INTRODUCTION — Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among females worldwide [1]. Despite the gains in early detection, up to 5 percent of individuals diagnosed with breast cancer in the United States have metastatic disease at the time of first presentation. In addition, up to 30 percent of individuals with early-stage, non-metastatic breast cancer at diagnosis will develop distant metastatic disease [2]. Although metastatic breast cancer is not curable, meaningful improvements in survival have been seen, coincident with the introduction of newer systemic therapies [3-5].

In this topic, we will use the terms "woman/en" or "patient" to describe genetic females. However, we recognize that not all people with breasts identify as female, and we encourage the reader to consider transgender and gender-nonbinary individuals as part of this larger group.

This topic will focus on the approach to chemotherapy in individuals with hormone receptor-positive advanced breast cancer. However, most of the trials in this topic enrolled patients with both hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancers and hormone receptor-negative, HER2-negative cancers (triple-negative breast cancer [TNBC]). Some also included a minority of patients with HER2-positive disease.

A detailed discussion on the approach to individuals with TNBC, and those with HER2-positive disease, is found elsewhere. Additionally, a general overview of the approach to metastatic breast cancer, endocrine therapy for hormone receptor-positive metastatic breast cancer, HER2-directed agents and other molecularly targeted therapy, and breast cancer in men are reviewed separately. In addition, commonly used treatment regimens used in the treatment of breast cancer are also compiled in a separate topic.

●(See "ER/PR negative, HER2-negative (triple-negative) breast cancer".)

●(See "Systemic treatment for metastatic breast cancer: General principles".)

●(See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents".)

●(See "Systemic treatment for HER2-positive metastatic breast cancer".)

●(See "Breast cancer in men".)

●(See "Treatment protocols for breast cancer".)

INDICATIONS — The goals of treatment of metastatic breast cancer are to prolong survival and improve quality of life by reducing cancer-related symptoms. In order to achieve these goals, an individualized approach is needed since no one strategy can be applied for all individuals. Cytotoxic chemotherapy may be used to achieve these goals in the following situations:

●Patients with symptomatic hormone receptor-positive breast cancer, in whom endocrine therapy is unlikely to result in a prompt clinical response [6]. These include patients who present with:

•Rapid disease progression following more than one endocrine therapy (ie, endocrine-resistant disease)

•A large tumor burden involving visceral organs and threatening organ function

●Patients refractory to multiple lines of endocrine therapy.

In general, we prefer not to administer chemotherapy with endocrine therapy for individuals with hormone receptor-positive disease in order to minimize side effects, including an increased risk of thromboembolic events [7]. In addition, a 1998 meta-analysis showed that combining these treatments was not more effective than the use of chemotherapy alone [8]. The administration of endocrine therapy for patients with hormone receptor-positive metastatic breast cancer is covered separately. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents" and "Systemic treatment for metastatic breast cancer: General principles", section on 'Systemic treatment'.)

For patients with metastatic HER2-negative breast cancer and germline breast cancer susceptibility gene (BRCA) mutations, the oral inhibitor of poly(ADP-ribose) polymerase (PARP) olaparib has shown efficacy. For such patients, chemotherapy versus PARP inhibition is discussed in more detail elsewhere. (See "Systemic treatment for metastatic breast cancer: General principles", section on 'PARP inhibition for BRCA carriers'.)

FACTORS INFLUENCING CHEMOTHERAPY CHOICE — For patients in whom chemotherapy is recommended, the choice between a single agent or a combination regimen, and the selection of a specific therapy, should take into account several factors in an effort to individualize therapy as much as possible.

Because of the availability of many agents to treat metastatic breast cancer, there is no ideal sequence of treatments that can be applied to all patients. It is likely that patients with metastatic breast cancer will receive many (if not all) of these treatments throughout the course of their disease. However, below we illustrate the principles that can guide the choice of therapy in the first- or later-line setting. Given that currently available systemic treatments for metastatic breast cancer are not curative, we encourage participation in well-designed clinical trials.

Tumor burden — Tumor burden (the extent of disease detected on imaging or clinical exam and/or the presence of tumor-related symptoms) can impact on whether single-agent chemotherapy or a combination regimen is administered:

●We prefer the sequential use of single-agent chemotherapy, especially for patients with a limited tumor burden and/or limited or minimal cancer-related symptoms. Sequential single-agent treatment is often less toxic and results in similar overall survival compared with combination chemotherapy [9]. (See 'Single-agent chemotherapy' below.)

●For select patients, we favor the use of a combination regimen rather than a single agent because combination therapy results in a higher response rate, which may justify the risks of treatment [10]. Appropriate patients include those with symptomatic disease due to the location of specific metastatic lesions (eg, right upper quadrant pain due to expanding liver metastases, or dyspnea related to diffuse lung metastases) and a large tumor burden, as well as those with rapidly progressive disease. (See 'Combination chemotherapy' below.)

●For patients with brain metastases, systemic treatment may not be required if there is no evidence of systemic disease. In the presence of systemic disease, treatment of both the central nervous system and systemic disease should be individualized. (See "Brain metastases in breast cancer".)

