Abstract
Neoadjuvant systemic therapy (NST) is a standard treatment approach for patients with early-stage breast cancer, particularly those with stage II-III disease and aggressive subtypes such as HER2-positive and triple-negative breast cancer. While NST improves surgical outcomes and provides prognostic information, accurately assessing preoperative treatment response remains a clinical challenge. Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker for monitoring disease dynamics and guiding therapeutic decisions. In this study, we aimed to evaluate whether ctDNA analysis in patients with stage II-III breast cancer (n = 20) could serve as a surrogate for invasive biopsies in molecular profiling and as a tool for monitoring response to NST. At baseline, ctDNA was detectable in the majority of patients by droplet digital (dd)PCR (15/18, 83%) and all patients with longitudinal follow-up had ctDNA clearance after NST (13/13; 100%). A positive correlation was observed between the allele fraction in ctDNA, histologic grade and molecular subtype, suggesting that ctDNA levels may be influenced by tumor biology. None of the three patients with undetectable baseline ctDNA had distant relapse, regardless of whether they achieved pathologic complete response (pCR), compared to 5/15 (33%) with detectable baseline ctDNA. These findings suggest that ctDNA assessment at baseline may provide additional prognostic information to define the risk of patients after NST. While ctDNA shows promise in capturing tumor burden and biological characteristics, its role in predicting pCR and long-term outcomes requires further investigation.
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Data availability
The assembled somatic mutational data of the primary tumor, plasma, residual disease as well as distant/ local relapse from the entire cohort are accessible through cBioPortal at https://www.cbioportal.org/study/summary?id=breast_msk_cfDNA_2026. All codes used in this manuscript are available for academic use on GitHub at https://github.com/ndbrown6/MSK-Early-Breast/.
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Acknowledgements
Research reported in this publication was supported by a Cancer Center Support Grant of the NIH/NCI (P30 CA008748), the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, by FDA 1U01FD007909-01A1 (F.P.), NIH/NCI MSK SPORE P50 CA247749-01 (F.P., BW), NIH R01 CA245069 (S.C.) and Breast Cancer Research Foundation (B.W., F.P., S.C.) grants.
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Conceptualization, T.A.K., J.S.R.-F. and B.W.; methodology, T.A.K., B.W., J.S.R.-F. and D.B.S.; formal analysis, F.P., S.H.K., D.N.B. and A.M.; investigation, T.A.K., G.P. and S.C.; data curation, A.M., S.H.K., F.P., T.B., B.W., and D.N. B.; writing, review and editing B.W., S.H.K., F.P., D.N.B. and A.M.; supervision, D.N.B. and T.A.K. All authors have read and agreed to the final version of the manuscript.
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A.M. reports personal fees from Menarini/Stemline, Roche, Lilly and AstraZeneca, outside the submitted work; reports travel support from Menarini/Stemline, AstraZeneca and Daiichi-Sankyo, outside the submitted work; and is supported by the ESMO José Baselga Fellowship for Clinician Scientists sponsored by AstraZeneca, outside the submitted work. F.P. reports membership on the Scientific Advisory Board of MultiplexDx and has received consulting fees and served on advisory boards for AstraZeneca. D.B.S. has consulted/received honoraria from Pfizer, Fog Pharma, PaigeAI, BridgeBio, Scorpion Therapeutics, FORE Therapeutics, Function Oncology, Pyramid, and Elsie Biotechnologies, Inc., Meliora Therapeutics, Inc. B.W. reports research funding from Repare Therapeutics and SAGA Diagnostics, paid to the institution. J.S.R.-F. is an employee of AstraZeneca and owns AstraZeneca stocks. Prior Conflicts of Interest in the last 2 years include the receipt of personal fees for the following activities: Board Membership at Grupo Oncoclinicas, consultant for Goldman Sachs Merchant Banking, consultant for Bain Capital, consultant for and SAB member of Paige.ai, consultant for and SAB member of Repare Therapeutics, Consultant of SAGA Diagnostics, Consultant of Personalis, and consultant at Multiplex Dx.
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Marra, A., Kim, S.H., Pareja, F. et al. Tracking response to neoadjuvant systemic therapy through circulating tumor DNA analysis in breast cancer. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00921-4
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DOI: https://doi.org/10.1038/s41523-026-00921-4
