Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas
Journal of Clinical Oncology, vol. 41, pp. 1684–1694
Abstract
PURPOSE Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL. PATIENTS AND METHODS We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL. RESULTS Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value. CONCLUSION We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL. [Media: see text]
Authors 27
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
University of Freiburg, Faculty of Biology, Freiburg, Germany
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Berta-Ottenstein-Programme for Clinician Scientists Medical Center, University of Freiburg, Freiburg, Germany
Department of Neurosurgery, Medical Center—University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Radiology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Center—University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Affiliation as printed
Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
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Affiliation as printed
Department of Hematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany
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University of Freiburg · University Medical Center Freiburg · Fraunhofer Institute for Laser Technology
Affiliation as printed
Department of Stereotactic and Functional Neurosurgery, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Fraunhofer Institute for Laser Technology (ILT), Aachen, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Stanford Medicine · Stanford University
Affiliation as printed
Department of Radiation Oncology, Stanford School of Medicine, Stanford, CA
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Stanford Medicine · Stanford University
Affiliation as printed
Divisions of Oncology and Hematology, Department of Medicine, Stanford University, Stanford, CA
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University of Freiburg · German Cancer Research Center · University Medical Center Freiburg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
German Cancer Consortium (DKTK) partner site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
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