INTRODUCTION — Although metastatic breast cancer (MBC) is unlikely to be cured, meaningful improvements in survival have been seen, coincident with the introduction of newer systemic therapies [1-3]. Median overall survival now is slightly over three years, with a range from a few months to many years [4].

The selection of a therapeutic strategy depends upon both tumor biology and clinical factors, with the goal being a tailored approach. Although a subset of patients with oligometastatic disease may benefit from an intensified locoregional approach, most patients with MBC receive systemic medical therapy consisting of chemotherapy, endocrine therapy, and/or biologic therapies, and supportive care measures [5,6].

General principles of management of MBC are presented here. Details of single-agent and combination chemotherapy, endocrine therapy, biologic therapy, and how to select among them, as well as locoregional approaches, osteoclast inhibitors (bisphosphonates and receptor activator of nuclear factor kappa-B [RANK] ligand inhibitors), and supportive care, are discussed separately.

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

●(See "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer".)

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

●(See "The role of local therapies in metastatic breast cancer".)

●(See "Treatment of metastatic breast cancer in older women".)

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

THERAPEUTIC GOALS — The primary goals of systemic treatment for MBC are prolongation of survival, alleviation of symptoms, and maintenance or improvement in quality of life, despite the toxicity associated with treatment [7-9]. The median survival for MBC varies widely based on subtype of tumor, sites of metastatic involvement, and burden of metastatic disease, and some patients experience long-term survival [1-3,10,11]. (See 'Prognosis' below.)

TUMOR BIOLOGY AND RISK ASSESSMENT — Biologic markers such as hormone receptor status, human epidermal growth factor receptor 2 (HER2) overexpression, and tumor burden have both prognostic and predictive value and are important factors in selecting appropriate treatment.

Disease assessment — Complete evaluation for the extent of metastatic disease includes confirmatory biopsy of suspected lesions and reassessment of molecular markers, particularly estrogen receptor (ER), progesterone receptor (PR), and HER2 overexpression. This is especially important if the primary cancer was deemed negative for ER, PR, and/or HER2, since a conversion to positive could dramatically change therapy.

We further assess tumors for presence of mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2). For patients whose tumors stemmed from mutations in BRCA1 or BRCA2, we suggest germline testing for these mutations, in view of therapeutic options (poly[ADP-ribose] polymerase [PARP] inhibitors), as per National Comprehensive Cancer Network guidelines [12-14]. (See 'PARP inhibition for BRCA carriers' below.)

We also evaluate tumors for mutations in tropomyosin receptor kinase (TRK) [15,16], as well as for the presence of microsatellite-high/DNA mismatch-repair deficiency [17]. (See 'General approach' below.)

Role of repeat biopsy — We advise patients with newly diagnosed, metastatic disease to undergo a repeat biopsy, which will not only establish the diagnosis of MBC, but will also allow a re-examination of receptor status. Although how these results should influence management is the subject of debate, we suggest not withholding targeted treatment based on the results of a metastatic biopsy. Results of the metastatic biopsy may, however, make targeted therapies available for those whose initial biopsy did not display hormone receptor or HER2 positivity.

In 2015, the American Society of Clinical Oncology (ASCO) reported its guidelines about the role of rebiopsy, suggesting that it should be performed, but there is no prospective evidence that changing treatment based on the information of the metastatic biopsy affects outcomes. Neverthess, per this guideline, in case a biopsy is performed and discrepancy is found between the primary and metastatic tumors, information from the metastatic setting should be utilized for management decisions [18]. A 2018 European Society for Medical Oncology (ESMO) guideline acknowledges the lack of prospective trials evaluating change in treatment based on immunohistochemical discrepancies between primary and metastatic tumors, but recommends consideration to utilize targeted treatment (endocrine therapy or anti-HER2 therapy) if the receptors are positive in at least one of the biopsies, regardless if in the primary or metastatic settings [19]. Our strategy is consistent with the ESMO guideline, although we recognize that in the setting of limited data, other experts may adopt a different approach.

