Breast cancer is the most common malignant tumor in women worldwide, and in recent years it has jumped to the top of the incidence rate in Chinese women. 20-30% of operable breast cancers inevitably recur and metastasize even after radical surgery. In addition, about 5% of cases are diagnosed at stage IV and have no chance of surgery. Metastatic breast cancer (MBC) is incurable disease, and the goals of treatment are to relieve and control disease symptoms, improve quality of life, and prolong survival.
Treatment decisions for metastatic breast cancer are influenced by various factors such as hormone receptor (HR) and human surface growth factor receptor-2 (HER-2) expression, treatment history and some prognostic factors such as length of disease-free interval, presence of visceral metastases, physical status, disease-related symptoms, etc. Systemic chemotherapy is mainly indicated for the treatment of HR-negative disease and for the follow-up of HR-positive disease after failure of endocrine therapy. This paper reviews the current status and progress of systemic chemotherapy for MBC.
I. Current status of treatment for metastatic breast cancer
Hormone receptor (HR), HER-2 status and previous treatment history are the most important decision factors for the initial treatment of metastatic breast cancer.
For HR-positive metastatic breast cancer, slow disease progression, only bone and soft tissue metastases without visceral metastases or asymptomatic visceral metastases, initial treatment starts with endocrine therapy. If endocrine therapy is satisfactory and disease progression still meets the indications for endocrine therapy, second-line endocrine therapy can still be chosen. If there are concerns about endocrine resistance, if multiple lines of endocrine therapy fail, or if symptomatic visceral metastases develop during the course of treatment, systemic chemotherapy is administered.
For HER-2 positive metastatic breast cancer, trastuzumab-based therapy should be used, usually in combination with chemotherapeutic agents, or in single agent application or in combination with endocrine therapy in the early stages of disease progression or in the stable phase. Research and new drugs are emerging in this therapeutic area, and drugs targeting HER-2 include lapatinib, patuximab, and T-DM1, which will be covered in detail in a separate section.
Systemic chemotherapy with cytotoxic agents is preferred for patients with HR-negative metastatic breast cancer, HR-positive with symptomatic visceral metastases or rapidly progressing disease.
Systemic chemotherapy for metastatic breast cancer
Cytotoxic drugs effective in metastatic breast cancer include anthracyclines (doxorubicin, epirubicin and liposomal doxorubicin), paclitaxel (paclitaxel, docetaxel and albumin-bound paclitaxel), non-paclitaxel microtubule inhibitors (ixabepilone, vincristine and eribulin) and antimetabolites (capecitabine and gemcitabine). Platinum-based agents (cisplatin and carboplatin) have also been seen for the first time for their efficacy in the treatment of triple-negative breast cancer.
(i) Combination regimens versus single agent sequential therapy
In clinical practice, when considering cytotoxic chemotherapy for patients, the first treatment choice encountered is whether to use single-agent sequential or combination chemotherapy, which has long been a controversial topic in the field of chemotherapy for metastatic breast cancer.
It is now accepted that combination chemotherapy offers higher objective remission rates and longer time to disease progression than single-agent sequential chemotherapy, but little benefit in terms of survival.
A meta-analysis found that combination chemotherapy regimens had a significant survival benefit compared to single-agent paclitaxel in the treatment of metastatic breast cancer. Combination therapy tends to have greater toxicity and is more likely to require dose reductions, with greater potential for treatment discontinuation. Patient and disease-related factors dictate the treatment regimen, and combination chemotherapy is more appropriate when disease is rapidly progressing, when there are life-threatening visceral metastases, or when symptom control is needed. Single-agent sequential strategies can achieve stable disease with lower toxicity and are also more appropriate in patients with medical comorbidities.
1. Single agent
Anthracyclines are usually considered the first-line treatment of choice for metastatic breast cancer, but increasingly they are being used in adjuvant or neoadjuvant therapy before and after radical surgery. When the disease metastasizes in the short term, these drugs are often no longer an option. Furthermore, anthracyclines are often limited by the total cumulative dose due to cardiotoxicity issues, with the vast majority of scholars previously considering a cumulative dose of 550 mg/m2 for doxorubicin (adriamycin) or 450 mg/m2 for hypertensive patients and those who have received chest radiotherapy; several studies now suggest that for patients who have received a cumulative dose of doxorubicin above 300 mg/m2 or epirubicin above cardioprotection is appropriate for patients with metastatic breast cancer who have received cumulative doses of doxorubicin above 300 mg/m2 or epirubicin above 550 mg/m2 and should be monitored regularly by cardiac function testing. Once the upper limit of cumulative dose of anthracyclines has been reached, a change of cytotoxic chemotherapeutic agent should be considered.
