Growth Differentiation Factor 15 as a Cerebrospinal Fluid Biomarker for the Diagnosis and Prognosis of Leptomeningeal Metastasis

Objective As leptomeningeal metastasis (LM) has a poor prognosis, reliable cerebrospinal fluid (CSF) diagnostic biomarkers are urgently needed. This study evaluated the diagnostic value of CSF growth differentiation factor 15 (GDF15) in LM from lung adenocarcinoma (LUAD) and breast cancer (BC). Methods A cohort of 726 CSF samples, including those from patients with LUAD LM, LUAD without LM (LUAD Non‐LM; comprising LUAD without brain metastasis and LUAD with parenchymal brain metastasis), neurological controls, and patients with primary intracranial solid tumors, as well as a BC cohort of 83 CSF samples from BC LM and BC Non‐LM patients, were enrolled in the study. The GDF15 and carcinoembryonic antigen‐related cell adhesion molecule 6 (CEACAM6) levels were measured by the chemiluminescence method. Results CSF GDF15 levels were elevated >25‐fold in LUAD LM compared with Non‐LM and neurological controls. CSF GDF15 excellently discriminated LUAD LM from Non‐LM (AUC 0.959 and 0.912) and neurological controls (AUC 0.975 and 0.929) in 2 independent cohorts. CSF GDF15 levels effectively distinguished LUAD LM from parenchymal brain metastasis (AUC 0.954) and primary intracranial solid tumors (AUC 0.950). High CSF GDF15 levels were associated with shorter overall survival in LUAD LM patients. CSF CEACAM6 similarly differentiated LUAD LM from parenchymal brain metastasis (AUC 0.956) and primary intracranial solid tumors (AUC 0.970). In the BC cohort, GDF15 (AUC 0.899) and CEACAM6 (AUC 0.869) both performed well in distinguishing LM from Non‐LM. The combination of GDF15 and CEACAM6 outperformed either biomarker alone in diagnosis of LUAD LM and BC LM. Interpretation CSF GDF15 is a high‐performance diagnostic biomarker for LUAD LM and BC LM. ANN NEUROL 2026 ANN NEUROL 2026