Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal

1st line – endocrine-based therapy ± CDK4/6 inhibitor

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
1st line – 

endocrine-based therapy ± CDK4/6 inhibitor

First-line options include 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).[28][46][73]

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 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 include: fulvestrant (a selective oestrogen receptor degrader) as a single agent or combined with ribociclib; or tamoxifen (a selective oestrogen receptor modulator).[28][46][73]​​​[81]

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]

Primary options

anastrozole: 1 mg orally once daily until tumour progression

OR

letrozole: 2.5 mg orally once daily until tumour progression

OR

anastrozole: 1 mg orally once daily until tumour progression

or

letrozole: 2.5 mg orally once daily until tumour progression

-- AND --

ribociclib: 600 mg orally once daily on days 1-21 of each cycle, followed by 7 days off before repeating, until tumour progression

or

abemaciclib: 150 mg orally twice daily until tumour progression

or

palbociclib: 125 mg orally once daily on days 1-21 of each cycle, followed by 7 days off before repeating, until tumour progression

Secondary options

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

ribociclib: 600 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

OR

tamoxifen: 20 mg orally once daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – exemestane + everolimus; or fulvestrant + CDK4/6 inhibitor; or fulvestrant + alpelisib; or fulvestrant + palbociclib + inavolisib; or fulvestrant + capivasertib; or elacestrant; or exemestane monotherapy

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
2nd line – 

exemestane + everolimus; or fulvestrant + CDK4/6 inhibitor; or fulvestrant + alpelisib; or fulvestrant + palbociclib + inavolisib; or fulvestrant + capivasertib; or elacestrant; or exemestane monotherapy

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.

Exemestane (a steroidal aromatase inhibitor) and 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 (e.g., palbociclib, ribociclib, or abemaciclib) 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]​​​​

The US Food and Drug Administration 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).

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 ATK 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]

Primary options

exemestane: 25 mg orally once daily until tumour progression

and

everolimus: 10 mg orally once daily until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

-- AND --

ribociclib: 600 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

or

abemaciclib: 150 mg orally twice daily until tumour progression

or

palbociclib: 125 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

alpelisib: 300 mg orally once daily until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

palbociclib: 125 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

and

inavolisib: 9 mg orally once daily until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

capivasertib: 400 mg orally twice daily on days 1-4 of each 7-day cycle until tumour progression

OR

elacestrant: 345 mg orally once daily until tumour progression

Secondary options

exemestane: 25 mg orally once daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – megestrol

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
3rd line – 

megestrol

Megestrol is a synthetic progestin that is generally used after other therapies fail. Progestogens are not used earlier because of adverse effects.

Megestrol may be effective in stimulating appetite in women with MBC who have anorexia.[115]

Primary options

megestrol: 160 mg orally once daily

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

4th line – chemotherapy or PARP inhibitor

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
4th line – 

chemotherapy or PARP inhibitor

After three lines of endocrine therapy, the likelihood of response to further hormonal manipulation is low.

Chemotherapy may be used at this stage, or at any stage of treatment if visceral crisis develops 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]​​​

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.

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.[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): capecitabine or gemcitabine (antimetabolites); vinorelbine or eribulin (microtubule inhibitors); ixabepilone (an epothilone B analogue); cyclophosphamide (an alkylating agent).[28]​​​​[46][96]​​​

Upon resolution of organ crisis and/or attaining disease stability, chemotherapy may be switched to endocrine therapy.

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]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

olaparib

OR

talazoparib

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

5th line – trastuzumab deruxtecan; or sacituzumab govitecan; or abemaciclib monotherapy

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
5th line – 

trastuzumab deruxtecan; or sacituzumab govitecan; or abemaciclib monotherapy

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 is defined as a HER2 immunohistochemistry score of 1+ or 2+ without amplification on in situ hybridisation.[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 (a monoclonal antibody-drug conjugate combining a Trop-2-directed 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] The US Food and Drug Administration has issued a warning that the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib 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).

Primary options

trastuzumab deruxtecan: consult local specialist protocol for dosing guidelines

OR

sacituzumab govitecan: consult local specialist protocol for dosing guidelines

OR

abemaciclib: 200 mg orally twice daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

6th line – targeted therapies

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
6th line – 

targeted therapies

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for dosing guidelines.

Primary options

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal

1st line – tamoxifen and/or ovarian ablation (surgical or medical)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
1st line – 

tamoxifen and/or ovarian ablation (surgical or medical)

First-line options include tamoxifen and/or ovarian ablation.[46]

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.

Primary options

tamoxifen: 20 mg orally once daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – endocrine therapy ± CDK4/6 inhibitor (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
2nd line – 

endocrine therapy ± CDK4/6 inhibitor (post-ovarian ablation)

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

First-line options include 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).[28][46][73]

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 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 include: fulvestrant (a selective oestrogen receptor degrader) as a single agent or combined with ribociclib; or tamoxifen (a selective oestrogen receptor modulator).[28][46][73]​​​​[81][92]​​

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]

Primary options

anastrozole: 1 mg orally once daily until tumour progression

OR

letrozole: 2.5 mg orally once daily until tumour progression

OR

anastrozole: 1 mg orally once daily until tumour progression

or

letrozole: 2.5 mg orally once daily until tumour progression

-- AND --

ribociclib: 600 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

or

abemaciclib: 150 mg orally twice daily until tumour progression

or

palbociclib: 125 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

Secondary options

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

ribociclib: 600 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

OR

tamoxifen: 20 mg orally once daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – exemestane + everolimus; or fulvestrant + CDK4/6 inhibitor; or fulvestrant + alpelisib; or fulvestrant + palbociclib + inavolisib; or fulvestrant + capivasertib; or elacestrant; or exemestane monotherapy (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
3rd line – 

exemestane + everolimus; or fulvestrant + CDK4/6 inhibitor; or fulvestrant + alpelisib; or fulvestrant + palbociclib + inavolisib; or fulvestrant + capivasertib; or elacestrant; or exemestane monotherapy (post-ovarian ablation)

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

exemestane plus everolimus;

fulvestrant plus a CDK4/6 inhibitor (ribociclib, abemaciclib, or palbociclib);

fulvestrant plus alpelisib (for patients with PIK3CA mutation);

fulvestrant plus palbociclib plus inavolisib (for patients with PIK3CA mutations);

fulvestrant plus capivasertib (for patients with PIK3CA/AKT1/PTEN alterations who have progressed during or following aromatase inhibitor therapy with or without a CDK4/6 inhibitor);

elacestrant (for patients with ESR1-mutations who have progressed following one or two lines of prior endocrine therapy);

exemestane monotherapy.

The US Food and Drug Administration 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). 

Primary options

exemestane: 25 mg orally once daily until tumour progression

and

everolimus: 10 mg orally once daily until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

-- AND --

ribociclib: 600 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

or

abemaciclib: 150 mg orally twice daily until tumour progression

or

palbociclib: 125 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

alpelisib: 300 mg orally once daily until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

palbociclib: 125 mg orally once daily on days 1-21 of each cycle followed by 7 days off before repeating, until tumour progression

and

inavolisib: 9 mg orally once daily until tumour progression

OR

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

and

capivasertib: 400 mg orally twice daily on days 1-4 of each 7-day cycle until tumour progression

OR

elacestrant: 345 mg orally once daily until tumour progression

Secondary options

exemestane: 25 mg orally once daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

4th line – megestrol (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
4th line – 

megestrol (post-ovarian ablation)

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

Megestrol is a synthetic progestin that is generally used after other therapies fail. Progestogens are not used earlier because of adverse effects.

Megestrol may be effective in stimulating appetite in women with MBC who have anorexia.[115]

Primary options

megestrol: 160 mg orally once daily

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

5th line – chemotherapy or PARP inhibitor (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
5th line – 

chemotherapy or PARP inhibitor (post-ovarian ablation)

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

After three lines of endocrine therapy, the likelihood of response to further hormonal manipulation is low.

Chemotherapy may be used at this stage, or at any stage of treatment if visceral crisis develops 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]​​​​​​

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.

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.[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 (an epothilone B analogue)

cyclophosphamide (an alkylating agent).​​

Upon resolution of organ crisis and/or attaining disease stability, chemotherapy may be switched to endocrine therapy.

