Guideline statement	LoE/GoR	Consensus
Image and disease assessment guidelines
Minimal staging work-up for ABC includes a history and physical examination, haematology and biochemistry tests, and imaging of chest, abdomen and bone.	II/A	67%
Brain imaging should not be routinely carried out in asymptomatic patients. This approach is applicable to all patients with ABC including those with HER2-positive and/or metastatic TNBC.	II/D	94%
The clinical value of tumour markers is not well established for diagnosis or follow-up after adjuvant therapy, but their use (if elevated) as an aid to evaluate response to treatment, particularly in patients with non-measurable metastatic disease, is reasonable. A change in tumour markers alone should not be used to initiate a change in treatment.	II/C	89%
Evaluation of response to therapy should generally occur every 2–4 months for ET or after two to four cycles for ChT, depending on the dynamics of the disease, the location and extent of metastatic involvement and type of treatment. Imaging of target lesions may be sufficient in many patients. In certain patients, such as those with indolent disease, less frequent monitoring is acceptable. Additional testing should be carried out in a timely manner, irrespective of the planned intervals, if PD is suspected or new symptoms appear. Thorough history and physical examination must always be carried out.	Expert opinion/B	81%
Biopsy guidelines
A biopsy (preferably providing histology) of a metastatic lesion should be carried out, if easily accessible, to confirm diagnosis particularly when metastasis is diagnosed for the first time.	I/B	98%
Biological markers (especially HR and HER2) should be reassessed at least once in the metastatic setting, if clinically feasible. Depending on the metastatic site (e.g. bone tissue), technical considerations need to be discussed with the pathologist.	I/B	98%
If the results of tumour biology in the metastatic lesion differ from the primary tumour, it is currently unknown which result should be used for treatment decision making. Since a clinical trial addressing this issue is difficult to undertake, we recommend considering the use of targeted therapy (ET and/or anti-HER2 therapy) when receptors are positive in at least one biopsy, regardless of timing.	Expert opinion/B	87%
Locoregional treatment general guidelines
To date, the removal of the primary tumour in patients with de novo stage IV breast cancer has not been associated with prolongation of survival, with the possible exception of the subset of patients with bone-only disease. However, it can be considered in selected patients, particularly to improve QoL, always taking into account the patient’s preferences.	I/C	70%
Of note, some studies suggest that surgery is only valuable if carried out with the same attention to detail (e.g. complete removal of the disease) as in patients with early-stage disease. Additional prospective clinical trials evaluating the value of this approach, the best candidates and best timing are currently ongoing.	II/B	70%
A small but very important subset of patients with ABC, for example those with oligometastatic disease or low-volume metastatic disease that is highly sensitive to systemic therapy, can achieve complete remission and a long survival. A multimodal approach, including locoregional treatments with curative intent, should be considered for these selected patients. A prospective clinical trial addressing this specific situation is needed.	Expert opinion/B	91%
Systemic treatment general guidelines
Treatment choice should take into account at least these factors: HR and HER2 status, previous therapies and their toxicities, DFI, tumour burden (defined as number and site of metastases), biological age, PS, comorbidities (including organ dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychological factors, available therapies in the patient’s country and patient’s preferences.	Expert opinion/A	100%
The age of the patient should not be the sole reason to withhold effective therapy (in elderly patients) nor to overtreat (in young patients). Age alone should not determine the intensity of treatment.	I/E	100%
ChT general guidelines
Both combination and sequential single-agent ChT are reasonable options. Based on the available data, we recommend sequential monotherapy as the preferred choice for ABC. Combination ChT should be reserved for patients with rapid clinical progression, life-threatening visceral metastases or need for rapid symptom and/or disease control.	I/A	96%
In the absence of medical contraindications or patient concerns, anthracycline- or taxane-based regimens, preferably as single agents, would usually be considered as first-line ChT for HER2-negative ABC, in those patients who have not received these regimens as (neo)adjuvant treatment and for whom ChT is appropriate. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient.	I/A	71%
In patients with taxane-naive and anthracycline-resistant ABC or with anthracycline maximum cumulative dose or toxicity (i.e. cardiac) who are being considered for further ChT, taxane-based therapy, preferably as single agent, would usually be considered as treatment of choice. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient.	I/A	59%
In patients pre-treated (in the adjuvant and/or metastatic setting) with an anthracycline and a taxane, and who do not need combination ChT, single-agent capecitabine, vinorelbine or eribulin are the preferred choices. Additional choices include gemcitabine, platinum agents, taxanes and liposomal anthracyclines. The decision should be individualised and take into account different toxicity profiles, previous exposure, patient preferences and country availability.	I/A	77%
If given in the adjuvant setting, a taxane can be re-used as first-line therapy, particularly if there has been at least 1 year of DFS.	I/B	92%
If given in the adjuvant setting, provided that maximum cumulative dose has not been achieved and that there are no cardiac contraindications, anthracyclines can be re-used in ABC, particularly if there has been at least 1 year of DFS.	I/B	93%
Metronomic ChT is a reasonable treatment option for patients not requiring rapid tumour response. The better studied regimen is CM (low-dose oral cyclophosphamide and methotrexate); other regimens are being evaluated (including capecitabine and vinorelbine). Randomised trials are needed to accurately compare metronomic ChT with standard dosing regimens.	I/B	88%
Duration of each regimen and the number of regimens should be tailored to each individual patient.	Expert opinion/A	96%
Usually each regimen (except anthracyclines) should be given until PD or unacceptable toxicity. What is considered unacceptable should be defined together with the patient.	I/B	72%
Other agents
Bevacizumab combined with ChT as first- or second-line therapy for ABC provides only a moderate benefit in PFS and no benefit in OS. The absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult. Bevacizumab can only therefore be considered as an option in selected cases in these settings and is not recommended after first/second line.	I/C	74%

No new statements for this section were developed at ABC 4.

ABC, advanced breast cancer; ChT, chemotherapy; Consensus, percentage of panel members in agreement with the statement; ET, endocrine therapy; DFI, disease-free interval; DFS, disease-free survival; GoR, grade of recommendation; HER2, human epidermal growth factor 2; HR, hormone receptor; LoE, available level of evidence; OS, overall survival; PD, disease progression; PFS, progression-free survival; PS, performance status; QoL, quality of life; TNBC, triple-negative breast cancer.