Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis

Tej D. Azad, Shigeki Nanjo, Michael C. Jin, Jacob J. Chabon, David M. Kurtz, Aadel A. Chaudhuri, Ian D. Connolly, Angela Bik Yu Hui, Chih Long Liu, David Merriott, Ryan Ko, Christopher Yoo, Justin Carter, Emily Chen, Rene Bonilla, Akito Hata, Nobuyuki Katakami, Kei Irie, Seiji Yano, Ross OkimotoTrever G. Bivona, Aaron M. Newman, Michael Iv, Seema Nagpal, Melanie Hayden Gephart, Ash A. Alizadeh, Maximilian Diehn

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

Original languageEnglish
Article number121
Journalnpj Precision Oncology
Volume8
Issue number1
DOIs
StatePublished - Dec 2024

Fingerprint

Dive into the research topics of 'Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis'. Together they form a unique fingerprint.

Cite this