The rates of discordance of receptor status between the primary and metastatic lesions vary, but typically range between 5 to 30 percent [20,21]. This type of conversion may represent a biologic evolution, partly due to selection pressure from the different agents administered. Some experts believe that the conversion could also represent a methodologic phenomenon, linked to status of which HER2 testing was being utilized, the condition of the fixed paraffin-embedded block, and even a sampling issue, as tumors are clearly heterogeneous. One report evaluated the conversion rate of hormone receptors and HER2 and concluded that patient outcomes are dictated by the new phenotype and not by the characteristics of the primary tumor [22]. However, this needs to be cautiously interpreted, in view of the influence of sampling or methodology errors, as we would not want to deprive patients from their targeted treatment when appropriate [20].

Prediction of response — The following are predictors or treatment response:

●Hormone receptor status and HER2 overexpression are the most important predictors of treatment response in patients with MBC. (See "Prognostic and predictive factors in metastatic breast cancer", section on 'Tests done on metastatic tissue'.)

●Patients who are carriers of genetic alterations in breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2) are more likely to respond to PARP inhibitors. Thus, we suggest germline testing for these mutations in patients with advanced breast cancer, as per National Comprehensive Cancer Network guidelines [14]. (See 'PARP inhibition for BRCA carriers' below.)

●In regards to response to chemotherapy, consistent predictors of poor response are progression with prior chemotherapy for advanced disease, relapse within 12 months of completing adjuvant chemotherapy, poor performance status, and multiple disease sites, especially visceral involvement [23-33].

Markers of increased cellular proliferation such as high S-phase fraction by flow cytometry, increased uptake of radiolabeled thymidine, and immunohistochemical staining for the proliferation antigen Ki67 are all associated with higher chemotherapy response rates [34-36]. By contrast, breast cancers that overexpress p-glycoprotein (gp170), a drug efflux pump that mediates multidrug resistance, or have a mutated tumor protein p53 (TP53) gene may be less likely to respond to chemotherapy [37-40]. At present, none of these markers should be used to make clinical decisions.

Another possible approach is the use of chemotherapy sensitivity and resistance assays [41-43]. However, the clinical utility of these assays remains unclear [37,44,45]. The detection and monitoring of circulating tumor cells during treatment for MBC is discussed below. (See 'Circulating tumor cells' below.)

SYSTEMIC TREATMENT — The following sections provide a brief overview of our approach to specific subsets of advanced cancers, with links to more detailed discussions.

General approach — The aim of treatment is to palliate symptoms, prolong survival, and maintain quality of life. Patients with visceral metastases (especially if rapidly progressing) and/or a short disease-free interval generally have an aggressive phenotype, while patients with soft tissue and bone metastases have a more indolent phenotype.

With these principles in mind, our general approach is as follows:

●Hormone receptor status and human epidermal growth factor receptor 2 (HER2) overexpression are important in estimating prognosis and the likelihood of response to therapy.

•Hormone receptor (estrogen receptor [ER] and/or progesterone receptor [PR]) status is the major determining factor for response to endocrine therapy.

-Endocrine therapy is favored over chemotherapy as initial treatment for most patients with hormone receptor-positive, HER2-negative MBC, but in patients presenting with frank visceral crisis, chemotherapy should be favored.

When using endocrine therapy, addition of certain targeted therapies for hormone receptor-positive cancers is often appropriate. Examples include cyclin-dependent kinase (CDK) 4/6 inhibitors, inhibitors of mechanistic target of rapamycin (mTOR), and phosphoinositide 3-kinase (PI3K) inhibitors for those whose tumors harbor mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents".)

•Likewise, HER2 overexpression is required for response to HER2-directed therapies. HER2-directed therapy is only appropriate for patients with tumors that overexpress HER2. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

●Chemotherapy is indicated for hormone-insensitive MBC (ie, patients with hormone receptor-negative breast cancer and those with hormone receptor-positive breast cancer who have become resistant to endocrine therapy).

•For those with advanced, triple-negative disease, the anti-programmed cell death protein 1 (PD-1) inhibitor atezolizumab is added to taxane-based chemotherapy. (See 'Hormone receptor-negative, HER2-negative patients' below.)

