Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease

Abstract

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained via lumbar puncture or intraventricular catheter, and may be a suitable fluid to assess ctDNA in patients with brain tumors. We detected melanoma-associated mutations by droplet-digital PCR (ddPCR) and next-generation sequencing in ctDNA obtained from the CSF (CSF-ctDNA) of melanoma patients with leptomeningeal disease. There is a strong correlation between mutation detection by ddPCR, the presence of circulating tumor cells in CSF and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by microscopic examination were positive for CSF-ctDNA by ddPCR. Our results demonstrate that CSF is a suitable fluid for evaluating ctDNA and ddPCR is superior to CSF-cytology for analysis of CSF in melanoma patients with leptomeningeal disease.

Leptomeningeal disease in melanoma patients: An update to treatment, challenges, and future directions

“…A recent report in melanoma patients with confirmed LMD highlighted the strong correlation of mutation detection by droplet‐digital PCR (ddPCR), the presence of circulating tumor cells in CSF, and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by cytology were positive for CSF ctDNA by ddPCR (Ballester et al, ).…”

Review: Peering through a keyhole: liquid biopsy in primary and metastatic central nervous system tumours

“…The possibility of detecting tumour‐derived cfDNA in patients with secondary CNS involvement has long been reported , but only during the last few years this approach has received specific consideration as a potential tool for the routine care of patients . Most data have been obtained in NM from non‐small‐cell lung carcinoma (NSCLC), but studies on breast carcinoma , melanoma and secondary haematological malignancies have also been reported (Table ).…”

Telomerase reverse transcriptase alterations in human cancers: Diagnosis, prognosis, and therapeutic implications

“…With the growing use of molecular diagnostic assays for establishing cancer diagnoses, treatments, and prognoses, it is conceivable to incorporate testing for TERT promoter mutations in cytology specimens. The evidence suggests that the presence of a TERT promoter mutation in a cytology specimen from cerebrospinal fluid, urine, or a fine‐needle aspirate of a subcutaneous or deep tissue lesion or even in circulating tumor DNA will support a diagnosis of cancer, regardless of whether cytologic features provide sufficient evidence for a diagnosis of malignancy on microscopic examination …”