Background and aims: Erdheim-Chester disease (ECD) is a rare, heterogeneous histiocytic disease with recurrent MAPK pathway mutations. Circulating cell-free DNA (cfDNA) is becoming a widely used prognostic and predictive biomarker in oncology. The aim of this study was to investigate the prognostic significance cfDNA at diagnosis and during follow-up in ECD cohort

Methods: Forty patients diagnosed with ECD with both biopsy and plasma samples available were included in this study. Lesion biopsy samples of enrolled patients were subjected to polymerase chain reaction (PCR) carrying the BRAFV600E mutation or next-generation sequencing (NGS). The presence and level of genetic alternations of plasma cfDNA in the MAPK pathway were detected by QX200TM Droplet Digital PCR System (Bio-Rad).

Results: The median age at diagnosis was 52 years (range 19-66). There were 21 males (52.5%) and 19 females (47.5%). Thirty-seven patients (92.5%) were treatment-naïve, and 3 patients (7.5%) were refractory or relapsed. The BRAFV600E mutation was detected in 34/40 patients (85.0%). KRAS and MAP2K1 alternations were detected in one patient, respectively. Four patients (10.0%) had no pathogenic MAPK pathway mutation. The baseline plasma cfDNA was analyzed in each patient, and 36 patients (90.0%, 34 BRAFV600E, 1 KRAS, 1 MAP2K1) were detected with the same mutations as the tissue lesion. The median variant allele Frequency (VAF) of plasma cfDNA was 0.386% (range 0-9.868%). Positive or VAF level of cfDNA in plasma was not associated with disease status, central nervous system, heart/major vessels, or retroperitoneum involvement.

Each patient underwent systemic therapy. 16 patients underwent interferon (IFN)-α and the remaining 24 patients underwent target therapy (BRAF inhibitors or MEK inhibitors). Disease response was based on radiographic evaluation in accordance with the most recent Histiocyte Society consensus guideline. After a median follow-up of 22 (range 6-73) months, 7 patients (17.5%) experienced disease relapse and 5 patients (12.5%) died. The overall response rate (ORR) was 82.5% (IFN-α 62.5%, target therapy 95.8%). The median overall survival (OS) was 27.3 months and the median event-free survival (EFS, with events defined as poor response to the treatment, or death from any cause) was 23.7 months. During follow-up, 15 of 17 patients (88.2%, 14 target therapy, 1 IFN-α) had a decrease level of cfDNA. Four patients (23.5%) treated with target therapy had negative cfDNA. The mean level of cfDNA decreased significantly after therapy, from 0.618% to 0.005% (p<0.0001). Among the 15 patients with a cfDNA decrease, 14 and 1 achieved overall partial response and complete response, respectively. No patient with stable or progression disease had a cfDNA response.

Conclusion: CfDNA is a promising biomarker for monitoring the response to therapy for patients with ECD.

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2025
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