•Discussions informing when to use single-agent versus combination chemotherapy, how to best incorporate biologic therapies, and whether combined modalities are of benefit are found elsewhere. (See 'Hormone receptor-positive, HER2-negative patients' below and 'Sequential single agents versus combination chemotherapy' below.)

●Poly(ADP-ribose) polymerase (PARP) inhibitor therapy is only appropriate for patients with breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) mutations, and is used after progression on chemotherapy in such patients. (See 'PARP inhibition for BRCA carriers' below.)

●For patients with tropomyosin receptor kinase (TRK)-positive cancers that have progressed on other available options, we offer treatment with TRK inhibitors (ie, entrectinib and larotrectinib) [15,16]. Those with microsatellite-high/DNA mismatch-repair deficiency may benefit from pembrolizumab, after progression on other treatment options [17].

Hormone receptor-positive, HER2-negative patients — In general, endocrine therapy (with or without CDK 4/6 inhibition) is very likely to be beneficial for these patients, with fewer side effects compared with chemotherapy. Therefore, these options should be used as initial treatment for most patients with hormone receptor-positive disease. However, patients with rapidly progressive, symptomatic disease or visceral metastases with end-organ dysfunction may be best treated with first-line chemotherapy, given the higher response rates observed with chemotherapy. After chemotherapy response stabilizes (usually four to six months), a switch to maintenance endocrine therapy is a commonly employed strategy, which can reduce the treatment side effects without compromising overall survival (OS) [7,46,47].

●Selection of endocrine therapy and accompanying targeted agents is discussed separately. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents".)

●Selection of chemotherapy is discussed separately. (See "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer".)

●Special considerations for patients with germline BRCA mutations are discussed below. (See 'PARP inhibition for BRCA carriers' below.)

Hormone receptor-positive, HER2-positive patients — Therapeutic options for these patients include chemotherapy, endocrine therapy, and human epidermal growth factor receptor 2 (HER2)-directed therapy. HER2-directed therapy has demonstrated improved survival for patients with tumors that overexpress HER2 and thus should be part of first-line therapy for these patients.

Whether it is better to use HER2-directed therapy combined with chemotherapy versus endocrine therapy as first-line treatment is unclear. HER2-directed therapy combined with chemotherapy or endocrine therapy is discussed separately. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

Hormone receptor-negative, HER2-negative patients — Many patients with triple-negative (ER-negative, PR-negative, human epidermal growth factor receptor 2 [HER2]-negative) breast cancer have a particularly aggressive subtype, and first-line chemotherapy is recommended, with or without immunotherapy. Whether chemotherapy agents are given in combination or sequentially should be determined based on symptoms and location and burden of disease, as well as patient-related factors (ie, preferences, goals, and overall health).

●Triple-negative breast cancer is discussed in detail separately. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer".)

●Selection of chemotherapy regimen is discussed separately. (See "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer".)

●Special considerations for patients with germline BRCA mutations are discussed below. (See 'PARP inhibition for BRCA carriers' below.)

Hormone receptor-negative, HER2-positive patients — The combination of human epidermal growth factor receptor 2 (HER2)-directed therapy and chemotherapy is recommended for treatment-naϊve patients.

●Regimens combining HER2-directed therapy with chemotherapy are discussed separately. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

SPECIFIC CONSIDERATIONS

Sequential single agents versus combination chemotherapy — In general, single-agent chemotherapy, used in sequence, is preferable to combination chemotherapy, since the single-agent chemotherapy is reasonably likely to induce palliation with fewer side effects, and no studies have demonstrated an overall survival (OS) benefit for the combination chemotherapy as long as both drugs are available in sequence. 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 that combination chemotherapy improves OS compared with single-agent, sequential cytotoxic chemotherapy. (See "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Combination chemotherapy'.)

Combining treatment modalities — In theory, combining chemotherapy, biologic therapy, and/or endocrine therapy might have additive efficacy, but it might also lead to increased toxicity. Clinical trials have failed to show a survival advantage for the concurrent administration of chemotherapy and endocrine therapy over either single modality [7,48,49].

