Detection of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) in patients with glioblastoma treated in phase I clinical trial

BackgroundAs circulating tumor DNA (ctDNA) has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. Thus, cerebrospinal fluid (CSF) has emerged as a potential source of ctDNA in the context of brain tumors.MethodsWe prospectively evaluated the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. We did CSF samples at C2D15 and at progression, after patient’s oral and written consent. CSF was collected by lumbar puncture after local anesthesia and analyzed, after DNA extraction, with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel.ResultsBetween January and April 2024, five patients, one woman and four men, aged from 46 to 55 years, were included. All of them underwent surgical resection at diagnosis, and received at least one previous systemic treatment associated with radiotherapy. At least one somatic mutation was identified in each of the five patients, including EGFR amplification in 2/5 patients (40%). CSF was not available at baseline. One patient provided CSF only at progression. Four patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. At data cut-off, one patient was still on treatment. We identified a detectable level of CSF-ctDNA in only one patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. The blood analysis of this patient showed only clonal hematopoiesis variants.ConclusionsWe showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible in clinical practice. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureK. Ouali: Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP), KO is principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, AstraZeneca Ab, AstraZeneca, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Cato Research, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, EverImmune, Exelixis, Faron Pharmaceuticals Ltd, Foghorn Therapeutics Inc, Forma Tharapeutics, Gamamabs, Genentech, Genmab, GSK, H3 Biomedicine, Hoffmann La Roche Ag, IGM Biosciences, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, K-Group Beta, Kinnate Biopharma, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France: Various drug companies. S. Postel-Vinay: Financial Interests, Institutional, Advisory Board, Steering Committee: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board, Steering committee: AMGEN; Financial Interests, Institutional, Local PI, As part of the Drug Development Department (DITEP) SPV is Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, MedImmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus: Various drug companies; Financial Interests, Institutional, Research Grant, Translational research funding: IMCore Hoffman LaRoche; Financial Interests, Institutional, Research Grant, preclinical research funding: AstraZeneca; Non-Financial Interests, Principal Investigator, Principal investigator of phase I/II clinical trials: AstraZeneca, GSK, PEP therapy, BMS, Novartis; Amgen, Oxford Biotherapeutics, Clovis, Roche. C.P. Massard: Other, Christophe Massard: Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Netcancer, PegascyPrincipal/sub-Investigator of Clinical Trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, MedImmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor: COMPANY. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, seattle genetics, tahio; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, astellas, Janssen; Financial Interests, Personal, Other, lectures, advisroy boards: roche, BMS; Financial Interests, Institutional, Research Grant: janssen, sanofi, MSD, roche, celsius; Financial Interests, Institutional, Steering Committee Member: janssen; Financial Interests, Steering Committee Member: msd, Astellas, Gilead/immunomedics, tahio; Financial Interests, Personal, Steering Committee Member: basilea; Financial Interests, Institutional, Local PI: Pfizer, MSD, Janssen, exelexis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Institutional, Coordinating PI: janssen; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, scientific committee: ARC. S. Champiat: Financial Interests, Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, Janssen, Merck KGaA, MSD, Novartis, Roche, Servier, Takeda; Financial Interests, Personal, Other, Principal Investigator of Clinical Trials: AbbVie, Amgen, Boehringer Ingelheim, Bolt Biotherapeutics, Centessa Pharmaceuticals, Cytovation, Eisai, GSK, Imcheck Therapeutics, Immunocore, Molecular Partners Ag, MSD, Ose Immunotherapeutics, Pierre Fabre, Replimune, Roche, Sanofi Aventis, Seagen, Sotio A.S, Transgene; Financial Interests, Personal, Advisory Board: Access Trial, Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Beigene, BioNTech, Celanese, Domain Therapeutics, Ellipses Pharma, Genmab, Harpoon therapeutics, Immunicom, Inc., Mariana Oncology, Mima Health, Nanobiotix, Nextcure, Oncovita, Pierre Fabre, Seagen, Takeda, Tatum Bioscience, Tollys, UltraHuman8; Financial Interests, Personal, Other, Travel and congress: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Ose Immunotherapeutics, Roche; Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP) =Principal/sub-Investigator of Clinical Trials: Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Adaptimmune, AdlaiAstex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Incyte Corporation, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, MedImmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, PharmaMar, Pierre Fabre Medicament, Relay Therapeutics, Inc, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor; Financial Interests, Personal, Other, Travel and Congress: Sotio; Financial Interests, Personal, Stocks/Shares: Avacta; Financial Interests, Institutional, Research Grant, As part of the Drug Development Department (DITEP) =Research Grants: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pfizer, Roche, Sanofi; Non-Financial Interests, Institutional, Product Samples, As part of the Drug Development Department (DITEP) =Non-financial support (drug supplied): AstraZeneca, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, EISAI, BMS; Financial Interests, Personal, Advisory Board: Basilea, Taiho, Relay Theraeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Principal Investigator, M19-345; M21-404: AbbVie; Non-Financial Interests, Principal Investigator, CO42216; WP42627; CO40939; GO44479; GO42216: Roche; Non-Financial Interests, Principal Investigator, MCLA-158 ; MCLA-128: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seatle Genetics; Non-Financial Interests, Principal Investigator, TAS-120-202: Taiho; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Principal Investigator, C4201002; SGNB6A: Pfizer; Non-Financial Interests, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Principal Investigator, Loxo-IDH; Loxo-RAS: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: Sotio; Non-Financial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim; Non-Financial Interests, Principal Investigator, CA120-1001: BMS. C. Baldini: Financial Interests, Institutional, Advisory Board: BMS, MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Coordinating PI: iTeos, Janssen, Seattle Genetics, Tahio, Pyramid Bioscience; Financial Interests, Institutional, Local PI: AZ, Amgen, Bicycle Therapeutics, MSD, Tango, Roche Genentech; Non-Financial Interests, Member: ASCO, SIOG, SOFOG, AACR, ESMO. All other authors have declared no conflicts of interest.