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

Authors :
N. Ari Wijetunga
Alexander G. Goglia
Nils Weinhold
Michael F. Berger
Michael Cislo
Daniel S. Higginson
Kiana Chabot
Ahmed M. Osman
Lauren Schaff
Elena Pentsova
Alexandra M. Miller
Simon N. Powell
Adrienne Boire
Jonathan T. Yang
Source :
Clinical Cancer Research. 29:775-783
Publication Year :
2022
Publisher :
American Association for Cancer Research (AACR), 2022.

Abstract

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.

Subjects

Subjects :
Cancer Research
Oncology

Details

ISSN :
15573265 and 10780432
Volume :
29
Database :
OpenAIRE
Journal :
Clinical Cancer Research
Accession number :
edsair.doi.dedup.....45b42fa98bc9483c6a1456f1f64be287