Paclitaxel analogs are microtubule-stabilizing agents and are the first choice after anthracycline or regimen resistance. However, paclitaxel analogs have also entered the field of pre- and post-surgical adjuvant or neoadjuvant therapy, and they are generally no longer used once the disease has metastasized, especially if the metastasis occurs within 12 months. It has also been suggested that paclitaxel and docetaxel are not fully cross-resistant and that different paclitaxel analogs can be chosen after disease progression and adjuvant therapy. The dose-limiting toxicity of paclitaxel drugs is peripheral neurotoxicity. The onset of neuropathy is usually dependent on the cumulative dose and appears 3 to 6 cycles after treatment. Patients should be carefully monitored for early signs of neuropathy, including abnormal sensation, numbness, burning, discomfort, or pain. In general, if grade 2 or higher neuropathy occurs, treatment needs to be discontinued until symptoms are reduced to at least grade 1 before resuming low-dose therapy.
When disease progression or toxicity is intolerable after treatment with anthracyclines and paclitaxel, the options are capecitabine, vincristine, and gemcitabine. phase II and phase III studies have reported that capecitabine and vincristine are 25% to 29% effective in patients resistant to anthracycline paclitaxel chemotherapy. The large reports of gemcitabine alone are less frequent, with 14% to 42% efficacy reported in phase II clinical trials.
Ixabepilone stabilizes microtubules by interacting with microtubule proteins in a different manner than paclitaxel, and is the first clinically available agent of the ebolycin class. Ixabepilone has low susceptibility to general resistance mechanisms and remains active against paclitaxel-resistant cell lines. The clinical efficacy of single-agent isapirone was demonstrated in a series of phase II clinical trials; isapirone 40 mg/m2 every three weeks achieved an objective remission rate of 11.5% and 50% disease stabilization in patients (n=126). Based on this trial, single-agent isabepilone treatment was approved by the FDA in previous trans-anthracycline, paclitaxel and capecitabine treatments for breast cancer.
Eizabalin is a microtubule inhibitor with a different mechanism of action than paclitaxel, epothilone, and perillyl alkaloids. Eribulin achieves objective remission rates of 11.5% and 9.3% in patients with MBC treated with multiple lines, respectively. In a follow-up phase I clinical trial (the EMBRACE study), in patients with MBC after prior treatment with at least two-line regimens including anthracyclines and paclitaxel, compared with the investigator’s treatment choice (TPC, tophysician choice) (primarily single-agent vincristine, gemcitabine or capecitabine), eribulin monotherapy for 1, 8 days at 1.4 mg/m2 for three-week regimen significantly improved overall survival (13.1 vs. 10.7 months, P=0.04) and had a trend toward longer progression-free survival (3.7 vs. 2.2 months, P=0.09). Objective remission rates were also more favorable in the eribulin group (12% vs. 5%, p=0.005). Another phase III clinical trial comparing the efficacy of eribulin with capecitabine in patients with MBC previously treated with anthracyclines and paclitaxel is still ongoing.
When disease progression occurs after first-line chemotherapy, a back-line treatment for relief is required. However, when patients fail to achieve remission from the three sequential regimens or have a PS score of 3 or higher (range: 0 to 5), they should be changed to supportive therapy alone.
2. Combination therapy
There are nine recommended regimens for combination chemotherapy for metastatic breast cancer in the 2013 edition of the NCCN guidelines. The first 4 regimens are anthracycline-based regimens (FAC, FEC, AC, EC), the anthracycline combined with paclitaxel regimen (AT regimen) in the previous version was removed due to high toxicity, and the 5th regimen is the oldest CMF regimen. These regimens can be preferred as first-line treatment in patients with stage IV breast cancer at initial diagnosis or in those who have not received anthracycline-based chemotherapy before or after radical surgery.
In contrast, among patients who have been treated with anthracyclines in adjuvant/neoadjuvant therapy, paclitaxel regimens, such as regimens 6 and 7 (docetaxel combined with capecitabine and gemcitabine combined with paclitaxel) recommended by the NCCN guidelines, may be preferred for treatment, considering the effects of cumulative anthracycline dose cardiotoxicity. Both regimens have been widely used in clinical practice, with registered clinical trials published in JCO in 2002 and 2008, respectively, and both two-drug combination regimens have improved efficiency, time to disease progression and overall survival compared with control single-agent paclitaxel regimens, and are among the few combination chemotherapy regimens that have improved overall survival.
Additional drug combination regimens have been reported after resistance to paclitaxel-based combination regimens. The following phase III randomized controlled trials comparing the efficacy of chemotherapy two-drug combinations to single-drug efficacy in this population validated the idea that combination chemotherapy improves efficiency and time to disease progression over single-drug, but lacks a survival advantage. As a result, it did not make the list of combination therapy regimens recommended by the NCCN guidelines.
In a phase III clinical trial published in the Lancet, patients with metastatic breast cancer previously treated with anthracyclines and paclitaxel were randomized to the gemcitabine and vincristine combination therapy group and the single-agent vincristine group. The results showed that combination therapy significantly prolonged the median progression-free survival of patients (6 months vs. 4 months, P=0.003). There was a trend toward greater {objective remission rates in the combination therapy group (36% vs. 26%, P=0.09), but no significant difference in overall survival (15.9 vs. 16.4 months, P=0.8). grade 3 or 4 non-hematologic toxicity was similar in both groups, but neutropenia was more common in the combination therapy group.
Ixabepilone in combination with capecitabine significantly prolonged progression-free survival compared with capecitabine alone, as demonstrated in two phase HI clinical trials. In the first study, which enrolled patients treated with or resistant to anthracyclines and resistant to paclitaxel, the median progression-free survival was 5.8 months vs. 4.2 months in the combination group vs. capecitabine alone (P=0.0003). The objective remission rate was significantly higher in the combination group (35%vS.14%,P < 0.001). Overall survival data also favored the combined group, but were not statistically different (12.9 months vs. 11.1 months, P = 0.19). The second trial enrolled patients with metastatic breast cancer previously treated with anthracyclines or paclitaxel, but drug resistance or not was not an inclusion criterion. Similarly, isabepilone combined with capecitabine significantly improved progression-free survival (6.2 months vs. 4.2 months, p<0.001) and objective remission rate (43% vs. 29%, p<0.001) compared with capecitabine alone, but overall survival was not statistically different (16.4 months vs. 15.6 months, p=0.12).
(B) Treatment of triple-negative breast cancer
Triple-negative breast cancer is defined as breast cancer that is clinically negative for ER, PR and HER-2 by immunohistochemistry. Compared with other subtypes, triple-negative breast cancer is highly aggressive and has poor prognosis. It overlaps with or is similar to basal cell-like tumors and tumors carrying mutations in BRGA1 or BRCA2 genes, is associated with defective DNA repair, and may be sensitive to DNA-damaging cytotoxic drugs. Based on this theoretical basis, platinum-based drugs have been studied in this field in a series of studies. Retrospective analyses have shown that a two-drug regimen of drills combined with gemcitabine is active in metastatic breast cancer, and that this combination regimen may be more effective in triple-negative breast cancer. These findings suggest that a platinum-based regimen may be a reasonable option for the treatment of metastatic triple-negative breast cancer.
The Breast Cancer Treatment Group of the Department of Medical Oncology at the Cancer Hospital of Fudan University has conducted a national multicenter phase III clinical trial (CBCSG006) using cisplatin in combination with gemcitabine as first-line chemotherapy for metastatic triple-negative breast cancer, compared with the standard treatment regimen of paclitaxel in combination with gemcitabine. The results of this trial will help validate the first-line status of platinum in the treatment of triple-negative breast cancer.
PARP-1 (poly(adenosine diphosphate) polymerase-1) is a key enzyme in the base excision repair pathway in the case of single-stranded DNA breaks, and it plays a critical role in repair when double-stranded breaks and homologous recombination are defective. It may also have this role in those with mutations in the BRCA1 gene or in patients with triple-negative breast cancer.Iniparib, originally thought to be a PARP-1 inhibitor, was combined with chemotherapy in a phase II study for triple-negative breast cancer, with encouraging results. However, subsequent phase III trials with or without iniparib on top of a combination regimen of gemcitabine and carboplatin (GC regimen) for triple-negative breast cancer did not observe a statistical difference. A later study showed that the primary mechanism of action of iniparib may not be PARP-1 inhibition. Although this trial did not confirm the effectiveness of PARP inhibitors, this large sample of studies led to the inclusion of gemcitabine in combination with carboplatin (GC regimen) in the NCCN recommended combination regimen for metastatic breast cancer. In addition, the PARP inhibitors olaparib and veliparib are currently in clinical trials.
Bevacizumab was initially fast-tracked for approval by the U.S. Food and Drug Administration (FDA) for the indication of first-line treatment of metastatic breast cancer. the EC0G2100 trial showed that bevacizumab in combination with weekly paclitaxel significantly prolonged progression-free survival compared to a single-agent weekly paclitaxel regimen (11.8 months vs. 5.9 months, hazard ratio = 0.6, P < 0.001). Follow-up studies with other drug combinations did not replicate the ecog21oo study with such a significant pfs difference. The meta-analysis showed that bevacizumab combined with chemotherapy significantly improved progression-free survival compared with chemotherapy alone, but there was no difference in overall survival. Several large studies and meta-analyses were performed on subgroups of triple-negative breast cancer and showed a pfs benefit consistent with the overall population that could be applied to triple-negative breast cancer. However, the lack of survival benefit and the potential for serious adverse events led the fda to reevaluate the drug and then withdraw bevacizumab from breast cancer indications. However, bevacizumab in combination with weekly paclitaxel remains in the combination regimen recommended by the nccn guidelines for some patients who have had poor results with conventional chemotherapy.
The anti-epidermal growth factor receptor monoclonal antibody cetuximab may be a target for the treatment of triple-negative breast cancer, with 30% to 60% of patients having tumors overexpressing the epidermal growth factor receptor. In a phase II clinical trial published in JCO in 2013, 173 patients with metastatic triple-negative breast cancer were randomized 2:1 to cisplatin combined with cetuximab and cisplatin monotherapy groups. The primary study endpoint was the effective rate (ORR), which was 20% and 10% in the combination versus monotherapy groups, respectively, with no statistically significant difference in P values. The secondary study endpoint, PFS, showed a statistical difference, and OS was not statistically different. Another JCO published phase II clinical trial tried a regimen combining carboplatin with less than 20% efficacy, and the authors suggested that bypass activation may exist in triple-negative patients.
(iii) Maintenance therapy
The question of when to stop treatment in patients who have achieved remission or stabilization after first-line therapy has been a difficult problem for breast cancer specialists in China and abroad. The concept of managing breast cancer as a “chronic disease” has been gradually proposed and accepted in clinical work, and the “advanced breast cancer full management treatment model” has been proposed, which is more consistent with the “chronic disease” treatment goal. The “advanced breast cancer management treatment model” is more consistent with the goal of “chronic disease” treatment. Maintenance therapy plays an important role in the management of advanced breast cancer.
Appropriate maintenance therapy includes endocrine therapy for hormone-sensitive patients who are not endocrine resistant, Herceptin-only targeted monotherapy maintenance for HER-2 positive patients, and chemotherapy maintenance for patients for whom endocrine and targeted agents are not indicated. Chemotherapy drug maintenance therapy should be selected according to the previous medication: first-line treatment with a single drug can continue the drug until disease progression; first-line treatment with a combination of chemotherapy, if the combination of chemotherapy can not continue because of adverse reactions, can consider the original combination of one of the single drugs in the program for maintenance therapy to maximize the time of disease control; broad maintenance therapy can also be replaced with another drug for maintenance or the original effective regimen is applied for as long as possible.
The MANTA1 study evaluated the efficacy of paclitaxel for maintenance therapy. The study randomized 459 patients without disease progression after 6-8 courses of doxorubicin or epirubicin combined with paclitaxel (AT/ET regimen) to paclitaxel 175 mg/m2 every 3 weeks, with a control group as a discontinuation observation group, with negative results, and failed to confirm a survival benefit in PFS and OS from maintenance treatment with this drug.
In the GEICAM 2001-01 study, after 288 metastatic breast cancers received 6 courses of first-line chemotherapy with an anthracycline-sequential paclitaxel regimen, 155 patients who did not experience disease progression were randomized to 6 cycles of maintenance therapy with liposomal doxorubicin (PLD) 40 mg/m2 every 4 weeks, with the control group as a discontinuation observation group. TTP) was prolonged (8.4 months vs. 5.1 months) in the trial group compared to the control group, but it was difficult to replicate clinically given the adverse effects, ease of use and price of PLD.
