Approach

Metastatic breast cancer (MBC) is incurable but treatable. Potential goals of therapy are to maximise progression-free and overall survival, reduce tumour-related symptoms, enhance/maintain performance status, preserve or improve quality of life, and minimise toxicity.[3]

Selecting the optimal treatment for patients with MBC is complex and highly individualised, and should involve an experienced multi-disciplinary team.[28] The needs and goals of each patient should inform treatment decisions and treatment planning.

Systemic therapy (i.e., hormone therapy, chemotherapy, immunotherapy, targeted therapy) is the standard approach for managing MBC.

All patients should be offered appropriate supportive care, including psychosocial and symptom-related interventions.[28] Enrolment into clinical trials should be strongly considered at any stage during management. 

Guideline recommendations for managing MBC may vary between countries. Recommendations by the UK National Institute for Health and Care Excellence may differ from what is presented here. Management of MBC in men is not specifically covered in this topic.

Selection of therapy

Several factors affect the selection of therapy.[28][46][57][58][59][65]​​​​​​[66][67][68][69][70]

  • Performance status: provides information regarding a patient's ability to tolerate treatment (e.g., chemotherapy). The Karnofsky and Zubrod scales are commonly used. ECOG Performance Status Scale Opens in new window​​ In the growing geriatric oncology population, the use of comprehensive geriatric assessment is strongly recommended to decide on treatment modalities and goals of care upfront.

  • Hormone receptor (oestrogen and progesterone) status and human epidermal growth factor receptor 2 (HER2) status: receptor discordance between the primary tumour and the metastatic site may be considerable (10% to 30% for oestrogen receptor status and 20% to 50% for progesterone receptor).​ In the presence of discordance, it is preferable to treat according to the receptor status of the metastatic lesion if supported by the clinical scenario and patient's goals for care.

  • Breast cancer susceptibility gene status: BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53.

  • Additional biomarker status: PIK3CA mutation; PD-L1 expression; ESR1 mutation; dMMR/MSI (deficient mismatch repair/microsatellite instability); TMB (tumour mutational burden); NTRK gene fusions; RET fusions; cancer antigen 15-3 (CA 15-3); cancer antigen 27.29 (CA 27.29); carcinoembryonic antigen (CEA).

  • Site and number of metastases.

  • Age.

  • Menopausal status.

  • Comorbid illnesses.

  • Response to prior therapies and toxicities.

  • Need for rapid symptom/disease control.

  • Psychological factors.

  • Patient preference.

Timing and aggressiveness of therapy

Decisions regarding the timing and aggressiveness of therapy are influenced by the site of metastases and the aggressiveness of the disease.[71]

Generally, where metastases are confined to bone and soft tissue, there is a more indolent course, and survival is longer.[2] Patients with visceral metastases generally have more aggressive disease and shorter survival. The term 'visceral crisis' is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease.[65] Visceral crisis is not the mere presence of visceral metastases but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, such as chemotherapy, particularly because another treatment option at progression will probably not be possible.[65] For example, liver visceral crisis includes rapidly increasing bilirubin >1.5 times the upper limit of normal in the absence of Gilbert syndrome or biliary tract obstruction; lung visceral crisis includes rapidly increasing dyspnoea at rest, not alleviated by drainage of a pleural effusion (if present).[65][72]

The following factors may also indicate aggressive disease:[15][72]​​​

  • A short (<2 year) disease-free interval

  • Oestrogen receptor (OR)-negative and progesterone receptor (PR)-negative tumour

  • OR-negative, PR-negative, and HER2-negative disease (triple-negative disease)

  • Germline BRCA1 or BRCA2 mutations (particularly in triple-negative disease)

  • Lack of response to prior treatment

  • Presence of central nervous system involvement

  • Multiple sites of disease

  • HER2-positive disease

Hormone receptor-positive, HER2-negative MBC

Endocrine-based therapy is the preferred initial therapy for most patients with hormone receptor (OR and/or PR)-positive, HER2-negative MBC, with metastases to skin, lymph nodes, or bone.[28][46][73][74]​​​ As long as the metastases do not progress to visceral crises or there is rapid clinical progression requiring prompt symptom and/or disease control, sequential endocrine-based therapies offer ease of treatment with minimal adverse effects.[73] 

