Analysis of cell-free circulating tumor DNA in 419 patients with glioblastoma and other primary brain tumors

Aim: Genomically matched trials in primary brain tumors (PBTs) require recent tumor sequencing. We evaluated whether circulating tumor DNA (ctDNA) could facilitate genomic interrogation in these patients. Methods: Data from 419 PBT patients tested clinically with a ctDNA NGS panel at a CLIA-certified laboratory were analyzed. Results: A total of 211 patients (50%) had ≥1 somatic alteration detected. Detection was highest in meningioma (59%) and gliobastoma (55%). Single nucleotide variants were detected in 61 genes, with amplifications detected in ERBB2, MET, EGFR and others. Conclusion: Contrary to previous studies with very low yields, we found half of PBT patients had detectable ctDNA with genomically targetable off-label or clinical trial options for almost 50%. For those PBT patients with detectable ctDNA, plasma cfDNA genomic analysis is a clinically viable option for identifying genomically driven therapy options.

[1]  M. Weller,et al.  Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  Hai Yan,et al.  Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA , 2018, Acta Neuropathologica.

[3]  M. Ladanyi,et al.  Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors , 2018, JAMA oncology.

[4]  R. McLendon,et al.  Molecular profiling of different glioma specimens from an Ollier disease patient suggests a multifocal disease process in the setting of IDH mosaicism , 2018, Brain Tumor Pathology.

[5]  R. Magge,et al.  Molecular Pathogenesis and Emerging Treatment for Glioblastoma. , 2018, World neurosurgery.

[6]  K. Nevel,et al.  The Utility of Liquid Biopsy in Central Nervous System Malignancies , 2018, Current Oncology Reports.

[7]  C. Paweletz,et al.  Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies , 2018, Clinical Cancer Research.

[8]  S. Mortimer,et al.  The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients , 2017, Clinical Cancer Research.

[9]  C. Paweletz,et al.  Discrimination of Germline EGFR T790M Mutations in Plasma Cell-Free DNA Allows Study of Prevalence Across 31,414 Cancer Patients , 2017, Clinical Cancer Research.

[10]  K. Aldape,et al.  Insights From Molecular Profiling of Adult Glioma. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  M. Berger,et al.  Cell-free DNA (cfDNA) mutations from clonal hematopoiesis: Implications for interpretation of liquid biopsy tests. , 2017 .

[12]  R. Kurzrock,et al.  Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma , 2017, Clinical Cancer Research.

[13]  Steven J. M. Jones,et al.  Spatial heterogeneity in medulloblastoma , 2017, Nature Genetics.

[14]  Gad Getz,et al.  Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. , 2017, Cancer discovery.

[15]  Marilyn M. Li,et al.  Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. , 2017, The Journal of molecular diagnostics : JMD.

[16]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[17]  A. Chinnaiyan,et al.  Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. , 2016, Journal of the National Cancer Institute.

[18]  R. Tamargo,et al.  Surgical complications following malignant brain tumor surgery: An analysis of 2002–2011 data , 2016, Clinical Neurology and Neurosurgery.

[19]  Gary D. Bader,et al.  Divergent clonal selection dominates medulloblastoma at recurrence , 2016, Nature.

[20]  B. Kermani,et al.  Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA , 2015, PloS one.

[21]  Y. Duan,et al.  Development of targeted therapies in treatment of glioblastoma , 2015, Cancer biology & medicine.

[22]  Juxiang Chen,et al.  The Challenges and the Promise of Molecular Targeted Therapy in Malignant Gliomas1 , 2015, Neoplasia.

[23]  H. Fine,et al.  Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date , 2015, Cancer.

[24]  L. Diaz,et al.  Liquid biopsies: genotyping circulating tumor DNA. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[26]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[27]  R. Lonser,et al.  Safety of closed brain biopsy: population-based studies weigh in. , 2013, World neurosurgery.

[28]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[29]  Debyani Chakravarty,et al.  Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response , 2012, Proceedings of the National Academy of Sciences.

[30]  Rebecca A Betensky,et al.  Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. , 2011, Cancer cell.

[31]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[32]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[33]  S. Goodman,et al.  Circulating mutant DNA to assess tumor dynamics , 2008, Nature Medicine.

[34]  M. Fleischhacker,et al.  Circulating nucleic acids (CNAs) and cancer--a survey. , 2007, Biochimica et Biophysica Acta.

[35]  M. Stroun,et al.  About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. , 2001, Clinica chimica acta; international journal of clinical chemistry.

[36]  E. Henze,et al.  Molecular biologic and scintigraphic analyses of somatostatin receptor-negative meningiomas. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[37]  J. Sneep,et al.  With a summary , 1945 .