Overview of the approach to metastatic breast cancer

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 among patients with metastatic breast cancer 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, targeted 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 for hormone receptor-positive, HER2-negative advanced breast cancer".)

●(See "Endocrine therapy resistant, 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, while balancing 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 ASSESSMENT — Immunohistochemical (IHC) subtype based on hormone receptor status and 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.

Complete evaluation for the extent of metastatic disease includes the following.

Biopsy of metastatic lesion — 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. Results of the metastatic biopsy may make targeted therapies available for those whose initial biopsy did not display hormone receptor or HER2 positivity.

●Biopsy of metastatic lesion – Confirmatory biopsy of a suspected metastatic lesion, with reassessment of estrogen receptor (ER), progesterone receptor (PR), and HER2 overexpression. This is important since change in hormone receptor and HER2 statuses from primary to metastatic disease from positive to negative or negative to positive may impact choice of therapy.

•According to American Society of Clinical Oncology/College of American Pathologists criteria, immunohistochemical (IHC) staining of 0 to <1 percent should be considered negative, whereas ≥10 percent should be considered positive, and patients should not, or should, be candidates for ET, respectively. Tumors with ER 1 to 9 percent IHC staining are considered positive and ET should be considered, but may be less likely to be effective. (See "Hormone receptors in breast cancer: Clinical utility and guideline recommendations to improve test accuracy", section on 'Interpretation of ER and PR tests'.)

•The approach to HER2 testing is summarized (table 1 and algorithm 1).

●IHC evaluation for programmed cell death ligand 1 (PD-L1) expression, among those with triple negative cancers, as this guides initial therapy selection. (See 'Hormone receptor-negative, HER2-negative patients' below.)

●Somatic testing for genetic alterations – For those in whom hormone receptor positivity is confirmed, we assess tumor PIK3CA status, either at initial diagnosis of metastatic disease, or at the time of progression on first-line therapy. We assess this using the companion diagnostic test approved by the US Food and Drug Administration to select patients for possible second-line treatment with the alpha isoform-specific phosphoinositide 3-kinase inhibitor alpelisib [12]. The diagnostic test is approved for use on tumor tissue specimens and circulating tumor DNA for the detection of 11 PIK3CA activating mutations. We prefer to use tissue, if it is available, given available trial data. However, if tumor tissue is not available, we assess plasma specimens for PIK3CA mutations. If the test is negative for PIK3CA mutations in plasma, more tissue should be acquired, when possible, for repeat testing for PIK3CA mutations in tumor tissue [13,14].

Cell-free DNA "liquid biopsy" is a means of identifying targetable mutations, especially when tissue biopsy may be difficult [15]. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Biopsy of a metastatic lesion'.)

For all cancers irrespective of tumor receptor status, assessment for mutations in tropomyosin receptor kinase (TRK) [16,17], as well as for presence of microsatellite-high/DNA mismatch-repair deficiency and tumor mutational burden, should be performed. However, these assessments may be undertaken after progression on initial and subsequent-line therapy, as they guide later-line treatments [18]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors" and "TRK fusion-positive cancers and TRK inhibitor therapy".)

In 2015, the American Society of Clinical Oncology 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 [19]. A 2018 European Society for Medical Oncology (ESMO) guideline acknowledges the lack of prospective trials evaluating change in treatment based on IHC 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 [20]. 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 [21,22]. 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 the type of HER2 testing that was conducted, the condition of the fixed paraffin-embedded block, and even a sampling issue, as tumors can be 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 [23]. 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 potentially effective targeted treatment [21].

Germline testing for BRCA1/2 pathogenic variants — Germline testing for breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) is also recommended for all patients with metastatic breast cancer in view of therapeutic options (poly[ADP-ribose] polymerase [PARP] inhibitors), as per National Comprehensive Cancer Network guidelines [24-26]. (See 'Special considerations' below.)

Laboratory and radiographic studies — All patients should have a complete blood count and comprehensive metabolic panel (including liver function tests) to determine whether the cancer is causing organ dysfunction, as well as whether any baseline comorbidities may affect the choice of treatment.

Additionally, we perform computed tomography (CT) of the chest, abdomen, and pelvis and nuclear medicine bone scan to determine the extent of disease. Positron emission tomography/CT may be obtained, alternatively.

Further imaging may be appropriate to evaluate specific signs or symptoms, as well. For example, for those with signs or symptoms suggestive of central nervous system involvement, we obtain dedicated imaging such as contrast-enhanced magnetic resonance imaging of the brain and/or spinal cord.

