The Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA can Predict Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastasis

Abstract

<h3>Purpose/Objective(s)</h3> Solid tumor leptomeningeal metastasis (LM) is a devastating disease with poor survival. Proton craniospinal irradiation (pCSI) is a promising treatment for LM, and there is a need for biomarkers for patient selection. Understanding the genetic variation of LM pre- and post-pCSI can elucidate differences in response to radiotherapy. We analyzed the observed mutations in cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) of LM patients treated with pCSI and explored whether the variant allele fraction (VAF) can predict survival. <h3>Materials/Methods</h3> We examined 14 patients from a phase I trial pCSI for solid tumor LM (NCT03281889) with pre- and post-pCSI ctDNA assessment. Mutations were identified using an institutional targeted-sequencing panel, MSK-IMPACT, and allele specific copy number variation was used to determine mutation clonality. Primary tumors or solid tumor metastases, and ctDNA in the plasma was also analyzed. VAF and cancer cell fraction (CCF) were calculated. An independent clinical sequencing cohort of 50 LM patients who did not receive pCSI was used for comparison. Kaplan Meier analysis was used to associate mutation measures and survival outcomes. <h3>Results</h3> The median overall survival for the cohort was 9 months (IQR: 5-21 months). The median number of mutations observed in the CSF ctDNA pre- pCSI was 10 (range:0-25) and post-pCSI was 9 (range:0-42). We observed the clonal evolution between solid tissue and ctDNA of the CSF and plasma, and we identified mutations that are unique by compartment, with more mutations seen in the CSF compared to plasma. A higher VAF pre-pCSI (VAF_pre) was associated with worse OS (8 months for VAF_pre≥0.32 [median] vs 21 months for VAF_pre<0.32, p=0.05). Patients with increased VAF after pCSI had significantly worse survival (6 months vs 18 months, p=0.008). The CCF of novel subclonal mutations after pCSI showed that higher values were associated with worse OS (8 months vs 17 months, p=0.05). In the comparison cohort, VAF≥0.37 [median] was associated with worse OS after CNS-directed RT (8 months vs 9 months, p=0.05). <h3>Conclusion</h3> In LM patients undergoing pCSI, there are unique baseline mutation profiles and distinct responses to pCSI that may be able to predict survival after radiotherapy. Analysis of the ctDNA of LM patients before and after pCSI shows that improved outcomes are associated with lower frequency of mutations. The quantification of these mutations has important implications for patient stratification in CNS-directed radiotherapy and escalation of therapy after pCSI.