CSF genotyping may help predict course of advanced lung cancer

August 2020 Cancer trials Eline Feenstra

Due to the improving systemic therapies for lung cancer, patients live longer, but the incidence of central nervous system (CNS) metastases also increases. Cerebrospinal fluid (CSF) has been proven better than plasma to reveal unique genetic profiling of intracranial metastases. How genetic alterations in CSF are associated with the prognosis of this heterogeneous patient group remains not fully understood. A new study published in JAMA network open focused on the association of molecular alterations in CSF with the survival of patients with a diagnosis of lung adenocarcinoma and CNS metastases.

A total number of 94 patients with advanced lung adenocarcinoma and CNS metastases were included in the retrospective 2-year study.  After collecting the patients’ CSF samples the CSF circulating tumor DNA was detected using next generation sequencing. The primary outcome was survival after diagnosis with CNS metastases. Genotyping of CSF circulating tumor DNA was studied to examine its association with the clinical outcomes of patients with CNS metastases.

Cluster analysis distinguishes five types

The most common genes seen in the CSF of 94 patients were EGFR (79 [84.0%]), TP53 (57 [60.6%]), MET (23 [24.5%]), CDKN2A (22 [23.4%]), MYC (20 [21.3%]), NTRK1 (19 [20.2%]), and CDK6 (15 [16.0%]). Cluster analysis identified 5 molecular subtypes of CNS metastases. Patients in cluster I had the shortest median survival compared with each of the other clusters (cluster I, 7.5 months; cluster II, 55.7 months; cluster III, 17.9 months; cluster IV, 27.9 months; cluster V, 21.0 months) and significantly increased risk of death compared with patients in the other clusters (cluster II: hazard ratio [HR], 4.95; 95% CI, 1.50-16.41; P = .009; cluster III: HR, 4.75; 95% CI, 1.49-15.12; P = .008; cluster IV: HR, 6.38; 95% CI, 1.76-23.09; P = .005; cluster V: HR, 5.42; 95% CI, 1.63-17.98; P = .006).

Genetic profiles

The genetic profiles of cluster I were characterized by a high detection rate of CDK4 (9 of 9 [100%]), TP53 (8 of 9 [88.9%]), MET (7 of 9 [77.8%]), and CDKN2A (7 of 9 [77.8%]). For those with EGFR variants, coalterations with CDK4 (HR, 2.02; 95% CI, 1.03-3.96; P = .04), CDK6 (HR, 2.52; 95% CI, 1.32-4.83; P = .005), and MYC (HR, 2.24; 95% CI, 1.21-4.15; P = .01) were associated with poor outcomes.

In conclusion, patients with a diagnosis of lung adenocarcinoma and CNS metastases experienced heterogeneous survival outcomes based on genetic profiling in CSF. This finding could help predicting the disease course and could be a target for further clinical research.


Li YS, Zheng MM, Jiang BY et al. Association of Cerebrospinal Fluid Tumor DNA Genotyping With Survival Among Patients With Lung Adenocarcinoma and Central Nervous System Metastases. JAMA Netw Open. 2020 Aug 3;3(8):e209077. doi: 10.1001/jamanetworkopen.2020.9077.