TRAIN-2

Design, population and eligibility

Treatment and comparator

Anthracycline arm: Three cycles FEC (5-FU 500 mg/m², epirubicin 90 mg/m², cyclophosphamide 500 mg/m²) followed by six cycles paclitaxel (80 mg/m² days 1 and 8) plus carboplatin (AUC 6). Anthracycline-free arm: Nine cycles paclitaxel (80 mg/m² days 1 and 8) plus carboplatin (AUC 6). Both arms received trastuzumab (8 mg/kg loading, then 6 mg/kg) and pertuzumab (840 mg loading, then 420 mg) every 3 weeks; anti-HER2 treatment continued to complete one year.

Primary and secondary endpoints

Primary endpoint: breast-and-axillary pathological complete response (ypT0/is ypN0). Secondary endpoints included 3-year EFS, OS and safety.

Key efficacy results

pCR was 67% (141/212; 95% CI 60–73) with anthracyclines and 68% (140/206; 95% CI 61–74) without anthracyclines (p=0.95).

At 3 years, EFS was 92.7% (95% CI 89.3–96.2) versus 93.6% (90.4–96.9); HR 0.90 (95% CI 0.50–1.63). Three-year OS was 97.7% versus 98.2%; HR 0.91 (95% CI 0.35–2.36). The EFS confidence interval is wide and does not establish formal non-inferiority.

Source-reported outcome visualization

pCR and 3-year EFS · arm-specific rates.

Separate endpoint pairs are shown as reported. Similar point estimates do not constitute a formal equivalence or non-inferiority conclusion.

Absolute effect

No superiority NNT is appropriate: observed pCR, EFS and OS were similar, and the trial was not designed or powered to prove non-inferiority for survival. Do not interpret the 0.9-point EFS difference as a treatment benefit.

Trial-specific toxicity and treatment burden

LVEF decline ≥10 percentage points to below 50% occurred in 7.7% with anthracyclines versus 3.2% without (p=0.04). Two patients in the anthracycline arm developed acute leukaemia. Anthracyclines were also associated with more febrile neutropenia and cardiotoxicity.

Completion of one year of trastuzumab was 89.0% in the anthracycline arm and 97.3% in the non-anthracycline arm. Cardiotoxicity accounted for 15/216 trastuzumab discontinuations in the anthracycline arm. Full grade 3–5 event tables are in the primary supplement.

Quality of life and patient-reported outcomes

No formal comparative QoL result is highlighted in the primary 3-year report. Treatment burden differs materially because the anthracycline arm adds three FEC cycles and a higher observed cardiac monitoring/discontinuation burden.

Subgroups and applicability

Exploratory results were similar across hormone-receptor and nodal-status subgroups; no reliable interaction establishes a subgroup requiring anthracyclines in the setting of dual HER2 blockade.

Current-practice context · reviewed 2 November 2026

Anthracycline-free taxane–carboplatin with trastuzumab and pertuzumab is an established neoadjuvant strategy for many stage II–III HER2-positive patients. Choice of regimen remains risk- and patient-dependent; TRAIN-2 supports omission of anthracyclines but does not prove formal non-inferiority.

Limitations and critical interpretation

The survival analysis had few events and wide confidence intervals. pCR was the primary endpoint; survival was secondary. The study was conducted in a Dutch population and does not compare every contemporary HER2-directed sequence or post-neoadjuvant strategy.

Bottom line: TRAIN-2 shows near-identical pCR and encouraging 3-year outcomes with anthracycline-free dual HER2 blockade, alongside less cardiac and haematologic toxicity. The evidence supports de-escalation but should not be labelled a formal non-inferiority result.

Primary sources and follow-up publications

1. TRAIN-2 primary report, Lancet Oncology 2018
2. TRAIN-2 3-year follow-up, JAMA Oncology 2021
3. TRAIN-2 registry

All outcome values above are transcribed from the linked trial reports or their prespecified follow-up publications. Unreported values are not imputed. No NNT is derived from median survival.