drug fulvestrant is one of the drugs of choice for patients with hormone receptor-positive, anti-estrogen or aromatase inhibitor-treated metastatic breast cancer that has progressed again. For patients with disease progression on prior tamoxifen therapy, fulvestrant is similar in efficacy to anastrozole, but remission lasts longer. In postmenopausal breast cancer patients with disease progression after aromatase inhibitors, a phase II study of fulvestrant showed a partial remission rate of 14.3%, with an additional 20.8% of patients achieving at least 6 months of stable disease. In receptor-positive postmenopausal patients with disease progression on prior nonsteroidal aromatase inhibition therapy, the clinical benefit rates for exemestane and fulvestrant were comparable (32.2%
vs 31.5%, P = 0.853).
V. Chemotherapy
Patients who are hormone receptor negative and whose metastases are not limited to bone or soft tissue, or who have symptomatic visceral metastases, or who are hormone receptor positive but have failed endocrine therapy, should be treated with chemotherapy-based combination or monotherapy.
Combination chemotherapy usually has better objective remission rates and time to progression compared to single agent chemotherapy. However, the toxicity of combination chemotherapy is higher and the overall survival benefit is not significantly different from that of sequential single-agent therapy. In addition, sequential use of single agents reduces the likelihood that patients will require dose reductions. Therefore, the panel found little strong evidence to support the superiority of combination chemotherapy over single-agent sequential chemotherapy. First-line regimens were chosen in clinical studies until disease progression. However, it is possible that side effects may lead to dose reduction or discontinuation of chemotherapy drugs before disease progression. Limited data suggest that continuous chemotherapy prolongs progression-free survival relative to short-term chemotherapy. Due to the lack of differences in overall survival, the adverse effects of continued chemotherapy on overall quality of life need to be weighed against whether long-term or short-term chemotherapy should be used.
Guideline recommendations for chemotherapy include single-agent sequential chemotherapy or combination chemotherapy. The recommended drugs include.
1. Anthracyclines – doxorubicin, epirubicin, and polyethylene glycolated liposomal doxorubicin;
2.Paclitaxel – paclitaxel, docetaxel, albumin-bound paclitaxel;
3.Anti-metabolites – capecitabine and gemcitabine;
4, non-paclitaxel microtubule formation inhibitors – vincristine.
5. Other drugs that can be used include oral cyclophosphamide, cisplatin, oral etoposide (class 2B), vincristine, mitoxantrone, isapirone and fluorouracil continuous intravenous dosing regimens.
Recommended combination chemotherapy regimens include.
CMF (cyclophosphamide, aminoglutethimide and fluorouracil);
CAF (cyclophosphamide, doxorubicin, and fluorouracil);
AC (doxorubicin, cyclophosphamide) or EC (epirubicin, cyclophosphamide);
AT (doxorubicin in combination with docetaxel or paclitaxel);
XT (docetaxel in combination with capecitabine);
GP (gemcitabine in combination with paclitaxel).
Principles of chemotherapy selection for recurrent metastatic breast cancer
1. Patients who have only used endocrine therapy in adjuvant treatment but not chemotherapy can choose CMF regimen or anthracycline-based CAF/CEF regimen;
2.Anthracycline combined with paclitaxel is preferred for patients who have not used anthracycline before in adjuvant therapy, and some patients who have used anthracycline or paclitaxel before in adjuvant therapy can also use AT regimen as long as drug resistance and treatment failure are not judged. However, anthracyclines have been the cornerstone of breast cancer treatment for many years, and the AT regimen is not the best choice for patients who have failed anthracycline therapy.
3.XT regimen and GP regimen can improve the efficiency of anthracycline-failed metastatic breast cancer, prolong the time of disease progression and have the advantage of prolonged survival compared with single-agent paclitaxel, so they are the preferred regimen for anthracycline-failed metastatic breast cancer.
4.As more and more breast cancer patients are treated with paclitaxel in postoperative adjuvant therapy, there is no standard treatment plan for recurrent metastasis, and the drugs that can be considered are capecitabine, vincristine, gemcitabine and platinum drugs, which can be considered as single drug or combination regimen.
5. Patients who have achieved efficacy after combination chemotherapy and cannot tolerate combination chemotherapy due to adverse reactions can also consider single drug maintenance therapy of the original effective combination regimen to maximize the duration of disease control.
For the treatment of advanced breast cancer, if there is no remission with three consecutive chemotherapy regimens or ECOG physical status score ≥3, it is recommended to give priority to best supportive therapy only, while actively but scientifically and rationally seeking individualized exploratory clinical research protocols according to the patient’s specific situation. Constantly changing chemotherapy regimens is often difficult for such patients to achieve actual survival time and quality of life benefits.