General health status — Treatment decisions should take into account the overall health status of the patient, which can be gauged by the performance status (table 1) or, in the case of older individuals, a comprehensive geriatric analysis (CGA). (See "Comprehensive geriatric assessment for patients with cancer" and "Treatment of metastatic breast cancer in older women".)

For patients in whom a single agent is recommended, an understanding of the patient's health status also may influence the appropriate selection of agents. As examples (see 'Single-agent chemotherapy' below):

●Patients with a history of cardiac disease or heart failure and those who are felt to be at a greater risk for cardiac injury (eg, older adult patients) should not be treated with an anthracycline. There are multiple appropriate alternatives (eg, paclitaxel or capecitabine).

●Patients with symptomatic peritoneal metastases, those who have difficulty swallowing pills, or those who are not able to follow instructions required to use a daily regimen may not be good candidates for oral therapies (eg, capecitabine).

●Patients at risk for hyperglycemia (eg, patients with diabetes) and those who cannot tolerate steroids for whatever reason may derive more of a benefit from agents that do not require steroid premedication (eg, nanoparticle albumin-bound paclitaxel [nabpaclitaxel], capecitabine, and gemcitabine).

●Patients with a poor performance status or those with significant competing comorbidities may not benefit from treatment at all, especially if they have well-controlled symptoms and a higher risk of dying from a cause other than breast cancer. Therefore, the benefits and risks of single-agent therapy should be balanced against overall prognosis.

For the select few patients in whom a combination regimen is preferred, the patient's health status also can help choose the most appropriate regimen. As examples (see 'Combination chemotherapy' below):

●Ideal candidates for an anthracycline-containing regimen include individuals with chemotherapy-naive, stage IV breast cancer (ie, no prior cytotoxic therapy and those who received endocrine therapy initially) and those who did not previously receive an anthracycline (eg, those who received docetaxel plus cyclophosphamide in the adjuvant setting). These are among the most active regimens for metastatic breast cancer. (See 'Anthracycline-containing regimens' below.)

●Patients with a cardiac history (including prior anthracycline-induced cardiac injury) should not be treated with an anthracycline. Our preference is to administer a taxane-based regimen (eg, gemcitabine plus paclitaxel or docetaxel). (See 'Non-anthracycline, taxane-based regimens' below.)

Prior treatment and toxicities — For the patient who has been previously exposed to chemotherapy (eg, as adjuvant treatment or previous therapy for metastatic breast cancer), there is no optimal sequence of administration of chemotherapy agents used to treat metastatic breast cancer. In general, treatment with chemotherapy drugs of different classes (non-cross resistant agents) may result in a higher probability of response, especially if disease progression occurred within six months following the previously administered regimen [11]. However, the treatment history (ie, agents used and any previous toxicity experienced or persisting) should be reviewed to help inform the choice of a subsequent regimen. As examples:

●Patients who received doxorubicin or epirubicin in the adjuvant setting, even years previously, may not be good candidates for repeat anthracycline therapy due to increasing risk of cardiac toxicity at higher cumulative doses. Of the available alternative agents, we typically administer a taxane in these patients. (See 'Taxanes' below.)

●Patients with a history of myelosuppression with prior therapy that resulted in dose modification or treatment delay may not be good candidates for agents or schedules with significant myelotoxicity risks (eg, ixabepilone, gemcitabine, carboplatin, and every-three-week docetaxel). In these situations, single-agent treatment using a weekly anthracycline, capecitabine, or a weekly taxane may be more appropriate. (See 'Taxanes' below and 'Anthracyclines' below.)

●Patients with baseline or a history of serious (grade 3/4) neuropathy may not be good candidates for microtubulin-directed agents (eg, taxanes, ixabepilone, eribulin, or vinorelbine), or for cisplatin. These patients are appropriate candidates for anthracyclines, especially in the first-line setting in a patient who was never treated with an anthracycline. Alternatives to anthracyclines include capecitabine, etoposide, carboplatin, or gemcitabine. (See 'Anthracyclines' below and 'Other agents' below.)

BRCA1 or 2 mutation carriers — Patients with known breast cancer susceptibility gene (BRCA) mutations may specifically derive benefit from platinum agents. In a phase II study, single-agent cisplatin yielded an 80 percent response rate in BRCA1 mutation-associated metastatic breast cancer [12]. The approach to therapy among patients with metastatic BRCA1/2-associated triple-negative breast cancer is discussed in detail elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Germline BRCA mutation'.)

Patient preferences — Patient preferences help to individualize treatment plans for metastatic breast cancer.

For example:

●Patients who prefer less frequent visits for intravenous treatments may opt for treatment administered every three weeks, rather than weekly. Appropriate regimens that can be administered every three weeks include single-agent taxanes, anthracyclines, or ixabepilone, or combination therapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin plus cyclophosphamide (AC). (See 'Taxanes' below and 'Anthracyclines' below and 'Other agents' below and 'Cyclophosphamide, methotrexate, and fluorouracil' below and 'Anthracycline-containing regimens' below.)

●Patients who prefer a low risk of alopecia may want to avoid taxanes and anthracyclines (where the risk of alopecia is close to 90 percent). Options in this circumstance include agents with a lower risk of alopecia, such as capecitabine (less than 10 percent), pegylated liposomal doxorubicin (less than 20 percent), and gemcitabine (up to 15 percent). (See 'Other agents' below.)

