Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer

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, designated "de novo" metastases. 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. More recently, a subset of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancers have been defined to have HER2 "low" disease. Chemotherapy choice in this group is also included in this topic.

It should be noted that many of the early trials (initiated prior to 2001) referenced in this topic enrolled patients with both hormone receptor-positive, 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. These entities continue to evolve; for example, given the benefits of trastuzumab deruxtecan in patients without highly over-expressed HER2, these definitions will need to be refined. Regardless, the discussions and recommendations in this topic are focused on patients with ER-positive disease, defined by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines as ≥1 percent positive cells by immunohistochemical staining [6-9].

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 "Overview of the approach to metastatic breast cancer".)

●(See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

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

●(See "Breast cancer in men".)

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

GOALS OF TREATMENT AND DEFINITIONS — 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.

Although endocrine therapy is typically employed for patients with hormone-receptor positive, HER2-negative breast cancer (particularly in the initial treatment setting), cytotoxic chemotherapy may be preferred in select patients with symptomatic hormone receptor-positive breast cancer, who have the following presentations [10]:

●Endocrine therapy resistant disease – Those who experience rapid disease progression following at least one endocrine therapy (ie, endocrine-resistant disease)

●Endocrine therapy refractory disease – Patients with disease that has progressed on multiple lines of endocrine therapy

Further discussion on the choice between endocrine therapy and chemotherapy is found elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'Choosing between endocrine therapy and chemotherapy'.)

The administration of endocrine therapy for patients with hormone receptor-positive metastatic breast cancer is covered separately. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer" and "Overview of the approach to metastatic breast cancer".)

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 (algorithm 1).

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 examination 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 [11]. (See 'Initial 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 [12]. 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 versus single agent 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. (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 'Initial 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, use of nanoparticle albumin-bound paclitaxel [nabpaclitaxel] instead of paclitaxel).

●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.

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 [13]. 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. (See 'Anthracyclines' below.)

●Patients with pancytopenia due to myelophthisic disease, or 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, every-three-week docetaxel). In these situations, single-agent treatment using a weekly anthracycline, capecitabine, or a weekly taxane may be more appropriate.

●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 capecitabine, fam-trastuzumab deruxtecan (T-DxD), sacituzumab govitecan, anthracyclines, or other agents.

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 [14].

For patients with metastatic HER2-negative breast cancer and germline 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 "Overview of the approach to metastatic breast cancer", section on 'Special considerations'.)

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 docetaxel, T-DxD, and liposomal doxorubicin.

●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). Alternatively, such individuals may prefer regimens given every three weeks, as discussed above, used with a scalp cooling device to reduce hair loss. (See "Alopecia related to systemic cancer therapy", section on 'Scalp hypothermia (scalp cooling)' and 'Single-agent chemotherapy' below and '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.)

INITIAL CHEMOTHERAPY — There are a number of agents with activity in metastatic breast cancer. Because the taxanes and capecitabine are most commonly administered, especially in the first-line treatment of metastatic breast cancer, they are presented first.

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 [15]. In addition, a 1998 meta-analysis showed that combining these treatments was not more effective than the use of chemotherapy alone [16].

Preferred options

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) [17]. 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 compared with weekly dosing [18]. Docetaxel is associated with a significant risk of fluid retention, which is reduced by premedication with dexamethasone [19].

●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) [17,18,20]. 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 (OS) in patients with advanced breast cancer (hazard ratio [HR] 0.78, 95% CI 0.67-0.89) [17].

It should be noted that patients treated with paclitaxel are at risk for infusion reactions as a result of the composition of paclitaxel, which is mixed with a solubilizer. At most institutions, steroids (eg, dexamethasone 20 mg the night before and morning of infusion), H1 blockers (eg, diphenhydramine 25 mg), and H2 blockers (eg, famotidine 10 mg) are administered, although these can often be discontinued if the first two or three doses are tolerated. However, the schedule and administration of premedications varies by institution.

●Nabpaclitaxel – Nabpaclitaxel has activity in metastatic breast cancer similar to other taxanes [21-23]. It may be of particular benefit to patients who are at risk for hyperglycemia, those who cannot tolerate steroids, or those with a history of infusion reactions to paclitaxel. Nabpaclitaxel has a lower risk of infusion 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. By 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, but otherwise has a toxicity profile similar to paclitaxel.

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 [24]. 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 administration with bevacizumab) in a randomized phase III trial [25]. 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 'Other agents' below.)

•No statistically 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 statistically significant difference in OS 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).

Capecitabine — 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 following 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 1500 mg twice daily on days 1 to 7 and 15 to 21 of a 28-day schedule has shown similar outcomes in a randomized trial, with less toxicity [26].

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 [27]. (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 [28,29]:

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

●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) [29].

