Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases

Abstract

PurposeBrain metastases from non-small cell lung cancer (NSCLC) engraft and grow either within the brain (solid) or diffusely on its surface (leptomeningeal disease; LMD). Routine clinical diagnostics have low sensitivity and provide no information about the underlying mutations. A recurrent mutation analysis of LMD and a comparison between solid and LMD NSCLC brain metastases have yet to be explored.\n\nExperimental DesignWe performed whole-exome sequencing (WES) on eight cerebrospinal fluid (CSF) specimens from NSCLC LMD patients. We compared our LMD sequencing data with a published data set of 26 NSCLC solid brain metastases to determine the relative mutation frequency. We then performed a retrospective chart review of an additional set of 44 NSCLC LMD patients to further evaluate LMD mutations and clinical prognosis.\n\nResultsSix (75%) LMD cases had mutations in EGFR, while none had KRAS mutations. Retrospective chart review revealed only 4 LMD cases (7.7%) with KRAS mutations, but 33 cases (63.5%) with EGFR mutations. TP53 was mutated in 4/8 LMD (50%) cases and 13/26 of solid metastasis (50%). The median interval for developing LMD from NSCLC was shorter in EGFR-mutant (16.3 mo) than wild-type (23.9 mo) patients (p = 0.017).\n\nConclusionsEGFR and TP53 mutations were frequent in LMD exomes (combined frequency 87.5%), suggesting that PCR-based mutation detection assays towards these two genes could be a useful complement to current diagnostics. Correlations of EGFR in LMD and KRAS in solid metastases suggest molecular distinctions or systemic treatment pressure underpinning differences in growth patterns within the brain.\n\nTranslational RelevanceLeptomeningeal disease is a diffuse, malignant, and incurable metastatic brain tumor that accounts for 5-10% of brain metastases. Patients with LMD do not undergo biopsy and their overall prognosis is poor (median survival 3 to 27 months), making it difficult to collect sufficient samples for recurrent mutation analysis. Standard diagnostic procedures (MRI and cytology) for LMD provide no genetic information. To understand the mutation landscape of LMD, we performed whole-exome sequencing on eight lung-derived LMD cases. We showed that mutations in EGFR occurred more frequently in LMD than solid brain metastases, but KRAS mutations were not present in LMD. Further, mutations in recurrent genes such as EGFR and TP53 could be reliably detected in CSF via droplet digital PCR. Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic toolkit, and differences in mutations between LMD and solid brain metastases suggest distinct molecular mechanisms for growth.