●Patients who prefer less intrusion on their lifestyle may opt for an orally administered agent, such as capecitabine, rather than treatments that require intravenous infusion. (See 'Capecitabine' below.)

SINGLE-AGENT CHEMOTHERAPY — There are a number of agents with activity in metastatic breast cancer. Because the taxanes and anthracyclines are most commonly administered, especially in the first-line treatment of metastatic breast cancer, they are presented first. (See 'Indications' above.)

Taxanes — Taxanes are among the most active agents for metastatic breast cancer. Agents in this class include:

●Docetaxel – Docetaxel can be administered every three weeks (80 to 100 mg/m²) or weekly (30 to 40 mg/m² weekly for three weeks followed by one week off) [13]. Of these schedules, we prefer dosing every three weeks based on the results of a randomized trial in the adjuvant setting that showed every-three-week dosing results in an improvement in disease-free survival (DFS) compared with weekly dosing [14]. Docetaxel is associated with a significant risk of fluid retention, which is reduced by premedication with dexamethasone [15].

●Paclitaxel – Paclitaxel can be administered weekly (80 to 100 mg/m² on days 1, 8, and 15 of a 28-day cycle) or every three weeks (175 mg/m²) [13,14,16]. Whenever possible, we prefer weekly scheduling based on the results of a 2010 meta-analysis, which showed that compared with every-three-week treatment, weekly administration of paclitaxel resulted in an improvement in overall survival in patients with advanced breast cancer (OS; hazard ratio [HR] 0.78, 95% CI 0.67-0.89) [13].

It should be noted that patients treated with paclitaxel are at risk for allergic reactions as a result of the composition of paclitaxel, which is mixed with Cremophor. At most institutions, steroid premedication (dexamethasone 20 mg the night before and morning of infusion) is administered, although it can usually be discontinued if the first two or three doses are tolerated. However, the schedule and administration of dexamethasone varies by institution.

●Nabpaclitaxel – Nabpaclitaxel has activity in metastatic breast cancer similar to other taxanes [17-19]. It may be of particular benefit to patients who are at risk for hyperglycemia and those who cannot tolerate steroids. Nabpaclitaxel has a lower risk of allergic reactions compared with other taxanes, which negates the requirement for steroid premedications and the risk of steroid-induced hyperglycemia.

Comparing taxanes — For patients in whom a taxane is indicated, the choice between taxanes can be based on their comparative safety profiles and patient preferences regarding scheduling of treatments. For example:

●The risks of neuropathy and myalgia are greater with paclitaxel than with docetaxel.

●Paclitaxel can be administered in the setting of mild-moderate hepatic dysfunction. In contrast, docetaxel should not be administered in this context.

●Docetaxel given every three weeks is the more myelosuppressive taxane agent. Risks from docetaxel also include febrile neutropenia, edema, and gastrointestinal toxicities.

●Nabpaclitaxel does not require premedication with steroids.

There are limited data comparing each of the taxanes against each other. However, they show that the activity and toxicity differ by which schedule was used (ie, weekly or every three weeks) and by agent. As examples:

●Docetaxel was compared with paclitaxel (both on a 21-day cycle) in a trial of 449 patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. Docetaxel produced a significantly better median time to progression (TTP, 5.7 versus 3.6 months) and OS (15.4 versus 12.7 months) compared with paclitaxel [20]. However, both hematologic and nonhematologic toxicity were worse with docetaxel.

Although this study found that every-three-week dosing of docetaxel is superior to the same schedule using paclitaxel, weekly paclitaxel (which is the preferred method of administration) has not been compared with every-three-week docetaxel in the metastatic setting.

●Paclitaxel and nabpaclitaxel were compared as a first-line treatment (as single agents or with optional administration with bevacizumab) in a randomized phase III trial [21]. The study randomized 799 patients (44 percent who were previously treated with adjuvant paclitaxel) to bevacizumab with either weekly treatment with paclitaxel (90 mg/m²) or nabpaclitaxel (150 mg/m²) on a three week on, one week off schedule. A third arm including weekly ixabepilone (16 mg/m²) was closed for futility at the first interim analysis. The results for paclitaxel versus nabpaclitaxel are discussed below. (See 'Ixabepilone' below.)

•No significant difference in progression-free survival between paclitaxel and nabpaclitaxel (11 versus 9.3 months, respectively; HR 1.20; 95% CI 1.00-1.40).

•No significant difference in overall survival between paclitaxel and nabpaclitaxel (26.5 versus 23.5 months, respectively, HR 1.17, 95% CI 0.92-1.47).

•A higher rate of serious toxicity (grade 3 or higher) in the nabpaclitaxel versus paclitaxel arms, including sensory neuropathy (27 versus 18 percent, respectively) and hematologic toxicity (55 versus 22 percent).

Anthracyclines — The anthracyclines are important agents for the treatment of breast cancer. However, their use in the adjuvant context often limits their application in individuals with metastatic disease. Despite this, anthracyclines may be appropriate in select patients, particularly those who were not treated with an anthracycline in the past. In addition, anthracyclines can be used in patients with mild to moderate hepatic dysfunction with dose modification.

