PMID- 36449664 OWN - NLM STAT- MEDLINE DCOM- 20230217 LR - 20230817 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 29 IP - 4 DP - 2023 Feb 16 TI - Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases. PG - 775-783 LID - 10.1158/1078-0432.CCR-22-2434 [doi] AB - PURPOSE: Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response. EXPERIMENTAL DESIGN: We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan-Meier analysis was used to associate genomic changes with survival. RESULTS: The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5-21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre >/= 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05). CONCLUSIONS: In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response. CI - (c)2022 American Association for Cancer Research. FAU - Wijetunga, N Ari AU - Wijetunga NA AUID- ORCID: 0000-0002-8518-4691 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Goglia, Alexander G AU - Goglia AG AUID- ORCID: 0000-0003-3970-2694 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Weinhold, Nils AU - Weinhold N AUID- ORCID: 0000-0003-3290-6192 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Berger, Michael F AU - Berger MF AUID- ORCID: 0000-0003-3882-5000 AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Cislo, Michael AU - Cislo M AUID- ORCID: 0000-0002-5880-2802 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Higginson, Daniel S AU - Higginson DS AUID- ORCID: 0000-0002-6686-7454 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Chabot, Kiana AU - Chabot K AUID- ORCID: 0000-0003-2897-0845 AD - Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Osman, Ahmed M AU - Osman AM AUID- ORCID: 0000-0002-5255-2136 AD - Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Schaff, Lauren AU - Schaff L AUID- ORCID: 0000-0002-4664-670X AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Pentsova, Elena AU - Pentsova E AUID- ORCID: 0000-0001-5854-0251 AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Miller, Alexandra M AU - Miller AM AUID- ORCID: 0000-0003-2048-579X AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Powell, Simon N AU - Powell SN AUID- ORCID: 0000-0002-8183-4765 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Boire, Adrienne AU - Boire A AUID- ORCID: 0000-0002-9029-1248 AD - Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Yang, Jonathan T AU - Yang JT AUID- ORCID: 0000-0001-9375-7384 AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 CA245499/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Circulating Tumor DNA) RN - 0 (Protons) RN - 0 (Biomarkers, Tumor) SB - IM MH - Humans MH - *Circulating Tumor DNA MH - Protons MH - *Craniospinal Irradiation MH - Biomarkers, Tumor MH - Mutation MH - *Lung Neoplasms/drug therapy MH - *Meningeal Carcinomatosis PMC - PMC9957915 MID - NIHMS1855560 COIS- Conflict of Interest Statement: The authors declare no potential conflicts of interest. EDAT- 2022/12/01 06:00 MHDA- 2023/02/18 06:00 PMCR- 2023/08/16 CRDT- 2022/11/30 14:23 PHST- 2022/08/04 00:00 [received] PHST- 2022/10/05 00:00 [revised] PHST- 2022/11/21 00:00 [accepted] PHST- 2022/12/01 06:00 [pubmed] PHST- 2023/02/18 06:00 [medline] PHST- 2022/11/30 14:23 [entrez] PHST- 2023/08/16 00:00 [pmc-release] AID - 711354 [pii] AID - 10.1158/1078-0432.CCR-22-2434 [doi] PST - ppublish SO - Clin Cancer Res. 2023 Feb 16;29(4):775-783. doi: 10.1158/1078-0432.CCR-22-2434.