Summary Background Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer. Methods We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts ( HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). Findings We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A . For EFS, HRs were 0·89 (95% CI 0·79–1·01) for HER2 non-amplified patients and 0·71 (0·58–0·86) for HER2 -amplified patients (pinteraction =0·0485); for overall survival, HRs were 0·91 (95% CI 0·79–1·05) for HER2 non-amplified patients and 0·73 (0·59–0·89) for HER2 -amplified patients (pinteraction =0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78–1·00) for normal, 0·63 (0·46–0·87) for deleted, and 0·62 (0·43–0·90) for amplified (pinteraction =0·0513); HRs for overall survival were 0·89 (0·78–1·03) for normal, 0·68 (0·49–0·95) for deleted, and 0·67 (0·46–0·98) for amplified (pinteraction =0·1608). When patients with TOP2A -deleted and TOP2A -amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50–0·81) for altered and 0·88 (0·78–1·00) for normal (pinteraction =0·0183); HRs for overall survival were 0·67 (0·52–0·86) for altered and 0·89 (0·78–1·03) for normal (pinteraction =0·0455). Interpretation Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2 -amplified or TOP2A -aberrated tumours. Funding Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.