The anthracyclines used in the treatment of metastatic breast cancer are:

●Doxorubicin (60 to 75 mg/m² every three weeks, or 20 mg/m² weekly for three weeks followed by one week off) – Overall response rate (ORR) 30 to 47 percent [22,23]

●Epirubicin (75 to 100 mg/m² every three weeks, or 20 to 30 mg/m² weekly for three weeks followed by one week off) – ORR 42 to 50 percent [24-26]

●Pegylated liposomal doxorubicin (40 mg/m² every four weeks) – ORR 10 to 33 percent [27,28]

One potential downside of using anthracycline regimens is the risk for cumulative cardiac toxicity, which may limit the duration of anthracycline-based therapy. However, for patients who are responding to treatment and otherwise are tolerating therapy, the use of dexrazoxane may minimize the risk of treatment-related cardiac damage. For patients treated with doxorubicin, dexrazoxane is an option after a cumulative doxorubicin dose of 300 mg/m². (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity".)

Comparing anthracyclines — Our preferred anthracycline is doxorubicin or epirubicin because they are both relatively easy to administer. A choice between them is based on geographic and institutional preferences. For example, doxorubicin is more commonly used in the United States, while epirubicin is more commonly used in Europe. Although there are no prospective trials comparing it to standard dosing every three weeks, we prefer the use of weekly anthracycline dosing in the metastatic setting because it is better tolerated.  

For patients who desire a less frequent administration schedule, pegylated liposomal doxorubicin administered every four weeks appears to be equally active and less toxic compared with doxorubicin administered every three weeks. This was shown in a trial of 509 patients with metastatic breast cancer (56 percent who had previously received anthracyclines) who were randomly assigned treatment with pegylated liposomal doxorubicin 50 mg/m² given every four weeks or doxorubicin 60 mg/m² given every three weeks [27]. Compared with pegylated liposomal doxorubicin, doxorubicin resulted in:

●Slightly higher ORR (38 versus 33 percent)

●Similar PFS (median, 7.8 versus 6.9 months; HR 1.0, 95% CI 0.82-1.22) and OS (median, 22 versus 21 months; HR, 0.94, 95% CI 0.74-1.19), though PFS measures were confounded by more frequent assessments in the every-three-week doxorubicin arm.

●An increase in the risk cardiotoxicity (26 versus 7 percent, HR 3.16; 95% CI 1.58-6.31).

●Higher rates of alopecia (66 versus 20 percent), nausea (53 versus 37 percent), vomiting (31 versus 19 percent), and neutropenia (10 versus 4). In contrast, pegylated liposomal doxorubicin was associated with a higher rate of plantar-plantar erythrodysesthesia (48 versus 2 percent), stomatitis (22 versus 15 percent), and mucositis (23 versus 13 percent).

Anthracycline versus taxane — There is no evidence of superiority of either anthracyclines or taxanes in the metastatic setting, although the duration of treatment using anthracyclines is more likely to be limited due to the cumulative risk of cardiac toxicity. (See 'Anthracyclines' above.)

A 2008 meta-analysis of individual patient data (n = 919 patients) found that administration of an anthracycline improved PFS (median, 7 versus 5 months) compared with taxanes, but not ORR (33 versus 38 percent) [29]. However, we do not feel that these small differences in ORR and PFS are clinically significant in the current era in which multiple other therapies are available. In addition, the analysis was limited by multiple factors, including:

●Heterogeneity between the included trials

●Differences in administration schedules for the taxane used (including the lack of inclusion of trials using weekly administration of paclitaxel)

●The inclusion of patients with or without prior exposure to endocrine therapy

●Lack of inclusion of patients treated with adjuvant taxanes

Capecitabine — In our practice, single-agent capecitabine (1000 to 1250 mg/m² twice daily for 14 days followed by seven days of rest) is a frequent choice as a first-line treatment for metastatic breast cancer, particularly in patients with bone-predominant, estrogen receptor-positive metastatic disease who have progressed despite at least two trials of endocrine therapy, at least one of which was in combination in combination with a cyclin-dependent kinase (CDK) 4/6 inhibitor. An alternative schedule of twice daily on days 1 to 7 and 15 to 21 of a 28-day schedule has shown similar outcomes in a retrospective study [30], and may be more tolerable.

In addition, capecitabine also appears to cross the blood brain barrier better than some agents and may be a good consideration in patients with a history of central nervous system metastases [31]. (See "Brain metastases in breast cancer".)

Capecitabine is a prodrug of the anti-metabolite fluorouracil. It is orally available, and unlike many agents used in the treatment of breast cancer, it causes very little alopecia or neuropathy. Its primary toxicities are hand-foot syndrome and diarrhea, and it can be used in settings of mild hepatic dysfunction. The dose of capecitabine must be adjusted, however, in the presence of mild renal dysfunction. The benefit of capecitabine was shown in two multicenter single-arm phase II trials [32,33]:

●In one study, 126 patients were treated with capecitabine (1250 mg/m² dose). The median TTP was 5 months and the ORR was 28 percent. Median OS was 15 months [32].

