A Genomic Score to Predict Local Control among Patients with Brain Metastases Managed with Radiation.

BACKGROUND: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. We developed a DNA-based signature of radiotherapeutic efficacy among patients with BrM to better characterize recurrence risk.METHODS: We identified 570 patients with 1,487 BrM managed with whole-brain (WBRT) or stereotactic radiation therapy at Brigham and Women's Hospital/Dana-Farber Cancer Institute (2013-2020) for whom next-generation sequencing panel data (OncoPanel) were available. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 genes. Genes with a q-value≤0.10 were utilized to develop a "Brain-Radiation Prediction Score" ("Brain-RPS").RESULTS: Genomic alterations in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes (FBXW7 and AURKA) were associated with decreased or increased risk of local recurrence, respectively (q-value≤0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray's competing risks regression, RPS [1.66 (1.44-1.91, p<0.001)], metastasis-associated edema [1.60 (1.16-2.21), p=0.004], baseline size [1.02 (1.01-1.03), p<0.001] and receipt of WBRT without local therapy [4.04 (2.49-6.58), p<0.001] were independent predictors of local failure.CONCLUSIONS: We developed a genomic score to quantify local recurrence risk following brain-directed radiation. To our knowledge, this represents the first study to systematically correlate DNA-based alterations with radiotherapeutic outcomes in BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation in BrM.