The optimal sequence of endocrine therapy in patients with hormone receptor-positive, HER2-negative MBC is unclear. The type of endocrine therapy offered to patients will depend on factors including menopausal status, prior endocrine therapy exposure, and patient preference.​[73]

Endocrine therapy in the metastatic setting should continue until disease progression or unacceptable toxicity.[73]

Post-menopausal women with hormone receptor-positive, HER2-negative MBC

First-line option:[28][46][73]

  • A non-steroidal aromatase inhibitor (anastrozole or letrozole) as a single agent, or in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (e.g., ribociclib, abemaciclib, or palbociclib)

Combining a non-steroidal aromatase inhibitor with a CDK4/6 inhibitor improves progression-free survival compared with a non-steroidal aromatase inhibitor alone in post-menopausal women with hormone receptor-positive, HER2-negative MBC.[75][76][77][78] Statistically significant improvement in overall survival has been demonstrated when a non-steroidal aromatase inhibitor is combined with ribociclib.[79]

CDK4/6 inhibitors are associated with a significant incidence of neutropenia (60%) but febrile neutropenia is less common (incidence <2%).[75][76][80][81]​​​​ The US Food and Drug Administration (FDA) has issued a warning that the CDK4/6 inhibitors ribociclib, abemaciclib, and palbociclib may cause rare but severe, life-threatening, or fatal interstitial lung disease and pneumonitis.[82] Patients should be advised to report any new or worsening respiratory symptoms and should be appropriately monitored for pulmonary signs or signs indicative of these conditions (e.g., hypoxia, cough, dyspnoea, or interstitial infiltrates on x-rays).

If disease progression occurs following endocrine therapy plus a CDK4/6 inhibitor, it is unclear if continuing CDK4/6 inhibitor therapy with subsequent lines of endocrine therapy is beneficial; studies are ongoing.[83][84][85][86][87]

Alternative first-line options:[28]​​​[46][73][81]

  • Fulvestrant (a selective oestrogen receptor degrader) as a single agent, or in combination with ribociclib

  • Tamoxifen (a selective oestrogen receptor modulator)

In the metastatic setting, first-line use of fulvestrant is superior to anastrozole, and first-line use of fulvestrant plus ribociclib is superior to fulvestrant plus placebo.[88][89][90][91][92]​​​​ First-line use of tamoxifen in the metastatic setting is less effective than aromatase inhibitors at improving progression-free survival in post-menopausal women.[73][93][94][95]

Endocrine-resistant MBC

Women with disease progression during endocrine therapy in the adjuvant or metastatic setting, or shortly after completion of adjuvant endocrine therapy (i.e., <2 years), are considered to have endocrine-resistant MBC.

Treatment options in the endocrine-resistant setting include:[46][59][73][74][96]​​​​​[97]​​​​​[98]​​[99]

  • Everolimus plus exemestane

  • Fulvestrant plus a CDK4/6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib)

  • Fulvestrant plus alpelisib (in patients with PIK3CA mutations)

  • Fulvestrant plus palbociclib plus inavolisib (in patients with PIK3CA mutations)

  • Fulvestrant plus capivasertib (in patients with PIK3CA/AKT1/PTEN alterations)

  • Elacestrant (in patients with ESR1 mutations)

  • Exemestane monotherapy

  • Progestational agent (e.g., megestrol)

  • Chemotherapy

  • Olaparib or talazoparib (in patients with germline BRCA1 or BRCA2 mutations)

  • Trastuzumab deruxtecan (in patients with 'HER2-low' status)

  • Sacituzumab govitecan

  • Abemaciclib monotherapy (if a CDK4/6 inhibitor has not been used previously)

  • Other targeted agents (depending on biomarker status)

Exemestane (a steroidal aromatase inhibitor) plus everolimus (a selective inhibitor of mTOR, a protein kinase required for oestrogen-induced breast tumour cell proliferation) improves progression-free survival compared with exemestane alone in post-menopausal women with endocrine-resistant MBC.[100][101][102]