●In a second study, 95 individuals were randomly assigned to capecitabine or cyclophosphamide, methotrexate, plus fluorouracil (CMF). Capecitabine resulted in a higher ORR compared with CMF (30 versus 16 percent, respectively). The median TTP was similar (4 versus 3 months) but capecitabine resulted in a slightly longer median OS (20 versus 17 months) [33].

Capecitabine may cause excess toxicity in the case of dihydropyridine dehydrogenase (DPYD) deficiency, which is present in approximately 5 percent of the population. Although pre-emptive genotyping has not been implemented into standard clinical practice due to the low carrier frequency and genotyping costs, if a patient is known to have a germline DPYD polymorphism that would lead to decreased enzymatic activity, either an alternative agent or dose reduction should be considered [34,35].

Other agents — For patients who are not candidates for, or who have progressed on the agents above, others are available and have documented activity against breast cancer.

Eribulin — Eribulin mesylate (1.4 mg/m² days 1 and 8 every 21 days) is derived from a marine sponge and inhibits the polymerization of tubulin and microtubules. It results in less neuropathy than other microtubule-directed agents and can be administered with dose adjustment for mild to moderate hepatic dysfunction.  

The activity of eribulin has been demonstrated in clinical trials [36-39]. For example, in a phase III trial of 762 heavily pretreated patients randomly assigned to treatment with eribulin or other chemotherapy (based on physician's and patient's choice), eribulin significantly improved OS (median, 13.1 versus 10.6 months) [38]. The primary toxicity with eribulin was neutropenia, with grade 3 and 4 neutropenia in 45 percent of patients, and grade 3 and 4 febrile neutropenia in 5 percent. Peripheral neuropathy was the most common adverse event leading to discontinuation of eribulin, occurring in 5 percent of patients. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Eribulin'.)  

Of note, a subsequent randomized trial was performed in individuals with metastatic breast cancer who had received prior anthracycline and taxane therapy with an aim to formally evaluate eribulin versus capecitabine as first-, second-, or third-line therapy [37]. Unlike the trial above, there was no difference between eribulin and capecitabine in terms of PFS (four months in each) or overall response rates (11 and 11.5 percent, respectively). In addition, there was no clinically meaningful difference in OS (15.9 versus 14.5 months, respectively; HR 0.88, 95% CI 0.77-1.00).

Vinorelbine — Vinorelbine is an intravenously administered agent usually dosed at 30 mg/m² on a weekly schedule (days 1 and 8 every 21 days) [40]. Vinorelbine causes little nausea, vomiting, and hair loss, and is active as a single agent (ORR 25 to 45 percent), even in heavily pretreated patients [41-43].

Gemcitabine — Although data suggest gemcitabine is active in combination with paclitaxel in first-line metastatic breast cancer, gemcitabine (commonly 800 to 1000 mg/m² days 1 and 8 of a 21-day cycle) is frequently used as a single agent. (See 'Gemcitabine plus paclitaxel or docetaxel' below.)

Gemcitabine appears to cross the blood brain barrier and may be a good option in patients with a history of central nervous system metastases [44]. Alopecia and gastrointestinal toxicity are mild, and its use is not associated with significant neuropathy. Gemcitabine is well tolerated and active in metastatic breast cancer, though when gemcitabine was directly compared with weekly epirubicin as first-line chemotherapy in individuals not previously exposed to an anthracycline, it resulted in a significantly shorter time to progressive disease and a lower OS [45-47]. Thrombocytopenia can be a dose-limiting toxicity, especially in heavily pretreated patients.

Ixabepilone — Ixabepilone is an epothilone, a class of non-taxane tubulin polymerizing agents that have activity in taxane-resistant patients. As single agent treatment, ixabepilone (40 mg/m² every 21 days) resulted in an ORR of 19 percent with a median duration of response of 5.7 months in a clinical trial [48]. Median OS was 8.6 months. Grade 3 and 4 peripheral sensory neuropathy occurred in 14 percent of patients.

Some data suggest that ixabepilone may have less activity when compared with the taxanes, although it may be better tolerated. In the trial referenced above [21], weekly ixabepilone resulted in a shorter median PFS compared with taxanes (7.6 months versus 10 months with paclitaxel and nabpaclitaxel) and OS (21 versus 26 and 27 months, respectively) but resulted in a lower incidence of hematologic toxicity (12 versus 21 and 51 percent) [49]. Of note, the incidence of serious (grade 3/4) sensory neuropathy was equivalent between ixabepilone and nabpaclitaxel (25 percent in both arms). Further results of CALGB 40502 are discussed above. (See 'Comparing taxanes' above.)

In the presence of mild to moderate hepatic impairment, ixabepilone doses should be adjusted. Its usefulness in later line therapy is often limited by its toxicities of neuropathy, anemia, and fatigue. However, epothilones may cross the blood brain barrier [50], suggesting it may be an option for patients with central nervous system disease. (See "Brain metastases in breast cancer".)

Despite US Food and Drug Administration approval, it is not available in Europe because the European Medicines Agency Committee for Medicinal Products for Human Use concluded that the benefit was marginal at best and the risk of peripheral neuropathy to be significant [51]. Alternate dosing schedules have also been reported.

