Dataset Information

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

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.

SUBMITTER: Wijetunga NA

PROVIDER: S-EPMC9957915 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Wijetunga N Ari NA Goglia Alexander G AG Weinhold Nils N Berger Michael F MF Cislo Michael M Higginson Daniel S DS Chabot Kiana K Osman Ahmed M AM Schaff Lauren L Pentsova Elena E Miller Alexandra M AM Powell Simon N SN Boire Adrienne A Yang Jonathan T JT

Clinical cancer research : an official journal of the American Association for Cancer Research 20230201 4

<h4>Purpose</h4>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.<h4>Experimental design</h4>We subjected CSF from 14 patients with LM ...[more]

PMID: 36449664

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Project description:PurposeTreatment options for leptomeningeal metastasis (LM) are limited. A recent phase 2 study found that proton craniospinal irradiation (pCSI) was well-tolerated and improved survival. We report our experience with pCSI for solid-tumor LM.Methods and materialsThis is a retrospective review of patients treated with pCSI for solid-tumor LM from December 2020 to January 2024 at our center. Patient characteristics were summarized using descriptive statistics. Median overall survival and median central nervous system progression-free survival from the first day of pCSI were estimated using Kaplan-Meier survival curves.ResultsWe identified 45 patients who completed pCSI. The median age was 54 years (range, 23-79); 73% were female, and 53% lived more than 100 miles from our center. Breast cancer (53%), lung cancer (20%), and melanoma (9%) were the most common primary cancers; 51% of patients had stable systemic disease at LM diagnosis. All had imaging evidence of LM, and 64% of cases were confirmed using cytologic examination of the cerebrospinal fluid. Eighty percent had symptomatic LM, and the median Karnofsky performance scale at LM diagnosis was 80. The median time from primary cancer diagnosis to LM detection was 23.1 months (range, 0-221.3). Fifty-three percent of patients had active brain metastasis at LM diagnosis; 33% of all patients had received prior intracranial radiation. The median time from simulation to pCSI start was 12 days. At the first visit following pCSI, the median Karnofsky performance scale score was 70. During or right after radiation, 76% of patients reported nausea, 51% headache, and 31% fatigue. Following pCSI, 4% received intrathecal chemotherapy, 67% systemic therapy, and 9% hospice care; 18% were observed and 2% lost to follow-up. Median overall survival was 13.7 months (95% confidence interval [CI], 11.2 to not reached), and median progression-free survival was 6.5 months (95% CI, 4.9-12.8).ConclusionsThe outcomes in our cohort are comparable to those recently reported in a phase 2 trial. Further study is indicated to determine the optimal candidates for pCSI and sequential therapies.

Project description:PurposeThe prognosis of patients with leptomeningeal metastasis (LM) remains poor. Circulating tumour DNA (ctDNA) has been proven to be abundantly present in cerebrospinal fluid (CSF); hence, its clinical implication as a biomarker needs to be further verified.MethodsWe conducted a retrospective study of 35 lung adenocarcinoma (LUAD) patients with LM, and matched CSF and plasma samples were collected from all patients. All paired samples underwent next-generation sequencing (NGS) of 139 lung cancer-associated genes. The clinical characteristics and genetic profiling of LM were analysed in association with survival prognosis.ResultsLM showed genetic heterogeneity, in which CSF had a higher detection rate of ctDNA (P = 0.003), a higher median mutation count (P < 0.0001), a higher frequency of driver mutations (P < 0.01), and more copy number variation (CNV) alterations (P < 0.001) than plasma. The mutation frequencies of the EGFR, TP53, CDKN2A, MYC and CDKN2B genes were easier to detect in CSF than in LUAD tissue (P < 0.05), possibly reflecting the underlying mechanism of LM metastasis. CSF ctDNA is helpful for analysing the mechanism of EGFR-TKI resistance. In cohort 1, which comprised patients who received 1/2 EGFR-TKIs before the diagnosis of LM, TP53 and CDKN2A were the most common EGFR-independent resistant mutations. In cohort 2, comprising those who progressed after osimertinib and developed LM, 7 patients (43.75%) had EGFR CNV detected in CSF but not plasma. Furthermore, patient characteristics and various genes were included for interactive survival analysis. Patients with EGFR-mutated LUAD (P = 0.042) had a higher median OS, and CSF ctDNA mutation with TERT (P = 0.013) indicated a lower median OS. Last, we reported an LM case in which CSF ctDNA dynamic changes were well correlated with clinical treatment.ConclusionsCSF ctDNA could provide a more comprehensive genetic landscape of LM, indicating the potential metastasis-related and EGFR-TKI resistance mechanisms of LM patients. In addition, genotyping of CSF combined with clinical outcomes can predict the prognosis of LUAD patients with LM.

Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

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