However, human epidermal growth factor receptor 2 (HER2)-directed therapy (trastuzumab, pertuzumab, lapatinib, etc) has been successfully combined as individual agents with chemotherapy and endocrine therapy, and with each other. Likewise, endocrine therapies with targeted treatments (cyclin-dependent kinase [CDK] 4/6 inhibitors, mechanistic target of rapamycin [mTOR] inhibitors, phosphoinositide-3 kinase [PI3K] inhibitors) have also been successfully combined. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents".)

PARP inhibition for BRCA carriers — Germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) have been detected in 5 percent of patients with metastatic breast cancer [50]. For patients with metastatic, HER2-negative breast cancer with germline BRCA mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease setting (and who have also received at least one line of endocrine therapy, if they have hormone receptor-positive disease), we suggest an oral inhibitor of poly(ADP-ribose) polymerase (PARP).

Olaparib has been approved by the US Food and Drug Administration (FDA) for patients with germline BRCA mutations and HER2-negative breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease setting [51]. Olaparib has also shown activity among those with somatic BRCA mutations and germline partner and localizer of BRCA2 (PALB2) mutations, although it has not been evaluated in randomized trials in these populations [52].

Talazoparib is FDA approved for patients with germline BRCA mutations and HER2-negative, locally advanced, or metastatic breast cancer [53]. Patients with hormone receptor-positive disease may also be considered for treatment with olaparib if they have progressed after one line of endocrine therapy. We opt for use of PARP inhibitors sequentially after chemotherapy rather than concurrently, for tolerability.

Two trials have demonstrated the single-agent activity of the oral inhibitors of PARP olaparib and talazoparib in this setting. In these trials, patients with germline BRCA mutations and metastatic disease, who had previously received chemotherapy in the neoadjuvant, adjuvant, or metastatic setting, were randomly assigned to the PARP inhibitor or to one of a few single-agent chemotherapeutic agents, which were chosen at the discretion of the treating clinician. In both trials, the PARP inhibitor was superior to chemotherapy for progression-free survival (PFS), the primary endpoint, as well as for response and toxicity. Thus, PARP inhibitors in this setting proved more effective and less toxic than conventional chemotherapy. However, neither of these trials compared PARP inhibitors specifically against platinum-based chemotherapy, though each study showed measurable clinical activity of the PARP inhibitor among the subset of patients previously treated with cisplatin or carboplatin.

Further details of these studies are as follows:

●Olaparib – In the phase III OlympiAD trial, over 300 patients with metastatic, HER2-negative, BRCA-associated breast cancer were randomly assigned in a 2:1 ratio to olaparib or to chemotherapy (either single-agent capecitabine, eribulin, or vinorelbine) [12]. All patients had received an anthracycline and a taxane in either the adjuvant or metastatic setting, and those with hormone receptor-positive disease had also received prior endocrine therapy.

At a median follow-up of approximately 14 months, those receiving olaparib experienced an improved PFS relative to those treated with chemotherapy (7.0 versus 4.2 months, respectively; hazard ratio [HR] 0.58, 95% CI 0.43-0.80). Overall survival (OS) between the two groups at approximately 25 months of follow-up was not significantly different, except for the prespecified subgroup with no prior chemotherapy for MBC (HR 0.51, 95% CI 0.29-0.90), although results are still immature [54]. PFS improvements with olaparib were greater in the triple-negative subgroup (HR 0.43, 95% CI 0.29-0.63) than among patients with hormone receptor-positive disease (HR 0.82, 95% CI 0.55-1.26).

The rate of grade 3 or higher adverse events was lower with olaparib than with chemotherapy (37 versus 51 percent), with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib, and neutropenia, palmar-plantar erythrodysesthesia, and liver function test abnormalities occurring more commonly with chemotherapy.

An open-label, single-arm phase IIIb study found similar efficacy (median PFS with olaparib of about eight months) and safety outcomes among similar patients as OlympiAD, in a setting reflecting clinical practice [55].

●Talazoparib – In the phase III EMBRACA trial, 431 patients with metastatic, HER2-negative, BRCA-associated breast cancer were randomly assigned in a 2:1 ratio to talazoparib or to chemotherapy (either single-agent capecitabine, eribulin, gemcitabine, or vinorelbine) [13].

