Work

Tlsb-15 Genomic and Clinical Determinants of Local and Distant Intracranial Progression Following Surgical Resection of Brain Metastases

Year: 2026

Type: article

Abstract: The role of molecular alterations in predicting local and distant progression following brain metastasis resection is poorly understood. In this study, we investigated clinical and molecular predictors of intracranial progression following brain metastasis resection. A retrospective analysis of 228 patients who underwent brain metastasis resection at the University of Pittsburgh Medical Center was performed. Tumor specimens underwent next-generation sequencing using the UPMC Oncomine Comprehensive Assay (161 genes; available in 138 patients, 60.5%). A three-stage analytical framework was employed: bootstrap forest analysis for variable importance ranking, univariable Cox regression with Benjamini-Hochberg false discovery rate correction, and multivariable Cox proportional hazards modeling integrating clinical and molecular predictors. Local progression occurred in 110 patients (48.2%; median LPFS 3.95 months) and distant progression in 98 patients (43%; median DPFS 6.1 months), across a cohort predominantly comprising lung (53.1%), breast (11.8%), genitourinary (11.8%), gastrointestinal (11%), and melanoma (9.6%) primaries. The most frequent alterations were TP53 mutations (61.6%), KRAS mutations (31.2%), and CDKN2A/B copy number alterations (24.6%/23.2%). For local progression, bootstrap forest analysis identified PTEN, STK11, KRAS, FGF3, and ATM alterations as top predictors. On multivariable analysis, independent predictors included RB1 mutations (HR 2.8, p = 0.006), PTEN copy number alterations (HR 0.29, p = 0.03), subtotal resection (HR 2.1, p = 0.02), solitary metastasis (HR 0.61, p = 0.04), and postoperative systemic therapy (HR 0.41, p = 0.001). For distant progression, PTEN, TERT, STK11, CDKN2A/B, and TP53 alterations ranked highest. TERT mutations (HR 3.2, p = 0.001) and postoperative systemic therapy (HR 0.47, p = 0.009) were the sole independent predictors on multivariable analysis. RB1 mutations, PTEN copy number deletions, and extent of resection were independently associated with local progression, while TERT mutations were associated with distant progression. Postoperative systemic therapy was associated with improved local and distant control. Integrating molecular profiling with clinical factors provides a framework for postoperative risk stratification in surgically resected brain metastases.

Source: Neuro-Oncology Advances

DOI: 10.1093/noajnl/vdag161.133