Guideline statement	LoE/GoR	Consensus
ET is the preferred option for HR-positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance.	I/A	93%
Many trials in ER-positive ABC have not included PRE-MENOPAUSAL women. Despite this, we recommend that young women with ER-positive ABC should have adequate OFS/OFA and then be treated in the same way as post-menopausal women, with endocrine agents and with or without targeted therapies.	Expert opinion/A	95%
Future trials exploring new endocrine-based strategies should be designed to allow for enrolment of both pre- and post-menopausal women, and men.	Expert opinion/A	92%
For pre-menopausal women, for whom ET was decided, OFS/OFA combined with additional ET is the preferred choice.	I/A	93%
OFA by laparoscopic bilateral oophorectomy ensures definitive oestrogen suppression and contraception, avoids potential initial tumour flare with LHRH agonist and may increase eligibility for clinical trials. Patients should be informed on the options of OFS/OFA and decisions should be made on a case-by-case basis.	Expert opinion/C	91%
Single-agent tamoxifen is the only available endocrine option for pre-menopausal women who decline OFS/OFA, but the panel believes it is a less effective option.	I/D	92%
The preferred first-line ET depends on the type and duration of adjuvant ET as well as the time elapsed from the end of adjuvant ET; it can be an AI, tamoxifen or fulvestrant, for pre- and peri-menopausal women with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal women.	I/A	84%
The addition of a CDK 4/6 inhibitor to an AI, in patients naïve or pre-exposed to ET, provided a significant improvement in median PFS (∼10 months), with an acceptable toxicity profile, and is, therefore, one of the preferred treatment options for pre- and peri-menopausal women with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal women. Patients relapsing <12 months from the end of adjuvant AI were not included in the published studies and may not be suitable for this combination. OS results are still awaited. QoL was comparable to that with ET alone.	I/A	90%
ESMO-MCBS v1.1 score: 3
The addition of a CDK 4/6 inhibitor to fulvestrant, in patients previously exposed to ET, provided significant improvement in median PFS (6–7 months) as well as improvement in QoL, and is one of the preferred treatment options, if a CDK 4/6 inhibitor was not previously used, for pre- and peri-menopausal women with OFS/OFA and post-menopausal women and men. OS results are awaited.	I/A	90%
ESMO-MCBS v1.1 score: 4
The addition of everolimus to an AI is a valid option for some patients [for pre- and peri-menopausal women with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal women] previously exposed to ET, since it significantly prolongs PFS, albeit without evidence of OS benefit. The decision to treat must take into account the toxicities associated with this combination, lack of statistical significant OS benefit, cost and availability.	I/B	88%
ESMO-MCBS v1.1 score: 2
Tamoxifen or fulvestrant can also be combined with everolimus.	II/B	80%
Adequate prevention, close monitoring and proactive treatment of adverse events is needed, particularly in older patients treated with everolimus due to the increased incidence of toxic deaths reported in the BOLERO-2 trial.	I/B	97%
The optimal sequence of endocrine-based therapy is uncertain. It depends on which agents were previously used [in the (neo)adjuvant or advanced settings], the burden of the disease, patients’ preference, costs and availability. Available options [for pre- and peri-menopausal women with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal women] include AI, tamoxifen, fulvestrant, AI/fulvestrant + CDK 4/6 inhibitor, AI/tamoxifen/fulvestrant + everolimus. In later lines, also megestrol acetate and oestradiol, as well as repetition of previously used agents, may be used.	I/A	95%
It is currently unknown how the different combinations of endocrine + targeted agents compare with each other, and with single-agent ChT. Trials are ongoing.
Everolimus and CDK 4/6 inhibitors should not be used after PD on that specific agent (i.e. beyond progression).	n/a/E	74%
At present, no validated predictive biomarkers other than HR status exist to identify patients who will/will not benefit from the addition of a targeted agent (i.e. CDK 4/6 inhibitor, mTOR inhibitor) to ET and none of the studied biomarkers is ready for use in clinical practice. Research efforts must continue.	I/E	95%
The combination of a non-steroidal AI and fulvestrant as first-line therapy for post-menopausal patients resulted in significant improvement in both PFS and OS compared with AI alone in one phase III trial and no benefit in a second trial with a similar design. Subset analysis suggested that the benefit was limited to patients without prior exposure to adjuvant ET (tamoxifen). Based on these data, combination ET may be offered to some patients with ABC without prior exposure to adjuvant ET.	II/C	Yes: 33%
		No: 53%
		Abstain: 14%
Concomitant ChT and ET has not shown a survival benefit and should not be carried out outside a clinical trial.	II/D	100%
Endocrine treatment after ChT (maintenance ET) to maintain benefit is a reasonable option, though it has not been assessed in randomised trials.	III/B	88%

In green, NEW ABC 4 statements.

ABC, advanced breast cancer; AI, aromatase inhibitor; CDK, cyclin-dependent kinase; ChT, chemotherapy; Consensus, percentage of panel members in agreement with the statement; ER, oestrogen receptor; ESMO-MBCS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; ET, endocrine therapy; GoR, grade of recommendation; HER2, human epidermal growth factor 2; HR, hormone receptor; LHRH, luteinising hormone-releasing hormone; LoE, available level of evidence; mTOR, mechanistic target of rapamycin; OFA, ovarian function ablation; OFS, ovarian function suppression; OS, overall survival; PD, disease progression; PFS, progression-free survival; QoL, quality of life.