Background: Circulating cell-free tumor DNA (ctDNA) provides a non-invasive approach for assessing somatic alterations. The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice. In this context, ctDNA testing was included to understand the motivations of clinicians to initiate testing, to identify somatic alterations, and to assess the clinical impact of the results obtained., Methods: Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting (PRAEGNANT study; NCT02338167). The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations. A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results., Results: ctDNA from 49 patients was analyzed prospectively: 37 (76%) had at least one somatic alteration in the analyzed geneset; 14 patients (29%) harbored alterations in TP53 , 12 (24%) in PIK3CA , and 6 (12%) in ESR1 . Somatic mutations in BRCA1 or BRCA2 were detected in 3 (6%) and 4 (8%) patients, respectively, and 59% of patients had hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Questionnaires regarding test intentions and clinical impact were completed for 48 (98%) patients. These showed that ctDNA testing influenced treatment decisions for 35% of patients., Discussion: The high prevalence of somatic alterations in TP53, PIK3CA, ESR1 , and BRCA1/2 genes, identified by ctDNA genotyping, highlights their potential as biomarkers for targeted therapies. Detection of specific mutations affected treatment decisions, such as eligibility for alpelisib, and might further facilitate treatment with e.g. elacestrant or capiversatib in future treatment lines., Competing Interests: P.W. has received honoraria from Roche, Novartis, Amgen, AstraZeneca, Pfizer, MSD, Clovis, Tesaro, Celgene, Teva, Eisai, Daiichi Sankyo, Seagen, and Eli Lilly. E.B. has received honoraria from Novartis, Celgene, Eisai, Daiichi Sankyo, Merrimack, AstraZeneca, Riemser, Pfizer, Hexal, Amgen, and onkowissen.de for consulting, clinical research management, or medical education activities. A.S. has received honoraria from Roche, Celgene, AstraZeneca, Novartis, Pfizer, Zuckschwerdt Verlag GmbH, Georg Thieme Verlag, Aurikamed GmbH, MCI Deutschland GmbH, bsh medical communications GmbH, and promedicis GmbH. H.T. has received honoraria from Novartis, Roche, Celgene, Teva, and Pfizer, and travel support from Roche, Celgene, and Pfizer. S.Y.B. received honoraria from Roche, Novartis, Pfizer, MSD, Teva, and AstraZeneca. V.M. has received speaker honoraria from Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Lilly, Medscape, Gilead, Pierre Fabre, and iMED Institut, consultancy honoraria from Roche, Pierre Fabre, PINK, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Seagen, Gilead, Stemline, institutional research support from Novartis, Roche, Seagen, Genentech, and Astra Zeneca, and travel grants from Astra Zeneca, Roche, Pfizer, Daiichi Sankyo, and Gilead. T.N.F. received honoraria from Novartis, Roche, Pfizer, TEVA, Daiichi Sankyo, AstraZeneca, MSD, Onkowisseng GmBH, and Medconcept. H.H. received speaker honoraria from Lilly and funding from Novartis and Sysmex. P.A.F. has received honoraria from Agendia, AstraZeneca, ClinSol GmbH, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Seagen, Stemline Therapeutics, TRIO Oncology, and Veracyte for consulting, participation in advisory boards and steering committees and/or lectures. His institution conducts research for Novartis. T.L. received honoraria for lectures or presentations from Amgen, Roche, MSD, Novartis, Pfizer, Lilly, GSK, Gilead, Astra Zeneca, Daiichi Sankyo, Stemline, and Seagen, advisory board/advise honoraria from MSD, Roche, Pfizer, Lilly, Myriad, Esai, GSK, Gilead, Daiichi Sankyo, Roche, and Astra Zeneca, and support for attending meetings and/or travel from Pfizer, Astra Zeneca, Gilead, Daiichi Sankyo, and Stemline. I.F. and M.H. are employees and stockholders at Guardant Health, Inc. E.L. reports travel expenses from Pierre Fabre, honoraria for educational events from Astra Zeneca, and Seagen, and consultancy honoraria from Novartis, Astra Zeneca, and Daiichi Sankyo. E.R. has received Speaker honoraria from Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Seagen, Onkowissen, Lilly, Gilead, and Pierre Fabre, consultancy honoraria from Roche, Pierre Fabre, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Seagen, Gilead, and Stemline, research research support from Roche, and travel grants from Astra Zeneca, Roche, Pfizer, and Pierre Fabre., (© The Author(s) 2024. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)