Abstract
Circulating tumor DNA (ctDNA) is a promising biomarker in early breast cancer for assessing treatment response, minimal residual disease (MRD), and recurrence risk. In the ABCSG-34 phase II trial, we previously reported that persistent ctDNA during neoadjuvant therapy (NAT) was associated with higher residual cancer burden and lower rates of pathological complete response. Here, we present long-term follow-up data evaluating the prognostic relevance of ctDNA dynamics. ABCSG-34 randomized 400 patients to chemotherapy or endocrine therapy, with or without the MUC1 vaccine tecemotide. Tumor-informed SiMSen-Seq assays were used to assess ctDNA at baseline, mid-therapy, and end-of-therapy. Of 145 patients with ctDNA data, 109 had long-term follow-up (median: 7.1 years). Baseline ctDNA positivity was significantly associated with inferior overall survival (HR 2.12, p = 0.043) and shorter survival durations across all endpoints. Trends toward improved outcomes were observed in patients who cleared ctDNA during NAT, though statistical significance was not reached—likely due to limited sample size. These findings support baseline ctDNA as a prognostic marker in early breast cancer. While ctDNA clearance may reflect treatment efficacy, further validation in larger trials is needed. Ongoing studies will determine the role of ctDNA in guiding therapy and monitoring MRD.
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Data availability
Sequencing data generated for the original publication are publicly available at the European Genome-phenome Archive (EGA; http://www.ebi.ac.uk/ega/), which is hosted by the EBI, under the accession number EGAS00001005798.
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Acknowledgements
We thank all the patients and their families who participated in the study. The clinical trial was supported by Merck. ctDNA projects were supported by the Austrian National Bank (## 16971) and by the Austrian Federal Ministry for Digital and Economic Affairs (Christian Doppler Research Fund for Liquid Biopsies for Early Detection of Cancer.
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D.E., D.H., S.H., G.R., R.B., H.D., M.G., E.Z and M.B. contributed to conceptualization. D.E., E.H., M.B. contributed to data analyses. D.E., D.H., C.S., R.B. contributed to writing and editing. S.G., G.R., C.S., G.P., Z.B.H., A.S.K., C.F., N.D., M.F., M.G., E.H., M.B. contributed to review and editing. D.H.,C.S., Z.B.H. contributed to data curation. D.H., C.S., A.S.K., contributed to formal analysis. D.H., A.S.K. contributed to software. C.S., A.P., Q.Z., R.G., S.H. contributed to investigation. C.S., G.P., R.B., G.H., E.P., M.G., E.H., M.B. contributed to resources. C.F., M.G. contributed to supervision. Q.Z. contributed to methodology. M.G. contributed to funding acquisition.
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DE reports disclosures caused by honoraria (Angelini, AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, Sirius Medical), consulting or advisory role (AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, Sirius Medical; Research Funding: Sirius Medical, Dr. Schär). SG reports disclosures caused by honoraria (Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, Seagen, Daiichi Sankyo, Janssen, Gilead), consulting or advisory role (Roche, Novartis, BMS, Pfizer, Lilly, AstraZeneca, Astellas, MSD, Seagen, Daiichi Sankyo, Stemline Therapeutics, Bayer), funding (Roche, Daiichi Sankyo, Novartis, Pfizer, Caris Life Sciences, Lilly, Seagen, Gilead, AstraZeneca, Stemline Therapeutics), travel/accommodations/expenses (Roche, Amgen, Novartis, Pfizer, Bayer, Celgene, Daiichi Sankyo, Janssen, Gilead). GR reports disclosures caused by honoraria (AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Roche, Seagen, Stemline), consulting or advisory role (AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Stemline), research funding (AstraZeneca, Daiichi Sankyo, Stemline) travel/accommodations/expenses (Daiichi Sankyo, Gilead, Roche, Servier). CS reports disclosures caused by travel and research grants and unrestricted grants (Amgen, AstraZeneca, Daiichi-Sankyo, Gilead, Novartis, Pfizer, Stemline). GF reports disclosures caused by grant and honoraria (Pfizer, Roche, AstraZeneca, Gilead, Novartis, MenariniStemline, MSD, Daiichi Sankyo, Lilly, Seagen). RB reports disclosures caused by advisory role (AstraZeneca, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, Seagen, Stemline), lecture honoraria (AstraZeneca, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Gruenenthal, MSD, MedMedia, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen, Stemline), research support (AstraZeneca, Daiichi-Sankyo). EP reports disclosures caused by lecture honoraria and advisory boards (Roche, GSK, MSD, AstraZeneca). ZBH reports disclosures caused by lecture honoraria (MSD, Astra Zeneca, Gilead, Abbvie, Daiichi Sankyo), advisory board (Astra Zeneca, MSD, Stemline, Gilead, Abbvie). MF reports disclosures caused by honoraria (AstraZeneca, Eli Lilly). MG reports disclosures caused by honoraria/travel support (Amgen, AstraZeneca, Bayer, DaiichiSankyo, EliLilly, EPG Health (IQVIA), Menarini-Stemline, MSD, Novartis, PierreFabre, Veracyte). EH reports disclosures caused by unrelated funding (Illumina, Roche, Servier, and PreAnalyti), honoraria: Roche, Astra Zeneca), advisory boards (Incyte). DH, GH, AP, ASK, KF, QZ, RG, SH, ND, MB declare no competing interests.
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Egle, D., Hlauschek, D., Gampenrieder, S.P. et al. Long-term prognostic value of ctDNA in early breast cancer: insights from the neoadjuvant ABCSG-34 Trial. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00934-z
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DOI: https://doi.org/10.1038/s41523-026-00934-z
