CSF Genotyping May Help Predict Course of Advanced Lung Cancer

By Marilynn Larkin

August 11, 2020

NEW YORK (Reuters Health) - A retrospective study of patients with advanced lung cancer and central nervous system (CNS) metastases suggests genetic profiling of cerebral spinal fluid (CSF) may facilitate survival risk stratification.

"Patients with CNS metastases of lung adenocarcinoma represent a challenging clinical dilemma," Dr. Yi-Long Wu of Guangdong Provincial People's Hospital in China told Reuters Health by email. "Our previous research showed the CSF was better than plasma to reveal unique genetic profiling of intracranial metastases (https://bit.ly/3gMXtoX). In this study, we defined five CNS subgroups of based on CSF characterized by next generation sequencing (NGS)."

As reported in JAMA Network Open, of the 94 evaluated patients (mean age, 53; 52% men), most (79) harbored an EGFR variant.

The most common genes seen in CSF were EGFR (84%), TP53 (60.6%), MET (24.5%), CDKN2A (23.4%), MYC (21.3%), NTRK1 (19), and CDK6 (16%).

As Dr. Wu noted, cluster analysis identified five molecular subtypes of CNS metastases associated with survival. Compared with the other clusters, cluster I, the subtype with many genetic alterations, was associated with the shortest survival (7.5 months).

The genetic profiles of cluster I patients were characterized by a high rate of CDK4 (100%), TP53 (88.9%), MET (77.8%), and CDKN2A (77.8%).

For those with EGFR variants, coalterations with CDK4 (hazard ratio, 2.02), CDK6 (HR, 2.52), and MYC (HR, 2.24) were associated with poor outcomes.

Summing up, the authors state, "Patients with a diagnosis of lung adenocarcinoma and CNS metastases experienced heterogeneous survival outcomes based on genetic profiling in CSF. These data suggest that CSF might facilitate risk stratifying CNS metastases into appropriate outcomes and provide reference for further clinical study."

Given the findings, Dr. Wu said, "in the future, we need to further explore the potential mechanisms of different subtypes and coalterations, and figure out the optimal strategies based on the different molecular subtypes for the patients."

Dr. Hossein Borghaei, Chief, Division of Thoracic Medical Oncology at Fox Chase Cancer Center in Philadelphia, commented in an email to Reuters Health, "This study suggests that molecular testing of CSF is feasible and can yield to additional data." However, he said, "I am not sure how to use this data. I can design studies around this concept but I am not sure it is immediately useful to me and my patients."

Caveats, he said, include the small number of patients and "lack of data about systemic treatment and responses. What's happening in the rest of the body, not just the brain? How were these patients treated for their CNS metastases?"

"Studies like this could help us develop better strategies if this can be shown in a larger group of patients," he noted. "Clinical utility remains to be determined."

Dr. Elaine Shum, a medical oncologist specializing in lung cancer at NYU Langone's Perlmutter Cancer Center in New York City, also commented by email. "The unsupervised hierarchical cluster analysis that was conducted to group the patients into five major molecular subtypes is a bit unclear, as the numbers of patients in each cluster is not uniform nor are the other findings, such as the number of positive CSF cytologic findings or other clinical features."

"As such," she told Reuters Health, "it is difficult to make clear conclusions that the genetic profiles of the clusters are what may drive their survival rates."

Like Dr. Borghaei, she noted, "Unfortunately, the study also did not incorporate information on what treatments patients received after diagnosis of brain metastases or leptomeningeal disease. This information would greatly factor into the interpretation of this survival data."

"As the use of NGS testing and analysis continues to be used more widely in treatment decisions for lung cancer, exploring and understanding the significance of the presence of genetic alterations in the CSF will hopefully one day also influence and direct personalized treatment for those patients," she concluded.

SOURCE: https://bit.ly/3afP4rC JAMA Network Open, online August 4, 2020.