Prediction of response — The following are predictors of 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'.)

●Presence of specific genetic alterations predicts response to certain targeted agents (eg, PARP inhibitors in germline BRCA1/2 mutation carriers, or tumor TRK fusions for entrectinib or larotrectinib).

●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 metastatic disease sites [27-37]. Patients with visceral metastases (especially if rapidly progressing) generally have an aggressive phenotype, while patients with soft tissue and bone metastases, or bone metastases only, have a more indolent phenotype.

The detection and monitoring of circulating tumor cells during treatment for MBC is discussed below. (See 'Circulating tumor cells' below.)

HER2-NEGATIVE TUMORS

Hormone receptor-positive, HER2-negative disease — In general, endocrine therapy (with cyclin-dependent kinase [CDK] 4/6 inhibition) is 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.

●Selection of endocrine therapy and accompanying targeted agents is discussed separately. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

●Selection of chemotherapy is discussed separately. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)

●Special considerations for patients with germline breast cancer susceptibility gene 1/2 (BRCA1/2) mutations are discussed below. (See 'Special considerations' below.)

Choosing between endocrine therapy and chemotherapy — Our approach to endocrine versus chemotherapy in hormone receptor-positive, HER2-negative metastatic cancers is as follows:

●Since ET (alone or in combination with targeted agents) is generally less toxic than chemotherapy, with comparable outcomes [38,39], it is preferable for most patients with hormone receptor-positive disease to begin treatment with ET. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

●For the minority of patients who have extensive visceral metastases, chemotherapy may be considered an appropriate alternative to endocrine therapy plus targeted agents; however, there are no data suggesting a survival benefit to this approach. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

●For women who progress after two lines of ET (with or without a targeted agent), or in whom rapid progression on ET has been observed, chemotherapy may be appropriate, depending on patient comorbidities and individual preferences. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)

Hormone receptor-negative, HER2-negative patients — Many patients with triple-negative (estrogen receptor [ER]-negative, progesterone receptor [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. Triple-negative breast cancer is discussed in detail separately. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer".)

Briefly,

●Initial treatment for metastatic triple-negative breast cancer is guided by expression of tumor programmed cell death ligand 1 (PD-L1), an immune checkpoint. Immune checkpoint inhibitor plus chemotherapy is offered in the first-line treatment for patients with for PD-L1-positive disease. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'PD-L1 combined positive score of at least 10'.)

●Most other patients are treated with chemotherapy alone, although some germline BRCA1/2 mutation carriers are treated with poly(ADP-ribose) polymerase (PARP) inhibitors. (See 'Special considerations' below.)

●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). (See 'Sequential single agents versus combination chemotherapy' below.)

●As a later-line option, sacituzumab govitecan (SG) is an antibody-drug conjugate targeting trophoblast cell-surface antigen-2 (TROP-2), which is upregulated in breast cancer [40,41]. SG is comprised of sacituzumab conjugated via a pH-labile hydrolyzable linker to SN-38 (the active metabolite of irinotecan). SG is US Food and Drug Administration (FDA) approved for patients with unresectable/locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for metastatic disease. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Sacituzumab govitecan'.)

Special considerations

BRCA 1/2 and PALB2 associated tumors — 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 [42].

●For patients with HER2-negative breast cancer with germline BRCA1/2 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) [43].

●Additionally, for patients with metastatic HER2-negative breast cancer who have either pathogenic somatic BRCA1/2 mutations or germline partner and localizer of BRCA2 (PALB2) mutations, and have received prior chemotherapy (and endocrine therapy, if appropriate), we also suggest PARP inhibitors.

●PARP inhibitors (olaparib or talazoparib) should be used sequentially after or before chemotherapy rather than concurrently. Concurrent use of PARP inhibitors with CDK/4/6 inhibitors has not been tested in clinical trials.

●The approach and supporting data for PARP inhibitors among patients specifically with germline BRCA1/2 mutation-associated, triple-negative breast cancer are discussed in more detail elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Germline BRCA mutation'.)

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 BRCA1/2 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 supporting the use of PARP inhibitors for germline BRCA1/2 mutation-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, BRCA1/2 mutation-associated breast cancer improved median PFS (14.5 versus 12.6 months; hazard ratio [HR] 0.71, 95% CI 0.57-0.88) [44]. OS results were similar (33.5 versus 28.2 months; HR 0.95, 95% CI 0.73-1.2) between the two groups. Veliparib does not have regulatory approval in metastatic breast cancer.