A 2011 meta-analysis analyzed 11 studies and showed that the duration of first-line chemotherapy in metastatic breast cancer was prolonged, as were PFS and OS. However, the number of cycles of first-line chemotherapy treatment was inconsistent across studies and the results were controversial as there was no good assessment of the possible increased toxicity of prolonged chemotherapy and inconsistent evaluation of quality of life and impact across trials. Questions remain unanswered about how long to use first-line chemotherapy, whether maintenance therapy is meaningful, and which patients need maintenance therapy.
The Korean multicenter, phase III clinical trial KCSG-BR0702, published in JCO in 2013, gives strong evidence of evidence-based medicine for maintenance therapy. The study randomized 231 patients who did not experience disease progression after 6 courses of first-line chemotherapy gemcitabine combined with paclitaxel (GT regimen) in 324 metastatic breast cancers to the maintenance GT treatment until disease progression group and the discontinuation observation group. The results showed that the maintenance treatment group significantly improved PFS and OS, with statistically significant differences in P values. Subgroup analysis showed that the population with PFS benefit in the maintenance chemotherapy group was mainly young, premenopausal, visceral metastases, hormone receptor negative, and high number of metastases. Toxicity in the maintenance treatment group, although greater than in the observation group, did not affect the quality of patient survival.
In the field of chemotherapy maintenance therapy research, our scholars have done a lot of work. The criteria for the ideal drug for maintenance therapy were proposed: effective as a single agent, relatively low toxicity, and easy to use for a long time. Capecitabine is the preferred drug for maintenance therapy for patients with advanced breast cancer. The results of a series of studies conducted in China have shown that after effective treatment with XT or XN regimens, maintenance therapy with capecitabine alone allows most patients to maintain the efficacy and safety of previous combination chemotherapy. Capecitabine-based combination chemotherapy followed by capecitabine monotherapy maintenance (“XBased X”) has become a reasonable option for the full management model of advanced breast cancer.
A phase II clinical trial at the Affiliated Hospital of the Academy of Military Medical Sciences in China enrolled 64 patients with metastatic breast cancer who were treated with capecitabine monotherapy for maintenance after remission or disease stabilization on first- or second-line treatment with the XT/XN regimen. The results showed a median TTP of 4.4 months, an objective remission rate of 5.1%, and a significant reduction in hematologic toxic events compared to previous combination therapy, confirming capecitabine as a less toxic and effective option for maintenance therapy.
A study at the Cancer Hospital of the Chinese Academy of Medical Sciences compared the efficacy of XT vs XN first-line chemotherapy followed by capecitabine monotherapy for maintenance treatment and found that XT-X significantly prolonged PFS compared to XN-X regimen, and XT neurotoxicity and hand-foot syndrome were more common than XN but generally well tolerated, suggesting that XT-X regimen is more suitable for first-line treatment of metastatic breast cancer, while XN-X regimen is suitable for paclitaxel-based treatment The XN-X regimen is suitable for advanced patients who have failed or are intolerant to paclitaxel therapy.
The Chinese Society of Clinical Oncology (CSCO) has initiated a large prospective multicenter clinical study to evaluate the efficacy and safety of the “X Based X” regimen, which is expected to be completed in December 2015. Data published to date show that 90.6% of patients had clinical benefit after “X Based” treatment, and approximately 83.9% of patients entered capecitabine maintenance therapy. PFS was significantly longer in patients receiving capecitabine maintenance therapy compared to those not receiving capecitabine maintenance therapy (14.1 months vs. 11.4 months, P=0.0004).
Conclusion
Treatment options for metastatic breast cancer are influenced by a variety of factors, including primarily biomarker status and the patient’s prior treatment history. Targeted therapies have evolved rapidly in recent years, with relatively few advances in chemotherapy. However, chemotherapy continues to play a pivotal role in the treatment of metastatic breast cancer.
Anthracyclines and paclitaxel are the most widely used cytotoxic agents among breast cancers, but their use in the early stages of the disease may compromise their continued use in subsequent disease courses, and toxicity issues or the development of drug resistance have led to the search for additional agents and regimens. Capecitabine, vincristine, and gemcitabine are already widely used in the clinic, and eribulin and isabepilone are also effective single agents. Combination regimens of effective drugs may further improve efficacy. Platinum-based agents are initially established in triple-negative breast cancer. Maintenance therapy is widely promoted in clinical practice, and scholars in Korea and China have made many contributions in this field.
Although metastatic breast cancer is still incurable, individualized application of drugs based on molecular characteristics of tumors and rationalization of various treatment strategies may allow metastatic breast cancer to become a chronic disease.