Guideline statement	LoE/GoR	Consensus
Anti-HER2 therapy should be offered early (as first line) to all patients with HER2-positive ABC, except in the presence of contraindications to the use of such therapy.	I/A	98%
Patients progressing on an anti-HER2 therapy combined with a cytotoxic or endocrine agent should be offered additional anti-HER2 therapy with subsequent treatment, except in the presence of contraindications, since it is beneficial to continue suppression of the HER2 pathway. The choice of the anti-HER2 agent will depend on country-specific availability, the specific anti-HER2 therapy previously administered and the relapse-free interval. The optimal sequence of all available anti-HER2 therapies is currently unknown. The optimal duration of anti-HER2 therapy for ABC (i.e. when to stop these agents) is currently unknown.	I/A	91%
In patients achieving a complete remission, the optimal duration of maintenance anti-HER2 therapy is unknown and needs to be balanced against treatment toxicity, logistical burden and cost. Stopping anti-HER2 therapy after several years of sustained complete remission may be considered in some patients, particularly if treatment rechallenge is available in case of progression.	Expert opinion/C	93%
Patients who have received any type of (neo)adjuvant anti-HER2 therapy should not be excluded from clinical trials for HER2-positive ABC. These patients remain candidates for anti-HER2 therapies.	I/B	100%
For the highly selected patientsa with ER-positive/HER2-positive ABC, for whom ET + anti-HER2 therapy was chosen as first-line therapy, dual anti-HER2 blockade (with either pertuzumab + trastuzumab or lapatinib + trastuzumab) can be used since it provides a benefit in PFS. This decision must be balanced against the higher side effects, higher costs and lack of OS benefit so far, when compared with ET + anti-HER2 monotherapy.	I/B	80%
For patients with ER-positive/HER2-positive ABC, for whom ChT + anti-HER2 therapy was chosen as first-line therapy and provided a benefit, it is reasonable to use ET + anti-HER2 therapy as maintenance therapy, after stopping ChT, although this strategy has not been studied in randomised trials. Duration of maintenance therapy should be until progression, unacceptable toxicity or patient request and needs to be evaluated in clinical trials. There are no data to decide between single-agent anti-HER2 or dual blockade, to combine with maintenance ET after stopping ChT, in ER-positive/HER2-positive ABC.	n/a/B	80%
In the first-line setting, for HER2-positive ABC previously treated (in the adjuvant setting with DFI >12 months) or untreated with trastuzumab, combinations of ChT + trastuzumab are superior to combinations of ChT + lapatinib in terms of PFS and OS.	I/A	95%
The standard first-line therapy for patients previously untreated with anti-HER2 therapy is the combination of ChT + trastuzumab and pertuzumab, because it has proven to be superior to ChT + trastuzumab in terms of OS in this population.	I/A	86%
For patients previously treated [in the (neo)adjuvant setting] with anti-HER2 therapy, the combination of ChT + trastuzumab and pertuzumab is an important option for first-line therapy. Few (88) of these patients were treated in the CLEOPATRA trial and all with trastuzumab-free interval >12 months.	I/A	76%
There are currently no data supporting the use of dual blockade with trastuzumab + pertuzumab and ChT beyond progression (i.e. continuing dual blockade beyond progression) and therefore this three-drug regimen should not be given beyond progression outside clinical trials.	Expert opinion/E	86%
In a HER2-positive ABC patient, previously untreated with the combination of ChT + trastuzumab + pertuzumab, it is acceptable to use this treatment after first line.	II/B	76%
After first-line, trastuzumab-based therapy, T-DM1 provides superior efficacy relative to other HER2-based therapies in the second line (versus lapatinib + capecitabine) ‘and beyond’ (versus treatment of physician’s choice). T-DM1 should be preferred in patients who have progressed through at least one line of trastuzumab-based therapy, because it provides an OS benefit. However, there are no data on the use of T-DM1 after dual blockade with trastuzumab + pertuzumab.	I/A	88%
In case of progression on trastuzumab-based therapy, the combination trastuzumab + lapatinib is a reasonable treatment option for some patients. There are however, no data on the use of this combination after progression on pertuzumab or T-DM1.	I/B	84%
Regarding the ChT component of HER2 positive ABC treatment:	I/A	88%
When pertuzumab is not given, first-line regimens for HER2 ABC can include trastuzumab combined with vinorelbine or a taxane. Differences in toxicity between these regimens should be considered and discussed with the patient in making a final decision. Other ChT agents can be administered with trastuzumab but are not as well studied and are not preferred.
For later lines of therapy, trastuzumab can be administered with several ChT agents, including but not limited to, vinorelbine (if not given in first line), taxanes (if not given in first line), capecitabine, eribulin, liposomal anthracyclines, platinum, gemcitabine or metronomic CM. The decision should be individualised and take into account different toxicity profiles, previous exposure, patient preferences and country availability.	II/A	91%
ChT agents to combine with a dual blockade of trastuzumab + pertuzumab are docetaxel [I/A] or paclitaxel [I/B]. Also possible are vinorelbine [II/A], nab-paclitaxel [II/B] and capecitabine [II/A].	See in statement	86%

In green, NEW ABC 4 statements.

ABC, advanced breast cancer; ChT, chemotherapy; CM, low-dose oral cyclophosphamide and methotrexate; Consensus, percentage of panel members in agreement with the statement; DFI, disease-free interval; ER, oestrogen receptor; ET, endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor 2; LoE, available level of evidence; OS, overall survival; PFS, progression-free survival; T-DM1, trastuzumab emtansine.

^aSee definition in text.