Talazoparib — Talazoparib is FDA approved for patients with germline BRCA1/2 mutations and HER2-negative, locally advanced or metastatic breast cancer [45].

In the phase III EMBRACA trial, 431 patients with metastatic, HER2-negative, germline BRCA1/2 mutation-associated breast cancer were randomly assigned in a 2:1 ratio to talazoparib or to chemotherapy (either single-agent capecitabine, eribulin, gemcitabine, or vinorelbine) [25].

●At a median follow-up of approximately 11 months, those receiving talazoparib experienced an improved PFS relative to those treated with chemotherapy (median 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 [46].

●Talazoparib caused more anemia than standard chemotherapy; rates of neutropenia were comparable. For most nonhematologic toxicities, talazoparib was better tolerated. Patients receiving talazoparib reported significant improvements in quality of life, while those receiving chemotherapy reported worsened quality of life outcomes [47].

Olaparib — Olaparib is FDA approved for germline BRCA1/2 mutation carriers with metastatic, HER2-negative breast cancer previously treated with chemotherapy (and endocrine therapy, if appropriate). We also suggest it for those with pathogenic somatic BRCA1/2 mutations and in patients with germline PALB2 mutation, previously treated with chemotherapy.

In the phase III OlympiAD trial, over 300 patients with metastatic, HER2-negative, germline BRCA1/2 mutation-associated breast cancer were randomly assigned in a 2:1 ratio to olaparib or to chemotherapy (either single-agent capecitabine, eribulin, or vinorelbine) [24]. 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; HR 0.58, 95% CI 0.43-0.80). 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) [48-50]. 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 (38 versus 50 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 [51].

In a single-arm phase II study, olaparib has also shown activity among those with pathogenic somatic BRCA1/2 mutations and germline PALB2 mutations, although PARP inhibitor therapy has not been evaluated in randomized trials in these populations [52].

HER2-low tumors — Fam-trastuzumab deruxtecan is approved by the FDA for patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-negative) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy [53]. We use this option in hormone receptor-positive disease only if refractory to endocrine therapy.

In a randomized trial, 557 patients with metastatic breast cancer who had received one or two previous lines of chemotherapy were enrolled, all of whom had cancers that were 1+ for HER2 on IHC, or 2+ on IHC with negative FISH [54]. In this trial, the antibody-drug conjugate fam-trastuzumab deruxtecan resulted in longer progression-free and overall survival compared to treatment with physician’s choice of chemotherapy (TPC). The median PFS was 9.9 months versus 5.1 months respectively, among those receiving fam-trastuzumab deruxtecan and TPC (HR 0.50, 95% CI, 0.40-0.63); median OS was 23.4 months versus 16.8 months, respectively (HR 0.64, 95% CI, 0.49-0.84). Approximately 11 percent of patients enrolled in this study had hormone receptor negative disease; benefit of fam-trastuzumab deruxtecan over TPC was noted in both hormone receptor-positive and hormone receptor-negative subgroups.

Adverse events of ≥grade 3 occurred in 53 percent of the patients who received trastuzumab deruxtecan and 67 percent of those who received TPC. Drug-related interstitial lung disease or pneumonitis occurred in 12 percent receiving fam-trastuzumab deruxtecan, 0.8 percent had grade 5 events.

Fam-trastuzumab deruxtecan has been endorsed by expert guidelines from the American Society of Clinical Oncology [55]. This agent also has an established role in HER2-positive metastatic breast cancer. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

HER2-POSITIVE CANCERS

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-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".)

LATER-LINE OPTIONS, IRRESPECTIVE OF TUMOR RECEPTOR STATUS

For TRK fusion-positive cancers — 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) [16,17]. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

For cancers with high TMB or MSI-H — Patients with microsatellite-high (MSI-H)/DNA mismatch-repair deficient unresectable or metastatic breast cancer (regardless of estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2] status) may also benefit from pembrolizumab or dostarlimab-gxly after progression on other treatment options. Similarly, patients with high tumor mutational burden (TMB; ≥10 mutations/megabase) unresectable or metastatic breast cancer (regardless of ER, PR, and HER2 status) may also benefit from pembrolizumab, after progression on other treatment options [18]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

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 [56]. 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'.)

ADDITIONAL 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 "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Combination versus single agent chemotherapy'.)

Combining different forms of systemic treatment — 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 [7,57,58].