At a median follow-up of approximately 14 months, those receiving talazoparib experienced an improved PFS relative to those treated with chemotherapy (8.6 versus 5.6 months, respectively; HR 0.54, 95% CI 0.41-0.71). With more than three years' follow-up, differences in OS between the two groups were not significantly different [56].

Talazoparib caused more anemia than standard chemotherapy; rates of neutropenia were comparable. For most nonhematologic toxicities, talazoparib was better tolerated. Patients receiving talazoparib reported improvements in quality of life, while those receiving chemotherapy reported worsened quality of life outcomes [57].

Further supporting the use of PARP inhibitors for BRCA-associated cancers, in preliminary reporting of a separate trial, the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel among patients with ≤2 prior lines of cytotoxic therapy for metastatic, BRCA-associated breast cancer improved median PFS (14.5 versus 12.6 months; HR 0.71, 95% CI 0.57-0.88) [58]. OS results were similar (33.5 versus 28.2 months; HR 0.95, 95% CI 0.73-1.2) between the two groups.

The approach and supporting data for PARP inhibitors among patients specifically with BRCA-associated, triple-negative breast cancer is discussed elsewhere. Chemotherapy in this subset is also discussed elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Germline BRCA mutation'.)

Osteoclast inhibitors — Patients with bone metastases should be treated with osteoclast inhibitors (bisphosphonates or receptor activator of nuclear kappa-B [RANK] ligand inhibition), as these agents have been shown to reduce the risk of skeletal-related events such as fractures, the need for surgery or radiation to bone, spinal cord compression, and hypercalcemia of malignancy. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "Use of osteoclast inhibitors in early breast cancer".)

High tumor mutational burden or microsatellite instability-high — For tumors that have high tumor mutational burden (≥10 mutations/megabase) or are microsatellite instability high or mismatch repair deficient, pembrolizumab is approved by the FDA. Supporting data largely come from "basket" studies, evaluating pembrolizumab in tumors representing multiple different primary sites that have these molecular features. However, these trials typically included only small numbers of patients with breast cancer [59]. Data from such studies and the approach to patients with breast cancer are discussed elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Clinical efficacy of anti-PD-1 therapy'.)

MONITORING THERAPY — Careful assessment of the response to therapy will assist in decisions for duration of treatment and in selection of subsequent treatments. However, the best approach for monitoring patients with MBC is not well established. Overall survival (OS) is the gold standard for comparing therapies, but it requires prolonged follow-up and may be diluted by the effects of subsequent treatment. However, no other endpoint, including progression-free survival (PFS), time to tumor progression, or objective response rate, has been shown to be a good surrogate for OS [60]. Comparisons of objective response rates are often used to determine relative treatment efficacy, but high response rates do not necessarily translate into clinically meaningful increases in survival [60-62]. In addition, symptom relief without measurable disease response and achievement of stable disease as compared with disease progression may be clinically important [63].

History and examination — If symptom palliation is the main objective, clinical history alone may suffice to determine the success of therapy. Physical examination may allow response quantitation if disease is easily accessible (eg, chest wall nodules, palpable lymphadenopathy). With a dramatic reduction in symptoms that were clearly disease related or obvious shrinkage of palpable lesions, serum markers and radiographic tests are likely to be irrelevant.

However, many patients have more subtle disease signs or symptoms that may be confused with treatment toxicity or other nonmalignant conditions. In addition, disease is not measurable by physical examination in nearly one-half of patients with MBC. In these patients, serial changes in tumor markers or radiographic studies are essential in establishing the response to therapy.

Tumor markers — Serial assay of serum tumor markers (eg, cancer antigen [CA] 15-3 and CA 27.29, both products of the mucin 1 [MUC1] gene, and carcinoembryonic antigen [CEA]) can aid in response assessment, particularly if disease sites are not assessable by usual criteria [64,65]. Judicious use of serial tumor marker measurements may decrease the need for periodic radiographic evaluation [66].

Guidelines from the American Society of Clinical Oncology (ASCO) expert panel suggest that it is reasonable to evaluate CA 15-3, CA 27.29, and CEA initially in patients with metastatic disease [64]. If CA 15-3 and/or CA 27.29 are elevated, there is no role for monitoring CEA, but if not, serial measurement of CEA levels may be useful.