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]

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

olaparib

OR

talazoparib

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

6th line – trastuzumab deruxtecan; or sacituzumab govitecan; or abemaciclib monotherapy (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
6th line – 

trastuzumab deruxtecan; or sacituzumab govitecan; or abemaciclib monotherapy (post-ovarian ablation)

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 is defined as a HER2 immunohistochemistry score of 1+ or 2+ without amplification on in situ hybridisation.[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] The US Food and Drug Administration has issued a warning that the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib 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).

Primary options

trastuzumab deruxtecan: consult local specialist protocol for dosing guidelines

OR

sacituzumab govitecan: consult local specialist protocol for dosing guidelines

OR

abemaciclib: 200 mg orally twice daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

7th line – targeted therapies (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
7th line – 

targeted therapies (post-ovarian ablation)

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for dosing guidelines.

Primary options

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-negative, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal

1st line – pertuzumab + trastuzumab + a taxane

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
1st line – 

pertuzumab + trastuzumab + a taxane

For women able to tolerate chemotherapy, dual HER2 blockade with trastuzumab and pertuzumab, in combination with a taxane (docetaxel or paclitaxel) is first-line treatment.[28][46][133]​​​​​ Patients with congestive heart failure or a low ventricular ejection fraction may need further consideration before initiating HER2 blockade therapy.

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]

Alternative first-line options are available for patients unable to tolerate chemotherapy.

See local specialist protocol for dosing guidelines.

Primary options

pertuzumab

-- AND --

trastuzumab

-- AND --

docetaxel

or

paclitaxel

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

1st line – trastuzumab + an aromatase inhibitor (non-candidate for chemotherapy)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
1st line – 

trastuzumab + an aromatase inhibitor (non-candidate for chemotherapy)

Trastuzumab plus an aromatase inhibitor is a first-line option for hormone receptor-positive, HER2-positive post-menopausal women who are unable to tolerate chemotherapy, or who have a poor performance status.

This combination improves progression-free survival and overall response rate compared with aromatase inhibitor alone.[139]​​

Primary options

trastuzumab: see local specialist protocol for dosing guideline

-- AND --

anastrozole: 1 mg orally once daily until tumour progression

or

letrozole: 2.5 mg orally once daily until tumour progression

or

exemestane: 25 mg orally once daily until tumour progression

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – trastuzumab deruxtecan

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
2nd line – 

trastuzumab deruxtecan

Trastuzumab deruxtecan (an antibody-drug conjugate combining trastuzumab with a topoisomerase I inhibitor) 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]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab deruxtecan

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – tucatinib + trastuzumab + capecitabine (for patients with active brain metastases)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
2nd line – 

tucatinib + trastuzumab + capecitabine (for patients with active brain metastases)

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]

See local specialist protocol for dosing guidelines.

Primary options

tucatinib

and

trastuzumab

and

capecitabine

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – individualised treatment

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
3rd line – 

individualised treatment

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: trastuzumab deruxtecan; tucatinib plus trastuzumab and capecitabine; trastuzumab emtansine; lapatinib plus capecitabine; margetuximab plus chemotherapy; neratinib plus capecitabine; trastuzumab plus chemotherapy (except anthracyclines); trastuzumab plus lapatinib; trastuzumab monotherapy; endocrine therapy alone (in highly selected patients with hormone receptor-positive, HER2-positive MBC); or other targeted agents (depending on biomarker status).​​​​[28][46][133]

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

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 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 anthracyclines 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]​​

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for choice of regimen and dosing guidelines.

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: post-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal

1st line – pertuzumab + trastuzumab + a taxane

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
1st line – 

pertuzumab + trastuzumab + a taxane

For women able to tolerate chemotherapy, dual HER2 blockade with trastuzumab and pertuzumab, in combination with a taxane (docetaxel or paclitaxel) is first-line treatment.[28][46][133]​​​​ Patients with congestive heart failure or a low ventricular ejection fraction may need further consideration before initiating HER2 blockade therapy.

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]

Alternative first-line options are available for patients unable to tolerate chemotherapy.

See local specialist protocol for dosing guidelines.

Primary options

pertuzumab

-- AND --

trastuzumab

-- AND --

docetaxel

or

paclitaxel

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

1st line – tamoxifen and/or ovarian ablation (surgical or medical) plus trastuzumab (non-candidate for chemotherapy)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
1st line – 

tamoxifen and/or ovarian ablation (surgical or medical) plus trastuzumab (non-candidate for chemotherapy)

Tamoxifen and/or ovarian ablation plus trastuzumab is the first-line option for pre-menopausal women with hormone receptor-positive, HER2-positive MBC who are unable to tolerate chemotherapy, or who have a poor performance status.

