TERT Mutations Are Associated with Decreased Time to Distant Central Nervous System Progression After Surgical Resection of Brain Metastases

Introduction: While genetic alterations associated with brain metastases (BMs) have been previously explored, there are limited data examining their association with surgical treatment outcomes. This study aimed to identify genetic alterations within BMs associated with distant CNS recurrence after surgical resection.

Methods: A retrospective, single-center study was conducted with patients who underwent resection of a BM with available clinical and gene sequencing data available. Distant CNS recurrence was the primary study outcomes. Next-generation sequencing of the coding regions in over 500 cancer genes was performed to detect mutations. A multivariate Cox proportional hazards analyses was performed to identify clinical features and gene mutations associated with more rapid distant CNS recurrence.

Results: Ninety patients undergoing resection of 91 BMs composed the cohort. TERT mutations were seen in 26 tumors (28.6%) and were seen across a variety of cancer types including NSCLC (n=3, 13.6%), melanoma (n=19, 86.4%), breast cancer (n=1, 6.7%), renal cell carcinoma (n=1, 25%), as well as other less common cancer types (n=2, 16.7%). TERT mutation was associated with increased number of brain metastases at surgery (4.6 vs 2.7 brain metastases, p=0.044). Furthermore, time to distant CNS progression after surgery was significantly shorter for tumors harboring a TERT mutation (4.2 mo vs no median time, Log-rank p=0.0004). In a multivariate Cox proportional hazard model, TERT mutation (HR 3.83, 95%CI 1.4-10.5, p=0.0087), increased number of brain metastases at the time of surgery (HR 9.9, 95%CI 1.5-46.2, p=0.3), and increased time harboring brain metastases (HR 8.2, 95%CI 1.5-46.2, p=0.02) were all associated with a decreased time to distant CNS progression.

Conclusion : TERT mutations are associated with more rapid distant CNS progression after surgical resection of brain metastases. Clinicians should consider more frequent screening paradigms for patients harboring this genomic alteration.