Abstract
PurposeCancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue.Materials and MethodsWe sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.ResultsWe detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.ConclusionThe study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
Highlights
The treatment of human cancer has shifted toward a precision medicine paradigm that increasingly relies on the genomic annotation of each patient’s tumor tissue
The study shows that cerebrospinal fluid (CSF) harbors clinically relevant genomic alterations in patients with central nervous system (CNS) cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS
Because CSF in healthy individuals contains a small number of WBCs (0 to 5/mL), we were concerned that germline DNA from normal or reactive WBCs would dilute the signal from tumor-derived DNA
Summary
The treatment of human cancer has shifted toward a precision medicine paradigm that increasingly relies on the genomic annotation of each patient’s tumor tissue. This trend is supported by the clinical observation that tumor responses to signal transduction inhibitors often are greatest in tumors that harbor mutations in the targeted pathway, by the discovery of specific drug-resistance mutations in tumors that resume growth during therapy, and by the recent association between effective immunotherapy and tumor-specific missense mutations. Outgrowth of drug-resistant tumor cell clones during therapy can limit the clinical relevance of the initial tumor profile and has motivated the development of technologies that can track the evolution of the cancer genome in accessible body fluids.[1].
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