Ovarian ablation is either surgical (oophorectomy) or medical (e.g., gonadotrophin-releasing hormone agonist, such as goserelin).

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.

Sequential endocrine therapy plus trastuzumab is given thereafter as appropriate.

Primary options

tamoxifen: 20 mg orally once daily until tumour progression

and

trastuzumab: see local specialist protocol for dosing guidelines

Plus – sequential endocrine therapy plus trastuzumab (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
Plus – 

sequential endocrine therapy plus trastuzumab (post-ovarian ablation)

Treatment recommended for ALL patients in selected patient group

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

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

Primary options

anastrozole: 1 mg orally once daily until tumour progression

or

letrozole: 2.5 mg orally once daily until tumour progression

or

exemestane: 25 mg orally once daily until tumour progression

or

fulvestrant: 500 mg intramuscularly on days 1, 15, 29, then once monthly until tumour progression

-- AND --

trastuzumab: see local specialist protocol for dosing guideline

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – trastuzumab deruxtecan (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
2nd line – 

trastuzumab deruxtecan (post-ovarian ablation)

Trastuzumab deruxtecan (an antibody-drug conjugate combining trastuzumab with a topoisomerase I inhibitor) 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]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab deruxtecan

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – tucatinib + trastuzumab + capecitabine (for patients with active brain metastases) (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
2nd line – 

tucatinib + trastuzumab + capecitabine (for patients with active brain metastases) (post-ovarian ablation)

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]

See local specialist protocol for dosing guidelines.

Primary options

tucatinib

and

trastuzumab

and

capecitabine

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – individualised treatment (post-ovarian ablation)

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
3rd line – 

individualised treatment (post-ovarian ablation)

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: trastuzumab deruxtecan; tucatinib plus trastuzumab and capecitabine; trastuzumab emtansine; lapatinib plus capecitabine; margetuximab plus chemotherapy; neratinib plus capecitabine; trastuzumab plus chemotherapy (except anthracyclines); trastuzumab plus lapatinib; trastuzumab monotherapy; endocrine therapy alone (in highly selected patients with hormone receptor-positive, HER2-positive MBC); or other targeted agents (depending on biomarker status).[28][46][133]​​​​​

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

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 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 anthracyclines 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]​​

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for choice of regimen and dosing guidelines.

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive, HER2-positive, without visceral crisis: pre-menopausal
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

hormone receptor-negative, HER2-positive, without visceral crisis

1st line – pertuzumab + trastuzumab + a taxane; or trastuzumab monotherapy (non-candidate for chemotherapy)

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
1st line – 

pertuzumab + trastuzumab + a taxane; or trastuzumab monotherapy (non-candidate for chemotherapy)

For women able to tolerate chemotherapy, dual HER2 blockade with trastuzumab and pertuzumab, in combination with a taxane (docetaxel or paclitaxel) is first-line treatment.[28][46][133]​​​ Patients with congestive heart failure or a low ventricular ejection fraction may need further consideration before initiating HER2 blockade therapy.

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]

Trastuzumab as a single agent may be considered for women who cannot tolerate chemotherapy or who have poor performance status.

See local specialist protocol for dosing guidelines.

Primary options

pertuzumab

-- AND --

trastuzumab

-- AND --

docetaxel

or

paclitaxel

OR

trastuzumab

Plus – supportive care

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – trastuzumab deruxtecan

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
2nd line – 

trastuzumab deruxtecan

Trastuzumab deruxtecan (an antibody-drug conjugate combining trastuzumab with a topoisomerase I inhibitor) 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]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab deruxtecan

Plus – supportive care

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – tucatinib + trastuzumab + capecitabine (for patients with active brain metastases)

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
2nd line – 

tucatinib + trastuzumab + capecitabine (for patients with active brain metastases)

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]

See local specialist protocol for dosing guidelines.