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 have been successfully combined with targeted treatments like cyclin-dependent kinase 4/6 inhibitors, mechanistic target of rapamycin inhibitors, and phosphoinositide-3 kinase inhibitors. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

Local treatments for the primary or metastatic sites — Although systemic therapy is the mainstay of treatment for metastatic breast cancer, local management of both of the primary breast cancer, as well as metastasis-specific local treatment (ie, metastasectomy, radiation therapy, surgery, etc.) may palliate symptoms and prevent cancer-related complications. Some evidence suggests a potential for prolonging survival, although available data are limited and conflicting. This is discussed in detail elsewhere. (See "The role of local therapies in metastatic breast cancer".)

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".)

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 [59]. 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 [59-61]. In addition, symptom relief without measurable disease response and achievement of stable disease as compared with disease progression may be clinically important [62].

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 [63,64]. Judicious use of serial tumor marker measurements may decrease the need for periodic radiographic evaluation [65].

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 [63]. 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 [66,67]. Patients with abnormal liver function may also have falsely elevated marker levels because they are cleared by the liver [66]. 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 [68-70].

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 two to four 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 [71,72].

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 [73-75]. There is also some evidence that metabolic changes in bone metastases in response to systemic therapy (ie, a change in standardized uptake value) can predict response duration or time to progression [76-78]. 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.

Approach not routinely used

Circulating tumor cells — Detection of circulating tumor cells (CTCs) in blood samples of patients with MBC (≥5 CTCs per 7.5 mL of blood) has been shown to be a predictor of PFS and OS [79-85]. 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 [63,86]. (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 [80], 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 (median, three versus seven months) and OS (median, 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 (median, two versus seven months) and OS (median, 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 [82,85,87].

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, disease response, 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 patients on combination chemotherapy, discussion of the use of chemotherapy beyond best response (ie, maintenance therapy) is covered separately. (See "Endocrine therapy resistant, 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 2) [88]. 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 diagnosis 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, cyclin-dependent kinase 4/6 inhibitors, and trastuzumab, pertuzumab, and other human epidermal growth factor receptor 2 (HER2) targeted agents [1,2,89-91]. 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]. Based on this study, 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.

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

●Goals of treatment – 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.

●Assessment of metastatic tumor biology

•Given the importance of hormone receptor and human epidermal growth factor receptor 2 (HER2) status in selecting treatment, hormone receptor and HER2 testing should be repeated upon diagnosis of MBC. (See 'Tumor assessment' above.)

•Presence of germline breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) mutations, tumor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation status, and tumor programmed cell death ligand 1 (PD-L1) status should also be assessed in a metastatic lesion, as they are important determinants in selecting appropriate treatment. (See 'Tumor assessment' above.)

●HER2-negative disease

•Hormone receptor-positive, HER2-negative disease – For most patients with hormone receptor-positive, HER2-negative MBC, we recommend initial treatment with endocrine therapy plus targeted therapy, rather than chemotherapy (Grade 2B). This includes patients with rapidly progressive, symptomatic disease or visceral metastases, although chemotherapy may be an acceptable alternative. Chemotherapy is used for endocrine-refractory disease. (See 'Hormone receptor-positive, HER2-negative disease' above.)

•Triple-negative disease – Many patients with triple-negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, HER2-negative) breast cancer have a particularly aggressive subtype, and first-line chemotherapy is recommended, with or without immunotherapy. Immune checkpoint inhibitor plus chemotherapy is offered in the first-line treatment for patients with for PD-L1-positive disease. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'PD-L1 combined positive score of at least 10'.)

Selection of chemotherapy is discussed elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Initial treatment in the absence of rapidly progressive visceral disease'.)

•BRCA1/2 and PALB2 associated tumors

-For patients with metastatic, HER2-negative breast cancer with germline BRCA1/2 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 germline partner and localizer of BRCA2 (PALB2) mutations 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 'Special considerations' above.)

•HER2-low cancers – For patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-negative) breast cancer who have received ≥1 prior chemotherapy in the metastatic setting, or developed disease recurrence during or within six months of completing adjuvant chemotherapy, we recommend fam-trastuzumab deruxtecan rather than further lines of chemotherapy (Grade 1B). We use this option in hormone receptor-positive disease only if refractory to endocrine therapy. (See 'HER2-low tumors' above.)

●HER2-positive disease – For patients with HER2-positive breast cancer, regardless of the hormone receptor status, we incorporate HER2-directed therapy in their first-line treatment. HER2-directed therapy combined with chemotherapy or endocrine therapy is discussed separately. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

●Monitoring therapy – 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.)

●Prognosis – 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.)