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

Abstract

Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and fractionation schemes are relatively homogeneous and prescribed with a "one-size-fits-all" approach. We hypothesized that tumor-specific genomic alterations may underlie radiation sensitivity among patients with BrM and sought to develop a DNA-based signature of radiation-based efficacy in this patient population, utilizing genes that are readily testable in modern-day assays, to identify subpopulations at greater vs. lesser risk of recurrence. We identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one extracranial or intracranial tumor specimen. 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 OncoPanel genes with a mutational frequency of >0.5%. Genes with a q-value<0.10 were utilized to develop a numeric "Brain-Radiation Prediction Score" ("Brain-RPS") to quantify local recurrence risk. Genomic alterations of potential biological relevance in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes (FBXW7 and AURKA) were associated with a 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 Brain-RPS. On multivariable Fine/Gray's competing risks regression, Brain-RPS [1.66 (1.44-1.92, p<0.001)], metastasis-associated edema [1.89 (1.38-2.59), p<0.001], and receipt of WBRT without SRS/SRT or neurosurgical resection [2.73 (1.78-4.20), p<0.001] were independent predictors of local failure. Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not focused on patients with BrM and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in real-world clinical practice for this patient population. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation treatment among patients with BrM.