Primary options

tucatinib

and

trastuzumab

and

capecitabine

Plus – supportive care

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – individualised treatment

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
3rd line – 

individualised treatment

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: trastuzumab deruxtecan; tucatinib plus trastuzumab and capecitabine; trastuzumab emtansine; lapatinib plus capecitabine; margetuximab plus chemotherapy; neratinib plus capecitabine; trastuzumab plus chemotherapy (except anthracyclines); trastuzumab plus lapatinib; trastuzumab monotherapy; or other targeted agents (depending on biomarker status).[28][46][133]

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

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 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 anthracyclines 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]

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for choice or regimen and dosing guidelines.

Plus – supportive care

Back
ONGOING
|
hormone receptor-negative, HER2-positive, without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis

1st line – chemotherapy

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
without germline BRCA mutation
1st line – 

chemotherapy

First-line treatment for PD-L1-negative, triple-negative MBC patients without germline BRCA mutations is chemotherapy.[28][46][96]​​​​​

Chemotherapy may be used at this stage, or at any stage of treatment if visceral crisis develops due to metastatic disease or worsening tumour burden.

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]

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 an agent.

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.[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.[167]​​

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

Plus – supportive care

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
without germline BRCA mutation
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – chemotherapy or sacituzumab govitecan

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
without germline BRCA mutation
2nd line – 

chemotherapy or sacituzumab govitecan

Patients with triple-negative MBC who progress following first-line treatment with chemotherapy can be considered for second-line treatment with a different chemotherapy regimen or sacituzumab govitecan (an antibody-drug conjugate combining a Trop-2-directed antibody with a topoisomerase inhibitor).[164]

The following single-agent chemotherapy regimens may be used depending on patient factors and prior treatment (and as indicated): doxorubicin or epirubicin (anthracyclines); docetaxel or paclitaxel (taxanes); pegylated liposomal doxorubicin; nanoparticle albumin-bound-paclitaxel; capecitabine or gemcitabine (antimetabolites); vinorelbine or eribulin (microtubule inhibitors); ixabepilone (an epothilone B analogue); cyclophosphamide (an alkylating agent).[28]​​​​[46][96]​​​​

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

sacituzumab govitecan

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
without germline BRCA mutation
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – chemotherapy or targeted therapies

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
without germline BRCA mutation
3rd line – 

chemotherapy or targeted therapies

​Patients with triple-negative MBC who progress following second-line treatment can be considered for treatment with chemotherapy (i.e., a different regimen to those already used) or targeted agents (depending on biomarker status) for third-line treatment and beyond.[28][46]

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
without germline BRCA mutation
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

​Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

1st line – PARP inhibitor or chemotherapy (platinum agent)

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
with germline BRCA mutation
1st line – 

PARP inhibitor or chemotherapy (platinum agent)

First-line treatment for PD-L1-negative, triple-negative MBC patients with germline BRCA mutations is a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor or 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]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

OR

talazoparib

OR

carboplatin

Plus – supportive care

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
with germline BRCA mutation
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – chemotherapy or sacituzumab govitecan

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
with germline BRCA mutation
2nd line – 

chemotherapy or 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 (an antibody-drug conjugate combining a Trop-2-directed antibody with a topoisomerase inhibitor).[164]

If chemotherapy was used for first-line treatment, then a different chemotherapy regimen can be considered for second-line treatment and beyond.

The following single-agent chemotherapy regimens may be used depending on patient factors and prior treatment (and as indicated): doxorubicin or epirubicin (anthracyclines); docetaxel or paclitaxel (taxanes); pegylated liposomal doxorubicin; nanoparticle albumin-bound-paclitaxel; capecitabine or gemcitabine (antimetabolites); vinorelbine or eribulin (microtubule inhibitors); ixabepilone (an epothilone B analogue); cyclophosphamide (an alkylating agent).[28]​​​​[46][96]​​​​ ​

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

sacituzumab govitecan

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
with germline BRCA mutation
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – chemotherapy or targeted therapies

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
with germline BRCA mutation
3rd line – 

chemotherapy or targeted therapies

​Patients with triple-negative MBC who progress following second-line treatment can be considered for treatment with chemotherapy (i.e., a different regimen to those already used) or targeted agents (depending on biomarker status) for third-line treatment and beyond.[28][46]

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for choice of regimen and dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
PD-L1-negative, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
|
with germline BRCA mutation
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

​Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis

1st line – pembrolizumab + chemotherapy

Back
ONGOING
|
PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
1st line – 

pembrolizumab + chemotherapy

Atezolizumab plus nanoparticle albumin-bound-paclitaxel [nab-paclitaxel] is approved in the EU and other countries (except the US; accelerated 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 (an immune checkpoint inhibitor targeting PD-1) 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.[163]

See local specialist protocol for dosing guidelines.

