Neo‐TAnGo 2014.

Methods	Accrual: 18 January 2005 to 28 September 2007 Open‐label, phase III randomised controlled trial conducted in the UK Neoadjuvant therapy Multicentre study (57 centres) Median follow‐up: 47 months (interquartile range 37–51)
Participants	Age: < 50 years: 63% (in both arms); ≥ 50 years: 37% (in both arms) 26% (arm 1) and 28% (arm 2) postmenopausal Tumour size > 20 mm Inflammatory or locally advanced disease: 25% Axillary node involvement: 50% ER‐positive: 67% (arm 1), 66% (arm 2); PR‐positive: 49% (arm 1), 53% (arm 2) HER2‐positive: 26% (arm 1), 28% (arm 2) Excluded: prior chemotherapy, radiotherapy or endocrine therapy
Interventions	4‐arm study with 1 treatment comparison relevant for inclusion in this review (labelled as "sequencing analysis" in trial publication) Arm 1: paclitaxel (175 mg/m²) with or without gemcitabine 200 mg/m² every 2 weeks for 4 cycles followed by epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks for 4 cycles Arm 2: epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) every 3 weeks for 4 cycles followed by paclitaxel (175 mg/m²) with or without gemcitabine (200 mg/m²) every 2 weeks for 4 cycles
Outcomes	Primary outcome pCR, defined as absence of invasive breast cancer in the breast and axillary lymph nodes Secondary outcomes DFS, defined as from the date of randomisation to the date of first event (locoregional relapse, distant relapse, progression on neoadjuvant chemotherapy or death) or to the date of censoring OS, defined as from the date of randomisation to the date of death or to the date of each participant's last clinic visit (for women who were not known to have died) Toxicity, assessed for each chemotherapy cycle according to the Common Terminology Criteria for Adverse Events Course‐delivered dose intensities
Notes	Clinical trial registration record: NCT00070278 Funding considerations: supported by Cancer Research UK, Eli Lilly, Bristol‐Myers Squibb. Trial authors declared that study design, data collection, data analysis, data interpretation, etc did not involve study sponsors. Statistical analysis: Warwick Clinical Trials Unit, Coventry, UK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Minimisation randomisation. Quote: "…treatment allocations were made by telephoning the Cancer Research UK Trials Unit (Birmingham UK) who used their central computerised minimisation procedure to generate the patient's random allocation."
Allocation concealment (selection bias)	Low risk	Central allocation. Quote: "…patients were randomly assigned via a central randomisation procedure to…"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Open‐label study. Participants in both groups received the same drugs though in different order. Therefore, it was judged to be unlikely that this would lead to a material bias in participants' and physicians' behaviours even when unblinded.
Blinding of outcome assessment (detection bias) Overall survival	Low risk	Lack of blinding unlikely to influence this outcome.
Blinding of outcome assessment (detection bias) DFS	Low risk	Unblinding is unlikely to have an impact on outcome assessment for this review question where trial participants received both treatment regimens.
Blinding of outcome assessment (detection bias) Toxicity and treatment adherence	Unclear risk	Toxicity was assessed using a range of laboratory tests as well as the CTCAE scale. Dose delays and dose reductions were based on laboratory tests (e.g. ANCs) and severe toxicities. As the study was unblinded, knowledge of treatment allocation may have had some influence on the physicians' assessments.
Blinding of outcome assessment (detection bias) Neoadjuvant studies only: pCR	Low risk	Each pathology report was reviewed by 2 people masked to the treatment group – 1 chief investigator and 1 study pathologist. Therefore, judged to have low risk of bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants randomised to treatment groups, except for 2/416 in the intervention group and 1/415 in the comparator group were included in analysis. 11 (2.6%) participants in the comparator group and 16 (3.85%) in the intervention group were protocol violators (reasons across groups were very similar). These participants were still included in ITT analysis for secondary outcomes. For the primary outcome, there were equal numbers of participants who did not undergo surgery (4 in each group).
Selective reporting (reporting bias)	Low risk	Prespecified outcomes in Clinical trials.gov record (NCT00070278) and the Methods section of the trial publication are generally the same. Some important outcomes have been added to the trial publication – i.e. toxicity and treatment adherence data.
Other bias	Low risk	None identified