Therapeutic management of neuro-oncologic patients - potential relevance of CSF liquid biopsy

Abstract

Background: In the era of precision medicine, cancer treatment is increasingly tailored according to tumor-specific genomic alterations. The analysis of tumor-derived circulating nucleic acids in cerebrospinal fluid (CSF) by next generation sequencing (NGS) may facilitate precision medicine in the field of CNS cancer. We therefore evaluated whether NGS from CSF of neuro-oncologic patients reliably detects tumor-specific genomic alterations and whether this may help to guide the management of patients with CNS cancer in clinical practice. Patient and methods: CSF samples from 27 patients with various primary and secondary CNS malignancies were collected and evaluated by NGS using a targeted, amplicon-based NGS-panel (Oncomine Focus Assay). All cases were discussed within the framework of a molecular tumor board at the Comprehensive Cancer Center Munich. Results: NGS was technically successful in 23/27 patients (85%). Genomic alterations were detectable in 20/27 patients (74%), 11/27 (40%) of which were potentially actionable. After discussion in the MTB, a change of therapeutic management was recommended in 7/27 (26%) of the cases. However, due to rapid clinical progression, only 4/27 (15%) of the patients were treated according to the recommendation. In a subset of patients (6/27, 22%), a high number of mutations of unknown significance suggestive of a high tumor mutational burden (TMB) were detected. Conclusions: NGS from cerebrospinal fluid is feasible in routine clinical practice and yields therapeutically relevant alterations in a large subset of patients. Integration of this approach into a precision cancer medicine program might help to improve therapeutic options for patients with CNS cancer.

Keywords: CNS Cancer; CSF; Next Generation Sequencing (NGS); cfDNA; liquid biopsy..

Figure 1

NGS-Results NGS-Analysis from CSF is technically feasible and yields tumor genetic mutations in the majority of patients analyzed. VUS: variants of unknown significance, *2 patients had both: actionable mutations and VUS.

Figure 2

Therapeutic management Flow Chart indicating the yield of actionable mutations in 27 patients, respective recommendations of the Molecular Tumor Board (MTB) and actual treatment

Figure 3

Illustrative patient example 45-year-old male patient (#1) with newly diagnosed metastatic (leptomeningeal, bone, lymph nodes, pulmonary) NSCLC with actionable mutation (EGFR Exon 21) diagnosed by NGS from CSF. A: Note the exceptional clinical course under treatment with oral erlotinib and intrathecal MTX with regression of preexisting contrast enhancing metastatic lesions (green arrows) and stable pulmonary disease over 24 months. B: Non-adherent LM was diagnosed by cytology and could not be eradicated; however, the percentage of atypical cells in the CSF remained low for the whole treatment period.