Elevated tumor markers may occasionally be spurious. Thus, for patients without clear clinical or radiographic signs of progression, a rise in tumor markers alone should not dictate a change in treatment, although more frequent monitoring may be appropriate, in some instances. Up to 20 percent of patients successfully treated with systemic therapy may experience a transient increase (marker "flare") during the first one or two months after treatment initiation, presumably due to release of antigen by cytolysis [67,68]. Patients with abnormal liver function may also have falsely elevated marker levels because they are cleared by the liver [67]. CA 15-3 levels may be aberrantly elevated in patients with vitamin B12 deficiency and megaloblastic anemia, as well as in patients with thalassemia or sickle cell disease [69-71].

Radiographic studies — Serial plain radiographs, computed tomography (CT) scan, or magnetic resonance imaging (MRI) can permit assessment of tumor response. A reasonable frequency of routine monitoring is every three to six months, although scans may be obtained earlier if there are clinical signs or symptoms of progression. Periodic scintigraphic bone scans, while helpful, may also be misleading. Technetium (Tc99) phosphonate accumulates in areas of osteoblastic activity rather than in cancer cells. In a patient experiencing a response to therapy, a "scintigraphic healing flare" may appear as early as two months and persist for as long as 12 months after initiating therapy [72,73].

Integrated positron emission tomography (PET)/CT is popular as a whole-body examination in monitoring response to therapy in MBC, as it has demonstrated high sensitivity and specificity in detecting metastatic disease and can reliably assess response to therapy [74-76]. There is also some evidence that metabolic changes in bone metastases in response to systemic therapy (ie, a change in standardized uptake value [SUV]) can predict response duration or time to progression [77-79]. However, many integrated PET/CT scanners in clinical use provide a limited CT scan primarily for orientational purposes (determining where the PET abnormality is) and not a higher-resolution, fine-cut, contrast-enhanced CT scan. This should be kept in mind when evaluating response between modalities (standard CT and PET/CT). There are no studies to demonstrate whether it is preferable to monitor patients with either PET/CT or scintigraphic bone scanning and dedicated CT or MRI.

Circulating tumor cells — Detection of circulating tumor cells (CTCs) in blood samples of patients with MBC (≥5 CTCs) has been shown to be a predictor of PFS and OS [80-86]. However, the role of CTCs in the monitoring of patients remains controversial. Therefore, we agree with ASCO expert panels, which have concluded that measurement of CTCs should not be used to influence treatment decisions in metastatic disease at this time [64,87]. (See "Prognostic and predictive factors in metastatic breast cancer", section on 'Circulating tumor cells'.)

Immunologic and RNA-based methods are used to detect CTCs in breast cancer. In a prospective trial of 177 patients who were beginning a new therapy for MBC [81], elevated CTCs at baseline (defined as five or more CTCs per 7.5 mL of blood) compared with the finding of fewer or no detectable CTCs predicted a significantly shorter PFS (three versus seven months) and OS (10 versus 22 months). Patients with elevated CTCs at the first follow-up visit (within three to five weeks of initiating therapy) also had a worse PFS (two versus seven months) and OS (8 versus greater than 18 months), whereas those with a decrease in the number of CTCs from baseline had improved PFS and OS. Subsequent analyses from this trial and others have suggested that elevated levels of CTCs at any time point during treatment are associated with tumor progression and that CTC levels may reliably estimate disease progression earlier than imaging studies [83,86,88].

DURATION OF TREATMENT — Unlike in the adjuvant setting, there is no predetermined duration of treatment. Therefore, the duration of therapy should be individualized, taking into account the patient's goals of treatment, presence of side effects, and alternative options that might be available. In general, patients should continue treatment to the best response, disease progression, or when toxicity requires discontinuation of treatment.

For women on combination chemotherapy, discussion of the use of chemotherapy beyond best response (ie, maintenance therapy) is covered separately. (See "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Duration of treatment'.)

