ICE II‐GBG 52.

Methods	Randomised controlled trial Multi‐centre (63 sites), Germany (part of German Breast Group), open‐label Randomisation performed centrally and stratified by participating centre, risk assessment method (pT3/4, pN2/3, or clinicopathological, or high urokinase plasminogen activator (uPA) or high plasminogen activator inhibitor 1 (PAI‐1)), age, oestrogen receptor/progesterone receptor/HER2 status Accrual April 2009 to April 2013 Baseline characteristics balanced between treatment groups
Participants	Female or male patients aged ≥ 65 years with Charlson co‐morbidity index ≤ 2 Median age 72 (range 65 to 84) Two‐thirds of patients had clinopathologically medium‐ to high‐risk pT1/2 pN0/1 breast cancer 65.5% hormone receptor‐positive/HER2‐negative disease; 16.9% HER2‐positive disease; 17.6% triple‐negative breast cancer Exclusion of metastatic disease Prior chemotherapy for any malignancy and concurrent or previous systemic investigational or established anti‐tumour treatment not permitted
Interventions	ARM 1 (EC or CMF) EC × 4 21‐day cycles (epirubicin 90 mg/m², cyclophosphamide 600 mg/m²) or CMF × 6 28‐day cycles (cyclophosphamide 500 mg/m², methotrexate 40 mg/m², 5‐fluorouracil 600 mg/m² on days 1 and 8) based on investigators’ decision ARM 2 (nPX) nPX × 6 21‐day cycles (nab‐paclitaxel 100 mg/m² on days 1, 8, and 15 every 3 weeks with a week of rest every 6 weeks) plus capecitabine (1000 mg/m²) twice daily on days 1 to 14 every 3 weeks Sequential radiotherapy, anti‐HER2 therapy, and endocrine treatment recommended as per national guidelines Primary prophylaxis with granulocyte colony‐stimulating factor not recommended
Outcomes	Primary endpoint: Compliance and safety Secondary endpoints: Invasive disease‐free survival (iDFS) and distant disease‐free survival (DDFS), defined as any local invasive or distant recurrence of breast cancer, any contralateral breast cancer, any second malignancy, and any death irrespective of its cause for iDFS Overall survival, defined as any cause of death Efficacy of treatment in subgroups according to clinical stratification factors Prognostic factors on tumour tissue collected from primary surgery and for correlation with study treatment effects Geriatric assessment scores at baseline and at completion of therapy Toxicity, assessed using Common Terminology Criteria for Adverse Events (version 3.0)
Notes	Median follow‐up: 22.8 months Clinical Trial Identifier: NCT01204437 (see clinicaltrials.gov/ct2/show/NCT01204437) Funded: supported received from Celgene and Roche; sponsored/collaborators were the German Breast Group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “…randomization at a 1:1 ratio was performed centrally and stratified according to participating center, risk assessment method, age, and estrogen receptor/progesterone receptor/HER2 status…”
Allocation concealment (selection bias)	Low risk	Randomisation performed centrally
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Open‐label study
Blinding of outcome assessment ‐ OS (detection bias)	Low risk	Assessment of overall survival unlikely to be influenced by no or incomplete blinding
Blinding of outcome assessment ‐ DFS & Toxicity (detection bias)	Unclear risk	Assessment including clinical visits and breast imaging techniques every 3 months for 2 years, then every 6 months from year 2 to 5 for the diagnosis of local, locoregional, ipsilateral, or contralateral recurrence; distant metastasis, or death. Toxicity graded according to National Cancer Institute Common Toxicity Criteria Comment: no involvement of an independent adjudication committee for outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Low risk	All efficacy analysis intention‐to‐treat; safety analysis including patients who received treatment
Selective reporting (reporting bias)	Low risk	Trial registry record outcomes reported in the trial publication
Other bias	Low risk	No other sources identified