Combination therapy with fulvestrant plus a CDK4/6 inhibitor following disease progression with endocrine therapy improves progression-free survival compared with fulvestrant alone in post-menopausal women with endocrine-resistant MBC.[73][89][103][104][105][106]​​ Significant improvement in overall survival has been demonstrated with fulvestrant plus ribociclib or abemaciclib (but not palbociclib) in this setting, compared with fulvestrant alone.[90][91][107][108]

Fulvestrant plus alpelisib (an alpha-specific phosphatidylinositol 3-kinase [PI3K] inhibitor) improves progression-free survival compared with fulvestrant alone in post-menopausal women with PIK3CA-mutated, hormone receptor-positive, HER2-negative MBC who have received prior endocrine therapy.[109] Significant improvement in overall survival has not been demonstrated.[110] 

Fulvestrant plus palbociclib plus inavolisib (an alpha-specific PI3K inhibitor) significantly improves progression-free survival compared with fulvestrant plus palbociclib in post-menopausal women with PIK3CA-mutated, hormone receptor-positive, HER2-negative MBC who have progressed during or within 12 months after the completion of endocrine therapy.[111]

Fulvestrant plus capivasertib (a serine/threonine kinase AKT inhibitor) significantly improves progression-free survival compared with fulvestrant alone in patients with hormone receptor-positive, HER2-negative MBC with one or more PIK3CA/AKT1/PTEN alterations, who have progressed during or following aromatase inhibitor therapy with or without a CDK4/6 inhibitor.[112]

Elacestrant (an oral selective oestrogen receptor degrader) significantly improves progression-free survival in patients with hormone receptor-positive, HER2-negative MBC who have progressed following one or two lines of prior endocrine therapy, compared with standard treatment used in the endocrine-resistant setting (including fulvestrant, anastrozole, or letrozole).[59][113]​​​​​ Significant improvement in progression-free survival was reported in the subgroup of patients with ESR1-mutated tumours, but not in those without ESR1-mutated tumours. 

Exemestane as a single agent has been used following tamoxifen failure in post-menopausal women with MBC.[114]

If further endocrine therapy is considered, a progestational agent such as megestrol can be used. Progestogens are not used earlier because of adverse effects. Megestrol may be effective in stimulating appetite in women with MBC who have anorexia.[115]

Responses tend to be shorter with each subsequent therapy until chemotherapy becomes inevitable. After three lines of endocrine therapy, the likelihood of response to further endocrine manipulation is low. Chemotherapy may be used at this stage, or at any stage of treatment if there is visceral crisis due to metastatic disease or worsening tumour burden. Sequential single-agent chemotherapy is recommended. Combination chemotherapy may be considered if a patient has life-threatening disease, visceral crisis, rapid clinical progression, or need for rapid symptom and/or disease control.[28][46][96]​​​​​​

Patients with BRCA1 or BRCA2 germline mutations who are no longer responding to endocrine therapy can be considered for treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (olaparib or talazoparib) instead of chemotherapy.[46][116][117]

Patients with hormone receptor-positive, 'HER2-low' MBC may be considered for treatment with trastuzumab deruxtecan (a monoclonal antibody-drug conjugate combining trastuzumab with a topoisomerase I inhibitor) if they are endocrine-resistant and have received at least one prior line of chemotherapy in the metastatic setting.[97][118]​​​​ 'HER2-low' status is defined as a HER2 immunohistochemistry (IHC) 1+ or 2+ and in situ hybridisation (ISH)-negative.[55][97]​​​

Patients with hormone receptor-positive, HER2-negative MBC who are endocrine-resistant and have received at least two prior lines of chemotherapy in the metastatic setting may be considered for treatment with sacituzumab govitecan (an antibody-drug conjugate combining a Trop-2-directed monoclonal antibody with a topoisomerase inhibitor).[98][119]​​​

Abemaciclib as a single agent can be considered if there is disease progression following endocrine therapy and chemotherapy (if a CDK4/6 inhibitor has not been used previously).[120]

Other targeted agents may be considered for MBC patients with certain biomarkers (irrespective of hormone receptor-status and HER2-status) who have progressed following treatment and/or have no satisfactory alternative treatments.[28][46][58] 

These agents include:[46][121][122][123][124][125][126][127]​​​​​[128]

  • Entrectinib, larotrectinib, or repotrectinib (tyrosine receptor kinase inhibitors) for patients with NTRK fusion-positive tumours

  • Pembrolizumab (an immune checkpoint inhibitor targeting PD-1) for patients with dMMR/MSI-high (dMMR/MSI-H) tumours, or TMB-high tumours (≥10 mutations/megabase)

  • Dostarlimab (an immune checkpoint inhibitor targeting PD-1) for patients with dMMR tumours

  • Selpercatinib (an RET kinase inhibitor) for patients with RET fusion-positive tumours.

