Abstract
BACKGROUND
Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted therapies have altered disease management. In this new era, outcomes of patients with LC-LM are not well-defined. This study identifies molecular and radiographic characteristics of LC-LM correlating with clinical outcome.
METHODS
We retrospectively reviewed charts of 171 patients with LC-LM between 6/2009 and 6/2017 at Memorial Sloan-Kettering Cancer Center. Presence of targetable mutations (TM) was determined by targeted exome sequencing (MSKCC IMPACT). Radiographic involvement was scored by number of gadolinium-enhancing sites in eight locations. CSF studies included cytopathology, quantification of circulating tumor cells (CTCs), and cell free DNA (cfDNA) analysis. Kaplan-Meier survival curves were compared by log-rank analyses.
RESULTS
Median overall survival after LC-LM diagnosis was 4.2 months; 84 patients (49%) harbored TM. Patients who received targeted therapy (Ttx) after LC-LM diagnosis demonstrated reduced hazard of death (HR:0.63; 95% CI:0.45–0.89; p=0.008). This trend was reversed for those receiving Ttx prior to LC-LM (HR:2.46; 95% CI:1.42–4.26; p-value: 0.001). A subset of 93 patients underwent MRI brain, spine and CSF cytology within 30 days of LC-LM diagnosis. Extent of radiographic involvement (3 or more sites vs. 2 or less sites) correlated with OS: (HR:1.56; 95% CI:0.96–2.54; p=0.075). Enumeration of CSF CTCs at diagnosis from 16 patients revealed that greater than 50 CTCs/3mL increased hazard of death (HR:3.66; 95% CI:1.195–11.22; p=0.02). Similarly, elevated ctDNA concentration in CSF was inversely correlated with survival in 21 patients (HR:2.74; 95% CI:1.01–7; p=0.02). CONCLUSIONS: In this largest study of LC-LM, presence of TM and Ttx for LC-LM was associated with improved survival. Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and CNS staging for clinical management, prognostication and clinical trial stratification of LC-LM.