Etoposide — Oral etoposide (50 mg/m² daily for 21 days every 28 days) is a reasonable choice, especially for patients with slow-growing disease who desire an oral agent. Etoposide has shown an ORR of 30 percent in pretreated patients, but may produce hematologic and gastrointestinal toxicity [52-54].

Platinum agents — Carboplatin and cisplatin are rarely used as single agents in metastatic breast cancer, although single-agent use in patients with germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) is supported by clinical data. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Chemotherapy-naϊve patients, or those with progression on PARP inhibitors'.)

Available data suggest the response rate to cisplatin is higher among chemotherapy-naϊve patients rather than in patients who were previously treated (ORR 42 to 54 percent versus less than 10 percent, respectively) [55]. There is also interest in using these agents as part of a combination regimen. (See 'Combination regimens incorporating platinum salts' below.)

COMBINATION CHEMOTHERAPY — Combination chemotherapy (rather than single-agent sequential therapy) is most appropriate when the higher chance of response is assessed to be more important than the potential for higher treatment toxicity, due to concerns about impending organ dysfunction from existing or rapidly progressing disease burden. However, both clinicians and patients should know there are no prospective data that show combination chemotherapy improves overall survival compared with single-agent sequential cytotoxic chemotherapy.

This was shown in the Eastern Cooperative Group 1193 trial, in which over 700 individuals were randomly assigned to doxorubicin plus paclitaxel (AP), doxorubicin, or paclitaxel. For those randomized to single-agent treatment, the protocol mandated cross over to the alternative agent at the time of disease progression. Treatment with AP resulted in:

●A higher overall response rate (ORR) compared with doxorubicin or to paclitaxel (47 versus 36 and 34 percent)

●A longer median time to progression (TTP; 8 versus 6 and 6 months)

●However, there was no difference in overall survival (OS; 22 versus 19 and 22 months)

Although a 2009 meta-analysis that included 43 trials (n = 9742 individuals, 55 percent of whom were treated in the first-line setting) showed that combination therapy could improve OS [10], these data are limited because they did not evaluate the benefits of combination chemotherapy compared with the sequential administration of agents (eg, drug A plus B versus drug A then B).

There are few data to inform the benefits of combination chemotherapy in the second- or later-line setting. However, the use of a combination in a heavily pretreated patient may be warranted, particularly if a patient has a significant tumor burden, desires the best chance of a response, and is willing to accept the potentially significant risks of combination therapy.

Available combination regimens are discussed below.

Anthracycline-containing regimens — Anthracycline-based chemotherapy regimens are associated with response rates of up to 60 percent in previously untreated patients with metastatic breast cancer [56-59], although they are more toxic than sequential single-agent treatment or non-anthracycline-containing combinations [24,60].

Among the available regimens, an anthracycline plus taxane combination results in a higher response rate compared with non-taxane containing regimens. This was demonstrated in a meta-analysis of pooled individual patient data from eight trials (n = 3000) that compared anthracycline-containing regimens (without a taxane) with anthracycline plus taxane combinations [29]. Compared with non-taxane containing therapy, taxane plus anthracycline treatment resulted in a significantly higher ORR (57 versus 46 percent) and an improvement in the risk of disease progression (hazard ratio [HR] 0.92, 95% CI 0.85-0.99). Despite these results, there was no difference in median overall survival between anthracycline plus taxane versus anthracycline combinations that do not contain a taxane [29].

Examples of commonly used anthracycline-based combinations include (see "Treatment protocols for breast cancer"):

●Doxorubicin plus cyclophosphamide (AC) – ORR ranges from 47 to 54 percent [61,62]

●Epirubicin with cyclophosphamide and fluorouracil (FEC) – ORR ranges from 45 to 55 percent [24,60]

●Doxorubicin, docetaxel, plus cyclophosphamide (TAC) – ORR 77 percent [63]

●Doxorubicin plus paclitaxel or docetaxel – ORR is approximately 40 percent for either combination [64]

Non-anthracycline, taxane-based regimens — For patients who are not suitable candidates for anthracyclines, taxane-based regimens can be administered. The choice among the taxanes is usually determined by the prior treatment history. Given the lack of complete cross-resistance between paclitaxel and docetaxel, we often will administer the alternative agent to the one used in the adjuvant setting (eg, if paclitaxel was used adjuvantly, docetaxel is used in the metastatic setting). For patients who are chemotherapy naive, the choice between them should be based on individual considerations around each of their toxicity profiles.

Gemcitabine plus paclitaxel or docetaxel — Gemcitabine (1250 mg/m² on days 1 and 8) plus paclitaxel (175 mg/m² on day 1) resulted in an ORR of 41 percent when administered as a first-line therapy for metastatic breast cancer [65]. In a separate trial, gemcitabine (1000 mg/m² on days 1 and 8) plus docetaxel (75 mg/m² on day 1) resulted in an ORR of 43 percent in first-line therapy [66]. These two regimens have not been compared directly, but presumably gemcitabine plus docetaxel would have higher toxicity, given that both are myelotoxic as single agents.