DEFINITION OF TREATMENT FAILURE — In our own practice, we monitor for treatment failure by taking into account serial changes in symptoms, physical findings, or tumor markers, as well as 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 disease-related symptoms, intolerable treatment toxicities, declining performance status)

●Evidence of new metastases

●Increasing size of previously documented metastatic lesions

The primary role of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is to standardize the reporting of results on clinical trials (table 1) [89]. 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 nontarget lesions, for example, bone metastases

PROGNOSIS — Clinical factors that predict the rate of progression and survival include the interval between initial therapy and relapse, the number of metastatic sites, the presence or absence of visceral involvement, performance status, and biologic markers. The role of these factors is discussed separately. (See "Prognostic and predictive factors in metastatic breast cancer", section on 'Prognostic factors'.)

Median survival for patients with MBC appears to have improved over time, a trend which has been attributed to the availability of new, more effective agents, including taxanes, aromatase inhibitors, and trastuzumab [1,2,90-92]. As an example, a meta-analysis and systematic review of 15 studies of recurrent MBC (n = 18,678 patients) revealed no survival improvement among patients recurring between 1980 and 1990, but median survival increased from 21 to 38 months from 1990 to 2010 [4], in which patients with estrogen receptor (ER)-positive MBC now have a median overall survival of 57 months, and patients with ER-negative MBC have a median survival of 33 months.

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high 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: Hereditary breast and ovarian cancer" and "Society guideline links: Breast cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Treatment of metastatic breast cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — The goals of systemic treatment for metastatic breast cancer (MBC) are prolongation of survival, alleviation of symptoms, and maintenance or improvement in quality of life.

●Hormone receptor status, human epidermal growth factor receptor 2 (HER2) overexpression, tumor burden, presence of germline breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) mutations, and disease-free interval have prognostic and/or predictive value and are important determinants in selecting appropriate treatment. (See 'Tumor biology and risk assessment' above.)

●Given the importance of hormone receptor and HER2 status in selecting treatment, hormone receptor and HER2 testing should be repeated upon diagnosis of MBC in case there is discordance in expression between the primary site and metastases, especially if the primary cancer was deemed negative, since a conversion to positive would dramatically change therapy. (See 'Disease assessment' above.)

●For most patients with hormone-positive MBC, we initiate endocrine therapy with or without targeted treatments rather than chemotherapy. However, for patients with rapidly progressive, symptomatic disease or visceral metastases with end-organ dysfunction, we offer first-line treatment with chemotherapy. (See 'Specific considerations' above and "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents", section on 'Choosing between ET and chemotherapy'.)

●In general, single-agent chemotherapy, used in sequence, is preferable to combination chemotherapy, since the single-agent chemotherapy is reasonably likely to induce palliation with fewer side effects, and no studies have demonstrated an overall benefit for the combination chemotherapy as long as both drugs are available in sequence. Combination chemotherapy may be preferable for select patients with rapidly progressive disease, visceral crisis, or if quick symptom control is desired. (See 'Sequential single agents versus combination chemotherapy' above and "Chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Tumor burden'.)

●For patients with HER2-positive breast cancer, regardless of their hormone receptor status, we incorporate HER2-directed therapy in their first-line treatment. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

●For patients with metastatic, HER2-negative breast cancer with germline BRCA mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease setting (and who have also received at least one line of endocrine therapy, if they have hormone receptor-positive disease), we suggest an oral inhibitor of poly(ADP-ribose) polymerase (PARP) (Grade 2B). For those with metastatic, HER2-negative breast cancer with either partner and localizer of BRCA2 (PALB2) mutations (somatic or germline) or somatic BRCA1/2 mutations, we also suggest treatment with a PARP inhibitor (Grade 2C), after progression on chemotherapy (and endocrine therapy, if appropriate). (See 'PARP inhibition for BRCA carriers' above.)

●Careful assessment of the response to therapy will assist in decisions for treatment continuation and in selection of subsequent treatments. Tools that are potentially useful to monitor treatment response include history and physical examination, radiographic imaging, and/or assay of serum tumor markers. The role of circulating tumor cells continues to be actively investigated. (See 'Monitoring therapy' above.)

●Median survival for patients with MBC appears to have improved over time, a trend which has been attributed to the availability of new, more effective agents, including taxanes, aromatase inhibitors, and trastuzumab. (See 'Prognosis' above.)