Pre-menopausal women with hormone-receptor-positive, HER2-negative MBC

First-line option:[46]

  • Tamoxifen and/or ovarian ablation

Tamoxifen should be continued until disease progression. Ovarian ablation is either surgical (oophorectomy) or medical (e.g., gonadotrophin-releasing hormone agonist, such as goserelin).[129][130]​ It is not clear whether one approach is superior to the other (i.e., tamoxifen vs. ovarian ablation), so ease of administration, patient preference, and tolerability are important considerations.[131][132]

Once menopausal state is attained following ovarian ablation, subsequent treatment options are the same as those for post-menopausal women with hormone-receptor-positive, HER2-negative MBC.

HER2-positive MBC: targeted therapies

HER2-targeted therapy (e.g., trastuzumab, pertuzumab) is recommended for patients with HER2-positive MBC, unless there are individual complicating factors (e.g., congestive heart failure or a low ventricular ejection fraction).[28][46]​​​​[133]

Upon progression, the later lines of therapies should incorporate continued use of HER2-targeted therapy (e.g., trastuzumab deruxtecan, trastuzumab emtansine, lapatinib, trastuzumab with different chemotherapy regimens).

HER2-targeted therapy should be continued until progression or unacceptable toxicity as a backbone of therapy in this group.

HER2-positive MBC (including hormone receptor-positive and hormone receptor-negative disease)

First-line option:[28][46]

  • Pertuzumab plus trastuzumab plus taxane (e.g., docetaxel or paclitaxel)

Pertuzumab plus trastuzumab and docetaxel significantly improves progression-free survival and overall survival compared with placebo plus trastuzumab and docetaxel, when used as first-line treatment for HER2-positive MBC.[134][135][136]​ Pertuzumab plus trastuzumab and docetaxel can be prescribed regardless of hormone receptor status.[133]​ Use of pertuzumab is associated with a significant incidence of rash and diarrhoea.[137]

A fixed-dose formulation of pertuzumab plus trastuzumab for subcutaneous injection is available, which may offer more convenient dosing for patients.[138]

First-line options for women unable to tolerate chemotherapy, or who have a poor performance status, vary depending upon hormone receptor status. They include:

  • Trastuzumab monotherapy for hormone receptor-negative HER2-positive MBC

  • Trastuzumab plus endocrine therapy for hormone receptor-positive, HER2-positive MBC[133]​

    • In post-menopausal women, this would be trastuzumab plus an aromatase inhibitor

    • In pre-menopausal women, this would be tamoxifen and/or ovarian ablation plus trastuzumab, then subsequent sequential endocrine therapy plus trastuzumab

In women with hormone receptor-positive, HER2-positive MBC, trastuzumab in combination with an aromatase inhibitor improves progression-free survival and overall response rate, compared with aromatase inhibitor alone.[139]​​

Second-line options:[28][46]

  • Trastuzumab deruxtecan

  • Tucatinib plus trastuzumab and capecitabine (if patients have active brain metastases)

Trastuzumab deruxtecan is the preferred second-line treatment following progression with first-line trastuzumab-based therapy.[28][46][133]​​​​ Trastuzumab deruxtecan significantly improves progression-free survival compared with trastuzumab emtansine (an antibody-drug conjugate combining trastuzumab with the microtubule-inhibitory agent DM1) in patients with HER2-positive MBC who have previously received trastuzumab plus a taxane.[140][141]​​ Close monitoring for pulmonary toxicity is required with use of trastuzumab deruxtecan.[142] 