Capecitabine may cause excess toxicity in the case of dihydropyridine dehydrogenase (DPYD) deficiency, which is present in approximately 5 percent of the population. Pre-emptive genotyping has not been routinely implemented into standard clinical practice due to the low carrier frequency and genotyping costs (although there has been an increasing call to do so [30,31]). 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 [32,33].

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 "Overview of the approach to metastatic breast cancer", section on 'Monitoring therapy'.)

Careful assessment for response to treatment requires serial clinical examination, repeat laboratory 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 examination 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) if they were elevated at baseline. If performed, we typically reevaluate them at the beginning of each treatment cycle.

DEFINITION OF TREATMENT FAILURE — In our own practice, we monitor for treatment failure by taking into account serial changes in or appearance of new symptoms, abnormal liver function tests, circulating tumor markers, and evidence of disease progression based on serial imaging. Some criteria that we use to define treatment failure include any of the following:

●Clinical deterioration during treatment (ie, increasing or new 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) [34]. 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

SUBSEQUENT LINE OPTIONS

HER2-"low" tumors

Fam-trastuzumab deruxtecan (T-DxD) — For patients with hormone receptor-positive, endocrine-refractory tumors that are HER2 immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization (ISH) negative, fam-trastuzumab deruxtecan (T-DxD) has been found to improve progression-free survival (PFS) and overall survival (OS) compared with other chemotherapy regimens in the second or later lines [35]. We offer T-DxD for patients with hormone receptor-positive, HER2-low metastatic breast cancer after progression on capecitabine and/or taxane in the metastatic setting. For patients with severe underlying lung disease, T-DxD may not be appropriate due to the risk of pneumonitis with this drug.

T-DxD is an antibody-drug conjugate consisting of a trastuzumab targeting molecule conjugated to deruxtecan, a topoisomerase-1 inhibitor. It was originally approved for HER2-positive metastatic breast cancer.

DESTINY-Breast04 was a phase III trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. Low expression of HER2 was defined as a score of 1+ on IHC analysis or as an IHC score of 2+ and negative results on ISH [35]. Patients were randomly assigned in a 2:1 ratio to receive T-DxD or the clinician's choice of chemotherapy. This trial included both patients with hormone receptor positive and those with hormone receptor negative tumors, and the overall results are discussed elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'HER2-low tumors'.)

Among the 494 patients with hormone receptor-positive disease, the median PFS was 10.1 months in the T-DxD group and 5.4 months in the clinician's choice group (hazard ratio [HR] for disease progression or death 0.51, 95% CI, 0.40-0.64), and OS was 23.9 months and 17.5 months, respectively (HR for death 0.64, 95% CI, 0.48-0.86).

Adverse events of ≥grade 3 occurred in 53 percent of the patients who received T-DxD and 67 percent of those who received the clinician's choice of chemotherapy. Drug-related interstitial lung disease or pneumonitis occurred in 12 percent of the patients who received T-DxD; 0.8 percent had grade 5 events.

T-DxD has shown activity in brain metastases in HER positive metastatic breast cancer, and may be a good option in patients with a history of central nervous system metastases. (See "Brain metastases in breast cancer" and "Brain metastases in breast cancer", section on 'Fam-trastuzumab deruxtecan'.)

The precise method to distinguish HER2 0 from 1+ after IHC staining has not been determined, and some have argued that the distinction is not biologically relevant, and that the benefit of antibody-drug conjugates in this setting is likely primarily related to the delivery of cytotoxic molecules, rather than the blockade of the HER2 pathway [36]. Indeed, in one phase II study, patients with HER2-low and HER2-nonexpressing cancers experienced similar objective response rates to T-DxD (38 and 30 percent, respectively, versus 71 percent among HER2-overexpressing cancers) [37].

In the DESTINY-Breast04 trial, all tissues were stained using a single monoclonal antibody (Mab 4D5) and were read in a central laboratory. The concordance among pathologist to distinguish 0 from 1+ is reported to be poor [38]. Efforts to use a more quantitative and accurate method to assess HER2 have been reported but are not yet validated for routine clinical use [39].

Upon progression on T-DxD

Single-agent chemotherapy — For patients with HER2-low tumors who have experienced progression on T-DxD, there is no standard approach. At this time, it is not known whether patients with HER2-low metastatic breast cancer who have progressed on T-DxD will have a good response to sacituzumab govitecan (SG), since both drugs have a topoisomerase-1 cytotoxic agent. In our practice, we do not routinely sequence these drugs, and instead go to a non-cross resistant drug. (See 'Preferred options' above and 'Later line (or alternative) single-agent chemotherapy options' below.)