Primary options

atezolizumab

and

paclitaxel nanoparticle albumin-bound

OR

pembrolizumab

-- AND --

paclitaxel nanoparticle albumin-bound

or

paclitaxel

OR

pembrolizumab

and

carboplatin

and

gemcitabine

Plus – supportive care

Back
ONGOING
|
PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – chemotherapy or sacituzumab govitecan

Back
ONGOING
|
PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
2nd line – 

chemotherapy or 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 (an antibody-drug conjugate combining a Trop-2-directed antibody with a topoisomerase inhibitor).[164]

The following single-agent chemotherapy regimens may be used depending on patient factors and prior treatment (and as indicated): doxorubicin or epirubicin (anthracyclines); docetaxel or paclitaxel (taxanes); pegylated liposomal doxorubicin; nanoparticle albumin-bound-paclitaxel; capecitabine or gemcitabine (antimetabolites); vinorelbine or eribulin (microtubule inhibitors); ixabepilone (an epothilone B analogue); cyclophosphamide (an alkylating agent).[28]​​​​[46][96]​​​ ​

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

sacituzumab govitecan

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

3rd line – chemotherapy or targeted therapies

Back
ONGOING
|
PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
3rd line – 

chemotherapy or targeted therapies

Patients with triple-negative MBC who progress following second-line treatment can be considered for treatment with chemotherapy (i.e., a different regimen to those already used) or targeted agents (depending on biomarker status) for third-line treatment and beyond.[28][46]

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for dosing guidelines.

Primary options

doxorubicin

OR

epirubicin

OR

docetaxel

OR

paclitaxel

OR

doxorubicin liposomal

OR

paclitaxel nanoparticle albumin-bound

OR

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Secondary options

capecitabine

OR

gemcitabine

OR

vinorelbine

OR

eribulin

OR

ixabepilone

OR

cyclophosphamide

Plus – supportive care

Back
ONGOING
|
PD-L1-positive, triple-negative (hormone receptor-negative, HER2-negative), without visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

hormone receptor-positive or negative, HER2-negative, with visceral crisis

1st line – chemotherapy

Back
ONGOING
|
hormone receptor-positive or negative, HER2-negative, with visceral crisis
1st line – 

chemotherapy

Chemotherapy is the mainstay of therapy in end-organ/visceral crisis, where the goal of therapy is to attain rapid disease control and palliation of symptoms.

Combination chemotherapy, if tolerated, is preferred as it offers better response rates in such scenarios.

See local specialist protocol for choice of regimen and dosing guidelines.

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive or negative, HER2-negative, with visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – targeted therapies

Back
ONGOING
|
hormone receptor-positive or negative, HER2-negative, with visceral crisis
2nd line – 

targeted therapies

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for dosing guidelines.

Primary options

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive or negative, HER2-negative, with visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

hormone receptor-positive or negative, HER2-positive, with visceral crisis

1st line – pertuzumab + trastuzumab + a taxane

Back
ONGOING
|
hormone receptor-positive or negative, HER2-positive, with visceral crisis
1st line – 

pertuzumab + trastuzumab + a taxane

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]

See local specialist protocol for dosing guidelines.

Primary options

pertuzumab

-- AND --

trastuzumab

-- AND --

docetaxel

or

paclitaxel

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive or negative, HER2-positive, with visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

2nd line – targeted therapies

Back
ONGOING
|
hormone receptor-positive or negative, HER2-positive, with visceral crisis
2nd line – 

targeted therapies

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 deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumours, or high tumour mutational burden (TMB-high [≥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.

See local specialist protocol for dosing guidelines.

Primary options

entrectinib

OR

larotrectinib

OR

repotrectinib

OR

pembrolizumab

OR

dostarlimab

OR

selpercatinib

Plus – supportive care

Back
ONGOING
|
hormone receptor-positive or negative, HER2-positive, with visceral crisis
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Supportive care 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 US Food and Drug Administration (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.

Enrolment into clinical trials should be strongly considered at any stage during management.

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