Association of lower tumor mutation burden with rapid local progression in patients with brain metastases.

Objective: Tumor mutational burden (TMB) has been proposed as a prognostic biomarker in patients with metastatic cancer, as well as in patients who receive immune checkpoint inhibitor (ICI) therapy. However, the role of TMB as a biomarker for progression after resection of brain metastases, as well as perioperative ICI treatment response, is less defined. This study examined the impact of TMB on local CNS progression events in patients who underwent resection of a brain metastasis, as well as in those who received postoperative ICI treatment.

Methods: This was a single-center, retrospective cohort study of adult patients with clinical and molecular data available who underwent resection of a brain metastasis from 2019 to 2022. TMB was derived from next-generation sequencing based on a Clinical Laboratory Improvement Amendments (CLIA)-certified clinical oncogene panel. Local progression was the primary endpoint. Kaplan-Meier curves and Cox proportional hazards regression analysis were used to assess the relationship between the primary endpoint and TMB. Thresholds for high and low TMB were obtained from recursive partitioning analysis (RPA).

Results: The cohort consisted of 82 patients with multiple primary cancer types with a median follow-up time of 7 months. Twelve patients (15%) experienced local progression. According to RPA, a threshold for low TMB (< 5.2 mutations/Mb) was identified, which was associated with more rapid local progression (p < 0.001) according to the Kaplan-Meier analysis. On multivariate Cox proportional hazards regression analysis, low TMB was associated with shorter freedom from local recurrence (HR 13.6, 95% CI 1.80-103, p = 0.011). Among the patients who received postoperative ICI (n = 34), low TMB trended toward shorter freedom from local recurrence on Kaplan-Meier analysis (p = 0.062).

Conclusions: Lower TMB was associated with shorter freedom from local recurrence in resected CNS metastases. Among patients who receive postoperative ICI treatment, lower TMB also trended toward more rapid local progression.