Tucatinib (a tyrosine kinase inhibitor targeting HER2) plus trastuzumab and capecitabine is a second-line option if patients have active brain metastases following progression with first-line trastuzumab-based therapy.[28][46][143]​​ Tucatinib plus trastuzumab and capecitabine improves progression-free survival and overall survival compared with placebo plus trastuzumab and capecitabine in patients with previously treated HER2-positive MBC, including those with brain metastases.[144][145]

The optimal sequence for third-line treatment and beyond is unclear; therefore, treatment decisions should be individualised (e.g., based on prior treatments, patient comorbidities, disease burden, treatment toxicity profile).[28][46][133]​​​

The following treatments can be considered upon further progression (i.e., third-line and beyond) if not used previously:[28][46][133]​​​​

  • Trastuzumab deruxtecan

  • Tucatinib plus trastuzumab and capecitabine (if patients have active brain metastases)

  • Trastuzumab emtansine

  • Lapatinib plus capecitabine

  • Margetuximab plus chemotherapy

  • Neratinib plus capecitabine

  • Trastuzumab plus chemotherapy

  • Trastuzumab plus lapatinib

  • Trastuzumab monotherapy

  • Endocrine therapy alone (in highly selected patients with hormone receptor-positive, HER2-positive MBC)

  • Other targeted agents (depending on biomarker status); for example, entrectinib, larotrectinib, or repotrectinib (for NTRK fusion-positive tumours), pembrolizumab (for dMMR/MSI-H or TMB-high tumours), dostarlimab (for dMMR tumours), and selpercatinib (for RET fusion-positive tumours)

Trastuzumab deruxtecan or tucatinib plus trastuzumab and capecitabine (if patients have active brain metastases) can be used as a third-line treatment if not previously used.

Trastuzumab emtansine may be considered after second-line treatment with trastuzumab deruxtecan, or if trastuzumab deruxtecan is unsuitable.[28][140]​​​​[141]​​

Lapatinib (a HER2 tyrosine kinase inhibitor) plus capecitabine is approved for use in patients with HER2-positive MBC who have received two or more prior HER2-targeted treatments in the metastatic setting.[146]

Margetuximab (an anti-HER2 monoclonal antibody) plus chemotherapy is approved in the US for use in patients with HER2-positive MBC who have received two or more prior HER2-targeted treatments, at least one of which was in the metastatic setting.[147] Margetuximab is not approved in Europe.

Neratinib (an irreversible pan-HER tyrosine kinase inhibitor) plus capecitabine is approved in the US for use in patients with HER2-positive MBC who have received two or more prior HER2-targeted treatments in the metastatic setting.[148] Neratinib is not approved for this indication in Europe.

Trastuzumab may be continued beyond progression, often in combination with different chemotherapy regimens (e.g., use of trastuzumab plus vinorelbine following progression with trastuzumab plus a taxane).[149][150] Trastuzumab is effective with anthracyclines or taxanes, improving response rate and overall survival compared with chemotherapy alone.[151][152] However, the combination of an anthracycline with trastuzumab is not recommended as it leads to greater cardiac toxicity.

Trastuzumab plus lapatinib is a chemotherapy-free option that may be considered for patients unsuitable for chemotherapy.[153][154]

Endocrine therapy alone may be an option for highly selected patients with hormone receptor-positive, HER2-positive MBC, such as those who are unsuitable for chemotherapy and HER2-targeted therapies, or who have low disease burden or a long disease-free interval.[133]​​

Hormone receptor-negative, HER2-negative (triple-negative) MBC

Patients with triple-negative MBC should undergo biomarker testing for PD-L1 and germline BRCA mutations.[28][46][58]​​[96]​​​​​[155] Testing for other biomarkers (e.g., dMMR/MSI; TMB; NTRK fusions; RET fusions) should also be considered.​​

First-line option for PD-L1 negative, triple-negative MBC patients without germline BRCA mutations:[28][46][96]​​​​

  • Chemotherapy

The chemotherapy regimen offered depends on the clinical condition of the patient, sites of disease, and prior therapy. Sequential single-agent chemotherapy is recommended. Combination chemotherapy may be considered in certain circumstances (e.g., life-threatening disease, visceral crisis, rapid clinical progression, or need for rapid symptom and/or disease control).[96]

Initial treatment is usually an anthracycline or a taxane, with the decision based on previous therapeutic exposure.[28]​ A different class of chemotherapy (e.g., antimetabolites, nontaxane microtubule inhibitors) should be considered for patients with prior exposure to these agents.