Capecitabine plus docetaxel — Capecitabine (1250 mg/m², twice daily for 14 of every 21 days) plus docetaxel (75 mg/m² every 21 days) (CD) resulted in an ORR of 42 percent [67]. Several studies also suggest it improves survival over single-agent docetaxel even when capecitabine was mandated on disease progression [67,68]. However, limited data suggest that CD is equivalent to gemcitabine plus docetaxel (GD) but is the more toxic combination [66].

Other regimens — For patients who are not candidates for anthracyclines or taxanes and those who have progressed despite prior treatment, there are several available alternate options. These are discussed below.

Ixabepilone plus capecitabine — Ixabepilone (40 mg/m² every three weeks) plus capecitabine (1000 mg/m² twice daily for 14 of every 21 days) resulted in an ORR of 35 percent [69].

Cyclophosphamide, methotrexate, and fluorouracil — Cyclophosphamide, methotrexate, and fluorouracil (CMF) is rarely administered for metastatic breast cancer because it appears to produce the same response rate when compared with oral capecitabine (20 percent) in one trial [70]. However, CMF resulted in a shorter OS (median, 22 versus 18 months; HR 0.72, 95% CI 0.55-0.94). CMF may be indicated in patients who cannot tolerate capecitabine or for patients in whom an oral regimen is not feasible for whatever reason.

Combination regimens incorporating platinum salts — Regimens combining platinum salts with chemotherapies such as taxanes, vinorelbine, or gemcitabine have been postulated to be specifically efficacious in tumors where DNA repair pathways are faulty.

However, no prospective trials have been completed that demonstrate a survival advantage to such regimens compared with non-platinum regimens. We typically reserve platinum-containing combination regimens for those individuals with good performance status, but high disease burden, whose disease has progressed on other available chemotherapy agents [71].

High-dose chemotherapy protocols — High-dose chemotherapy with autologous stem cell transplantation is not an option for the standard treatment of metastatic breast cancer. A 2011 systematic review that included six randomized trials concluded that high-dose chemotherapy did not significantly improve overall survival and that any benefit from this treatment was minimal. Therefore, we advise against these treatments for metastatic breast cancer [72].

ADJUNCTIVE THERAPY — The role of adjunctive therapy, such as pain medications and osteoclast inhibitors, in the treatment of patients with metastatic breast cancer is covered separately.

●(See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs" and "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: General principles and risk management for patients receiving opioids" and "Cancer pain management: Interventional therapies".)

●(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

MONITORING THERAPY — The ongoing evaluation of patients during therapy (including timing of imaging and the selection of imaging modality) should be individualized according to patient and provider preferences. Further discussion on the monitoring of patients with metastatic breast cancer is covered separately. (See "Systemic treatment for metastatic breast cancer: General principles", section on 'Monitoring therapy'.)

Careful assessment for response to treatment requires serial clinical examination, repeat lab evaluation (including tumor markers), and radiographic imaging. Although there is no standard schedule for evaluation during treatment, a reasonable approach would be as follows:

●History and physical exam prior to the start of each treatment cycle (ie, day one of a new 21- or 28-day treatment cycle).

●Repeat imaging studies (using the same imaging modality throughout) after completion of two cycles of therapy (ie, after cycle two, cycle four, etc).

●Serial assay for serum tumor markers (eg, cancer antigen [CA] 15-3, CA 27.29, and/or carcinoembryonic antigen [CEA]) if they were elevated at baseline. If performed, we typically reevaluate them at the beginning of each treatment cycle.

DURATION OF TREATMENT — Unlike in the adjuvant setting, there is no predetermined duration of treatment. Therefore, the duration of chemotherapy should be individualized taking into account the patient's goals of treatment, presence of treatment toxicities, and alternative options that might be available. In our experience, patients with endocrine-refractory, estrogen receptor (ER)-positive metastatic breast cancer rarely, if ever, have a complete clinical response to chemotherapy. For a patient with endocrine-refractory disease who is responding to treatment, we continue chemotherapy until the time of progression. However, for patients who experience side effects to treatment or prefer not to continue treatment for whatever reason, discontinuation of treatment is reasonable. Patients with ER-positive disease who are not known to be refractory to endocrine therapy, who received chemotherapy in the first line may consider switching to endocrine therapy for maintenance treatment.

For patients who respond to chemotherapy, some data suggest that there are benefits to continuing treatment beyond their best response (ie, maintenance therapy):

●A 2011 meta-analysis of first-line treatment randomized trials that included almost 2300 individuals compared maintenance treatment with treatment over a prespecified duration (range, three to eight cycles) [73]. Longer chemotherapy duration was associated with improvement in progression-free survival (PFS; hazard ratio [HR] 0.64, 95% CI 0.55-0.76) and overall survival (OS; HR 0.91, 95% CI 0.84-0.99).

●A randomized trial published in 2013 consisted of 324 patients with metastatic breast cancer, all of whom were treated with paclitaxel and gemcitabine [74]. Patients who achieved disease control (complete or partial response, or stable disease) to treatment (n = 231) were randomly assigned to observation or maintenance chemotherapy with the same agents until disease progression.

