Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases.

Autor:	Wijetunga NA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Goglia AG; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Weinhold N; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Berger MF; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Cislo M; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Higginson DS; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Chabot K; Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York., Osman AM; Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York., Schaff L; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York., Pentsova E; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York., Miller AM; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York., Powell SN; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Boire A; Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York., Yang JT; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Feb 16; Vol. 29 (4), pp. 775-783.
DOI:	10.1158/1078-0432.CCR-22-2434
Abstrakt:	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. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu