Genomic correlates of leptomeningeal disease after brain metastasis resection.

Abstract

2032 Background: Leptomeningeal disease (LMD) remains a frequent and devastating pattern of failure following surgical resection of brain metastases (BM), occurring in up to one-third of patients despite optimal local therapy. Although mechanical disruption of BM tissues may increase the risk of subsequent LMD, the underlying biologic determinants of postoperative LMD remain undefined. This study aims to identify genomic alterations in resected BM and their association with LMD development using the largest craniotomy cohort to date with paired next-generation sequencing and longitudinal CNS outcomes data. Methods: We retrospectively identified patients who underwent surgical resection and MSK-IMPACT next-generation sequencing of one or more BM. LMD was diagnosed using brain and spine MRI and CSF cytology and classified as either classical LMD (cLMD; diffuse coating of meningeal spaces and/or positive CSF cytology), nodular LMD (nLMD; discrete nodular deposits with negative CSF cytology), or both. Fine–Gray subdistribution hazard (sHR) estimated the cumulative incidence of LMD, treating death as a competing risk. Results: Among 1,006 patients, NSCLC (360, 36%), breast (181, 18%), and melanoma (128, 13%) predominated; most patients had single (530, 53%), supratentorial (796, 79%), and large (>2cm, 886, 88%) BM, and underwent postoperative cavity radiotherapy (890, 88%). Median follow-up and OS were 24.8 and 21.5 months, respectively. The cumulative incidence of LMD was 31% (cLMD 18%, nLMD 19%) at 2 years, with the highest rates seen in breast cancer patients (45% LMD; cLMD 28%, nLMD 23%). Median time to cLMD and nLMD were 7.7 and 6.4 months, respectively. Median OS after cLMD and nLMD diagnosis were 5.7 and 12 months, respectively. The most frequently altered genes in resected BM were TP53 (62%), CDKN2A (25%), TERT (23%), KRAS (20%), ERBB2 (12%), PIK3CA (12%), PTEN (12%), and RB1 (11%). In a pan-cancer analysis, alterations in CDH1 (sHR 3.0, q=0.03), EGFR (HR 2.5, q<0.001), GATA3 (sHR 2.2, q=0.03), or RB1 (sHR 1.7; q=0.04) were associated with an increased risk of cLMD; alterations in PTEN were associated with an increased risk of nLMD (sHR 1.8, q=0.02). Within breast and lung cohorts, alterations in RB1 or EGFR, respectively, were associated with an increased risk of cLMD. BM from patients who developed LMD exhibited greater genomic instability, with a higher fraction of the genome altered compared to those who did not (0.47 vs 0.40, p<0.001). Conclusions: LMD is a common and deadly form of progression following BM resection. Distinct genomic features, present in the resected BM specimen, may identify patients at increased risk of LMD. These findings support the development of a clinicogenomic model to select BM patients for intensified surveillance and postoperative care.