Liquid Biopsy of Cerebrospinal Fluid May Improve Treatment Considerations in NSCLC

The unique genomic variations of cerebrospinal fluid may be leveraged as a liquid biopsy to effectively and safely improve decision-making regarding treatment of patients with non–small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM), according to study findings published in Frontiers in Oncology.

As incidence of LM in NSCLC has increased amid improved treatment and subsequent prolonged survival, researchers note that survival in those who develop LM is poor, varying from 3 to 11 months after diagnosis.

Notably, individual targeted therapy based on molecular genotyping has been indicated to improve the survival of patients with NSCLC, but classifying genetic characteristics of the tumor cells that can invade the leptomeningeal space remains a significant obstacle.

“Tissue biopsy was regarded as the golden standard of molecular classification and was critical in decision-making concerning treatment for advanced patients with NSCLC,” said the study authors. “However, it is a clinical challenge to collect tumor tissue for genotyping, as the invasive and time-consuming procedures may be risky to these advanced-stage patients with NSCLC.”

Regarding alternative approaches, liquid biopsy based on body fluids such as plasma and CSF can detect tumor-related biomarkers to predict clinical outcomes safely and early in the management of NSCLC, they said. In prior research, efficacy has been demonstrated for liquid biopsy based on CSF in patients with central nervous system cancers.

With the genotyping of CSF for NSCLC with LM remaining largely unknown, researchers sought to investigate the clinical utility of CSF as an alternative liquid biopsy for patients with NSCLC with LM.

In the study, they investigated the genetic alterations of CSF and compared the genetic difference of CSF with matched plasma and tissue samples in 131 patients with NSCLC with LM (median age, 53 years). Of the study cohort, 24 patients were indicated to have matched CSF, plasma, and tissue samples for analysis; 72 patients had matched CSF and plasma samples; and 124 patients had CSF analyzed.

In assessing the detection of tumor mutations in patients with matched CSF and plasma samples, positive cell-free DNA (cfDNA) results were shown in 52 samples of CSF and 59 samples of plasma, with no statistically significant difference observed between the 2 methods (P = .2339).

For genomic alterations, 94 were detected in both plasma and CSF, but CSF was found to detect 81 alterations that were not found in plasma, whereas 15 were found in plasma that were not detected in CSF. Greater alterations were also observed via CSF in copy number variations and single nucleotide variants.

With epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) serving as the most common and critical actionable targets in NSCLC, researchers then used panel sequencing to detect EGFR and ALK across the liquid biopsy methods.

In their findings, the status of EGFR-activating mutations was found to be highly consistent across CSF, plasma, and primary tumors; ALK translocation was detected in 8.3% of tumor tissues but only 2.4% in CSF and 2.7% in plasma; other action targets, including ROS1 rearrangement, RET fusion, HER2 mutation, NTRK1 fusion, and BRAF V600E mutation, were detected in 7.9% of CSF samples, 11.1% of tumor tissues, and only 4% of plasma samples.

“CSF samples demonstrate unique molecular features and are concordant with tumor tissues regarding the molecular analysis,” concluded the study authors. “Thus, it may represent a better surrogate for NSCLC patients for molecular analysis when no tumor tissues are available.”

Reference

Wang Y, Jiang F, Xia R, et al. Unique genomic alterations of cerebrospinal fluid cell-free DNA are critical for targeted therapy of non-small cell lung cancer with leptomeningeal metastasis. Front Oncol. Published online October 4, 2021. doi:10.3389/fonc.2021.701171