First-line options for PD-L1 negative, triple-negative MBC with germline BRCA mutations:[28][46][96]​​​​

  • Olaparib or talazoparib

  • Chemotherapy (platinum agent)

The PARP inhibitors olaparib and talazoparib significantly improve progression-free survival compared with chemotherapy (capecitabine, vinorelbine, eribulin, or gemcitabine) in patients with HER2-negative MBC and germline BRCA mutations, particularly among patients with triple-negative disease.[116][117]​ No significant improvement in overall survival has been demonstrated.[156][157]

The platinum agent carboplatin significantly improves response rate and progression-free survival compared with docetaxel in patients with triple-negative MBC and germline BRCA mutations.[158]

First-line options for triple-negative MBC patients who are PD-L1-positive:[28][46][96]​​​​​

  • Atezolizumab plus nanoparticle albumin-bound-paclitaxel (also known as nab-paclitaxel)

  • Pembrolizumab plus chemotherapy

Atezolizumab (an immune checkpoint inhibitor targeting PD-L1) plus nanoparticle albumin-bound-paclitaxel is approved in the EU and other countries (except the US; approval was withdrawn for this indication in 2021) for first-line treatment in adults with unresectable, locally advanced or metastatic, PD-L1-positive, triple-negative MBC whose tumours have PD-L1 expression ≥1% and who have not received prior chemotherapy for metastatic disease.

In one phase 3 study of patients with untreated triple-negative MBC, atezolizumab plus nanoparticle albumin-bound-paclitaxel significantly improved progression-free survival compared with placebo plus nanoparticle albumin-bound-paclitaxel in PD-L1-positive patients.[159]

Atezolizumab in combination with paclitaxel (the non-protein-bound formulation) is not approved for use in breast cancer.[160][161][162] In one phase 3 study, atezolizumab plus paclitaxel did not improve progression-free survival compared with placebo plus paclitaxel in PD-L1-positive patients.[160] Nanoparticle albumin-bound-paclitaxel should not be replaced with paclitaxel.[161][162]

Pembrolizumab plus chemotherapy is approved as a first-line treatment for patients with locally recurrent inoperable or metastatic triple-negative breast cancer who are PD-L1-positive (combined positive score [CPS] ≥10), as determined by a companion diagnostic test. Pembrolizumab plus chemotherapy (nanoparticle albumin-bound-paclitaxel [nab-paclitaxel], paclitaxel, or gemcitabine plus carboplatin) improves progression-free survival compared with placebo plus chemotherapy in patients with PD-L1-positive (CPS ≥10) triple-negative MBC.[163]

Second-line treatment options for triple-negative MBC patients:[28][46][96]​​​

  • Chemotherapy

  • Sacituzumab govitecan

Patients with triple-negative MBC who progress following first-line treatment can be considered for second-line treatment with chemotherapy or sacituzumab govitecan.[164] If chemotherapy was used for first-line treatment, then a different chemotherapy regimen should be considered for second-line treatment. 

Third-line (and beyond) treatment options for triple-negative MBC patients:[28][46]

  • Chemotherapy (i.e., a different regimen to those already used)

  • Other targeted agents (depending on biomarker status), for example: entrectinib or larotrectinib (for NTRK fusion-positive tumours), pembrolizumab (for dMMR/MSI-H or TMB-high tumours), dostarlimab (for dMMR tumours), and selpercatinib (for RET fusion-positive tumours)

Considerations concerning chemotherapy

Unless the patient has life-threatening disease, visceral crisis, rapid clinical progression, or a need for rapid symptom and/or disease control, sequential single-agent chemotherapy is preferred, allowing maximal drug dosing, with reduced risk of overlapping toxicities that can occur with combination chemotherapy.[28][46][96]​​​

The choice of chemotherapy agent is mainly dictated by prior response, toxicity profile of the drugs (e.g., avoiding paclitaxel, with its known neurotoxicity, in patients with pre-existing neuropathy), patient tolerability, and the tumour burden. Most patients will have received multiple agents over time, and this must be considered in the selection of subsequent agents. The addition of endocrine therapy to chemotherapy in hormone receptor-positive MBC is usually avoided because of the lack of demonstrable benefit.[73]​ If there is no response to several chemotherapeutic regimens and a declining performance status, it is important to consider palliative and/or supportive care. 