The administration of maintenance chemotherapy resulted in a higher PFS rate at six months compared with observation (60 versus 36 percent, respectively; HR 0.73, 95% CI 0.55-0.97) and improved OS (median, 32 versus 24 months; HR 0.65, 95% CI 0.42-0.99). However, continuation of paclitaxel and gemcitabine resulted in a higher incidence of serious (grade 3/4) neutropenia (61 versus 0.9 percent) and grade 2/3 neuropathy (0.9 versus 0 percent).

Despite these findings, several issues limit the universal application of these data in metastatic breast cancer:

•Over 70 percent of patients in this study had hormone-positive breast cancer; of these patients, only about 20 percent of these individuals had received prior endocrine therapy and, for those in the control arm, endocrine therapy was not initiated after chemotherapy was discontinued.

•The median age of participants was 48, suggesting that younger patients were preferentially enrolled.

•The benefit in PFS was seen predominantly in the subgroup who were age <50 years, had hormone receptor-negative disease, had responded to chemotherapy, and had visceral disease.

While these data support maintenance chemotherapy for individuals with metastatic breast cancer, it should not be considered a universal approach to the treatment of these patients, especially when one considers the biologic heterogeneity of breast cancer and the multiple ways that disease can be treated. However, in the setting of endocrine-refractory disease, the options other than chemotherapy are limited to observation or a clinical trial [75].

DEFINITION OF TREATMENT FAILURE — In our own practice, we monitor for treatment failure by taking into account serial changes in tumor markers, evidence of disease progression based on serial imaging, and the clinical status of the patient. Some criteria that we use to define treatment failure include any of the following:

●Clinical deterioration during treatment (ie, increasing disease related symptoms, intolerable treatment toxicities, declining performance status)

●Evidence of new metastases

●Increasing size of previously documented metastatic lesions

RECIST criteria — The primary role of Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is to standardize the reporting of results on clinical trials (table 2) [76]. RECIST primarily applies to imaging of metastatic disease, and it encompasses two of the three reasons for treatment failure.

According to RECIST, disease progression on imaging is defined as any of the following:

●A 20 percent or more increase in the sum of measurable target lesions compared with the smallest sum previously recorded

●The appearance of any new lesions

●Worsening of existing non-target lesions, for example, bone metastases

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Despite the gains in early detection, up to 5 percent of individuals diagnosed with breast cancer have metastatic disease at the time of first presentation. In addition, up to 30 percent of individuals with early-stage, non-metastatic breast cancer at diagnosis will develop distant metastatic disease. Although metastatic breast cancer is unlikely to be cured, meaningful improvements in survival have been seen, coincident with the introduction of newer systemic therapies. (See 'Introduction' above.)

●The goals of treatment of metastatic breast cancer are to prolong survival and improve quality of life by reducing cancer-related symptoms. In order to achieve these goals an individualized approach is needed since no one strategy can be applied for all individuals. (See 'Indications' above.)

●For most patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, endocrine therapy with inclusion of a cyclin-dependent kinase (CDK) 4/6 inhibitor in either the first or second line is the preferred treatment. However, we suggest chemotherapy if the disease is rapidly progressive, and the patient is at risk for organ failure if a rapid response is not achieved (Grade 2C). (See 'Indications' above.)

●For patients in whom chemotherapy is recommended, the choice of regimen (ie, single-agent or a combination) and selection of a specific therapy depends on multiple factors, including the tumor burden (both in tumor volume and the presence of disease-related symptoms), general health status, prior treatments and toxicities, and patient preferences. These factors can help in the formulation of an individualized treatment plan in the first- or later-line setting. (See 'Factors influencing chemotherapy choice' above.)

●For patients with hormone receptor-positive, HER2-negative metastatic breast cancer that is refractory to endocrine therapy, we suggest single-agent chemotherapy administered sequentially rather than combination chemotherapy (Grade 2B). (See 'Single-agent chemotherapy' above.)

●For select patients with symptomatic disease due to the location of specific metastatic lesions (eg, right upper quadrant pain due to expanding liver metastases, or dyspnea related to diffuse lung metastases) and a large tumor burden, we suggest a combination regimen rather than a single-agent (Grade 2B). Combination therapy results in a greater likelihood of a response compared with single-agent therapy, which may be of a sufficient benefit to justify the risks of treatment. (See 'Combination chemotherapy' above.)

●Careful assessment for response to treatment requires serial clinical examination, repeat lab evaluation (including tumor markers), and radiographic imaging. (See 'Monitoring therapy' above.)

●Unlike in the adjuvant setting, there is no predetermined duration of treatment. For a patient with endocrine-refractory disease who is responding to treatment, we continue chemotherapy until the time of progression. However, for patients who experience side effects to treatment or prefer not to continue treatment for whatever reason, discontinuation of treatment is reasonable. Patients with estrogen receptor-positive disease who received chemotherapy in the first line may consider switching to endocrine therapy for maintenance treatment. (See 'Duration of treatment' above.)

●Some criteria that we use to define treatment failure include any of the following: clinical deterioration during treatment (ie, increasing disease-related symptoms, intolerable treatment toxicity, a decline in performance status), appearance of new metastases, and increasing size of previously documented metastatic lesions. (See 'Definition of treatment failure' above.)