Other HER2-negative cancers (HER2 "0")

Single-agent chemotherapy — For patients who have progressed on a taxane and capecitabine and have HER2 0 tumors, a subsequent line of single-agent chemotherapy is appropriate, provided that the patient remains a candidate for therapy. (See 'Preferred options' above and 'Later line (or alternative) single-agent chemotherapy options' below.)

Upon progression on two prior chemotherapies

Sacituzumab govitecan — SG has received approval by the US Food and Drug Administration (FDA) for patients with unresectable locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting [40,41]. We consider use of SG in our hormone receptor-positive, HER2 0 (not low) metastatic breast cancer patients after progression on endocrine therapy, as well as capecitabine and taxanes in the metastatic setting. Although SG is also an option in hormone receptor-positive, HER2-low tumors after progression on two prior lines of chemotherapy, patients with such cancers are typically offered T-DxD earlier in their treatment course, and therefore may not be good candidates for further treatment with a topoisomerase-1 cytotoxic agent. If they have not received T-DxD, SG is an appropriate option after progression on two chemotherapies.

SG is an antibody-drug conjugate consisting of an antibody targeting TROP-2, conjugated to SN-38, a topoisomerase-1 inhibitor. It was originally approved for triple-negative metastatic breast cancer. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Sacituzumab govitecan'.)

TROPiCS-02 was a randomized trial involving patients with metastatic or locally recurrent inoperable hormone receptor-positive/HER2-negative breast cancer that progressed after at least one endocrine therapy, a cyclin-dependent kinase (CDK) 4/6 inhibitor in any setting, and at least two, but no more than four, lines of chemotherapy for metastatic disease [42,43]. Prior treatment must have included a taxane in either the neo/adjuvant or advanced disease setting. Patients were randomly assigned in a 1:1 ratio to receive SG or the clinician's choice of chemotherapy (choices included capecitabine, vinorelbine, gemcitabine, or eribulin).

Among 543 patients, the median PFS was 5.5 months in the SG group and 4.0 months in the clinician's choice group (HR for disease progression or death 0.66, 95% CI 0.53-0.83) [44]. In a subsequent publication with longer follow up SG resulted in a longer median OS relative to the clinician's choice group (14.4 versus 11.2 months, HR 0.79, 95% CI 0.65-0.96) [45].

Grade ≥3 treatment-emergent adverse events occurred in 74 percent on SG and 60 percent on TPC; neutropenia (51 versus 38 percent) and diarrhea (9 versus 1 percent) were most common.

LATER LINE (OR ALTERNATIVE) SINGLE-AGENT CHEMOTHERAPY OPTIONS — For patients who have progressed on initial lines of chemotherapy (or are not candidates for the agents above), others are available and have documented activity against breast cancer.

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 [46,47]

●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 [48-50]

●Pegylated liposomal doxorubicin (PLD; 40 mg/m² every four weeks) – ORR 10 to 33 percent [51,52]

Approach to managing cardiotoxicity — One potential downside of using anthracycline regimens is the risk for cumulative cardiac toxicity, which may limit the duration of anthracycline-based therapy. The recommended lifetime cumulative dose limit of doxorubicin hydrochloride is 450-550 mg/m². 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 [53]. Further, the clinician may wish to use alternative doses and schedules than are commonly used in the adjuvant setting, such as low-dose weekly (20 mg/m²) treatment, or as a longer (24 hours) infusion.

The use of an alternative anthracycline agent, PLD also limits cardiotoxicity [54]. Although there is no dose limit of PLD, our practice is to initiate cardiac monitoring in patients with cardiac risk factors who have received >450 mg/m². We have not found it necessary to add dexrazoxane to PLD. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Comparing anthracyclines — Our preferred anthracycline in the metastatic hormone receptor-positive setting is PLD administered at 40 mg/m² every four weeks, because it 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 PLD 50 mg/m² given every four weeks or doxorubicin 60 mg/m² given every three weeks [51]. Compared with doxorubicin, PLD, resulted in:

●Slightly lower ORR (33 versus 38 percent).

●Similar progression-free survival (PFS; median, 6.9 versus 7.8 months) and OS (median, 21 versus 22 months; HR 0.94), though PFS measures were confounded by more frequent assessments in the every-three-week doxorubicin arm.

●A decrease in the risk of cardiotoxicity (7 versus 26 percent).

●Lower rates of alopecia (20 versus 66 percent), nausea (37 versus 53 percent), vomiting (19 versus 31 percent), and neutropenia (4 versus 10).

●Higher rate of plantar-plantar erythrodysesthesia (48 versus 2 percent), stomatitis (22 versus 15 percent), and mucositis (23 versus 13 percent).

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 [55-58]. For example, in a phase III trial of 762 heavily pretreated patients randomly assigned to treatment with eribulin or other chemotherapy (based on clinician's and patient's choice), eribulin significantly improved OS (median, 13.1 versus 10.6 months) [57]. 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 [56]. Unlike the trial above, there was no difference between eribulin and capecitabine in terms of PFS (four months in each) or ORR (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) [59]. 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 [60-62]. As it is also a microtubule-directed agent, we rarely use vinorelbine in patients who have already received eribulin.

Other agents

●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.

Gemcitabine appears to cross the blood brain barrier and may be a good option in patients with a history of central nervous system metastases [63]. 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 [64-66]. 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 [67]. 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 [25], 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) [68]. 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 [69], 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 [70]. Alternate dosing schedules have also been reported.

Given the large number of other options, we rarely use ixabepilone in our practice, and encourage clinical trial participation for our patients who have received all other available approved therapies.

●Etoposide – Oral etoposide (50 mg/m² daily for 21 days every 28 days) is a later-line choice 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 [71-73].

●Platinum agents – Carboplatin and cisplatin are rarely used as single agents in hormone receptor-positive metastatic breast cancer, although single-agent use in patients with germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2), or other homologous recombination deficiency 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) [74]. There is also interest in using these agents as part of a combination regimen. (See 'Other regimens' below.)

Given the large number of other options, we rarely use single-agent platinums in our patients with hormone receptor-positive metastatic breast cancer, and encourage clinical trial participation for our patients who have received all other available approved therapies.

SPECIAL CONSIDERATIONS FOR THOSE WITH RAPIDLY PROGRESSIVE DISEASE

Combination chemotherapy versus endocrine therapy with targeted agents — The choice between chemotherapy and endocrine therapy is discussed elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'Choosing between endocrine therapy and chemotherapy'.)

Combination versus single agent chemotherapy — Combination chemotherapy (rather than single-agent sequential therapy) may be 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 (OS) 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 (8 versus 6 and 6 months)

●However, there was no difference in 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 relative to single-agent chemotherapy [12], 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.

Combination chemotherapy regimens — For patients in whom combination chemotherapy is chosen, 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 [75-78], although they are more toxic than sequential single-agent treatment or non-anthracycline-containing combinations [48,79].

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 [80]. 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 OS between anthracycline plus taxane versus anthracycline combinations that do not contain a taxane [80].

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

●Doxorubicin plus cyclophosphamide – ORR ranges from 47 to 54 percent [81,82]

●Epirubicin with cyclophosphamide and fluorouracil – ORR ranges from 45 to 55 percent [48,79]

●Doxorubicin, docetaxel, plus cyclophosphamide – ORR 77 percent [83]

●Doxorubicin plus paclitaxel or docetaxel – ORR is approximately 40 percent for either combination [84]

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 naïve, 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 [85]. 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 [86]. 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 [87]. Several studies also suggest it improves survival over single-agent docetaxel even when capecitabine was mandated on disease progression [87,88]. However, limited data suggest that CD is equivalent to gemcitabine plus docetaxel but is the more toxic combination [86].

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 [89].

●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 [90]. 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 [91].

Avoidance of 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 OS and that any benefit from this treatment was minimal. Therefore, we advise against these treatments for metastatic breast cancer [92].

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 "Interventional therapies for chronic pain".)

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

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) [93]. 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 [94]. 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 approximately 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 [95].

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

●Introduction – 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, designated "de novo" metastases. In addition, up to 30 percent of individuals with early-stage, non-metastatic breast cancer at diagnosis will develop distant metastatic disease. (See 'Introduction' above.)

●Goals of treatment and general approach – 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 'Goals of treatment and definitions' above.)

Although endocrine therapy is typically employed for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (particularly in the initial treatment setting), cytotoxic chemotherapy may be used to achieve these goals in select patients (eg, those presenting with rapid disease progression following more than one endocrine therapy or disease that is refractory to multiple lines of endocrine therapy). (See "Overview of the approach to metastatic breast cancer", section on 'Choosing between endocrine therapy and chemotherapy'.)

●Choice of chemotherapy

•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 2C). (See 'Tumor burden' above.)

•However, for select patients with symptomatic disease due to the location of specific metastatic lesions and a large tumor burden, a combination regimen rather than a single-agent is more appropriate. 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 versus single agent chemotherapy' above.)

●Subsequent line options – For second- and third-line chemotherapy, two antibody-drug conjugates have recently been shown to be more effective than other available chemotherapies, fam-trastuzumab deruxtecan, in HER2-"low" tumors, and sacituzumab govitecan. (See 'Subsequent line options' above and "Overview of the approach to metastatic breast cancer", section on 'HER2-low tumors'.)

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

●Duration of treatment – 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. (See 'Duration of treatment' above.)

●Definition of treatment failure – 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.)