Single-agent chemotherapy regimens

Anthracyclines (e.g., doxorubicin, epirubicin) and taxanes (e.g., docetaxel, paclitaxel) have the greatest single-agent activity and are preferred agents, providing that the patient has not been treated with these agents previously.[46][165]​ Other formulations of these agents (e.g., pegylated liposomal doxorubicin and nanoparticle albumin-bound-paclitaxel [nab-paclitaxel]) are widely used as single-agent therapies for MBC due to their improved toxicity profile.[166][167]

The following single-agent chemotherapy regimens may also be used depending on patient factors (and as indicated):[28][46][96]

  • Capecitabine or gemcitabine (antimetabolites)

  • Vinorelbine or eribulin (microtubule inhibitors)

  • Ixabepilone (epothilone B analogue)

  • Cyclophosphamide (alkylating agent)

Combination chemotherapy regimens

Patients with life-threatening disease, visceral crisis, rapid clinical progression, or need for rapid symptom and/or disease control may be considered for combination chemotherapy to maximise the likelihood of tumour response.[28][96]​​​​​ Combination chemotherapy has a higher response rate than single-agent therapy, although salvage with a second single agent provides equivalent overall survival to combination chemotherapy.[3]

The current standard of care for combination chemotherapy is doxorubicin plus cyclophosphamide (AC). It is often followed by a taxane (paclitaxel or docetaxel).

Depending upon patient factors, other combinations include:

  • Doxorubicin plus paclitaxel or docetaxel (AT or AD)

  • Capecitabine plus docetaxel (XT)

  • Gemcitabine plus docetaxel (GT)

  • Docetaxel plus cyclophosphamide (TC)

  • Cyclophosphamide plus doxorubicin plus fluorouracil (CAF)

  • Fluorouracil plus doxorubicin plus cyclophosphamide (FAC)

For older patients, or for those where the risk of doxorubicin cardiac disease is of concern, CMF (cyclophosphamide, methotrexate, and fluorouracil) is often chosen. For patients who progress after therapy with an anthracycline or a taxane, a combination regimen using ixabepilone plus capecitabine can be considered.[168] The choice depends upon the physician's preference, balancing effectiveness and toxicity, and need for subsequent therapy.

Most of these drugs are given intravenously, necessitating venous access devices in the majority of women.[169]

Supportive care

All patients with MBC should receive supportive care that includes therapy for bone metastases and bone destruction (e.g., bisphosphonate or denosumab; palliative radiotherapy), and multi-disciplinary team support with symptom management.[170][171][172]

The FDA is investigating the risk of severe hypocalcaemia in patients on dialysis receiving denosumab (Prolia® 60 mg/mL approved for treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer).[173] Interim results from two safety studies of denosumab suggest an increased risk of hypocalcaemia in patients with advanced kidney disease, with serious outcomes (hospitalisation and death) in dialysis patients. While the investigation continues, health care professionals should: consider the risk of hypocalcaemia with denosumab in dialysis patients; provide adequate calcium and vitamin D supplementation, and frequent blood calcium monitoring; and report adverse effects. The FDA has not issued a warning with respect to the brand of denosumab approved specifically for the prevention of skeletal-related adverse events in malignancy (Xgeva® 120 mg/1.7 mL).

Palliative breast surgery is considered primarily in patients whose life expectancy is measured in months or years (not days or weeks) and if it is likely to improve symptoms and quality of life. It is usually performed in patients with limited disease, in whom surgery will render the patient clinically disease-free, or in individuals in whom local disease is difficult to manage by the patient and physician.[174] Breast surgery in patients with de novo MBC has been shown to improve locoregional progression, but not overall survival or quality of life.[175] Breast surgery in MBC should be considered on a case-by-case basis.​

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