Effect of pre-operative stereotactic radiosurgery on brain metastasis: analysis of dna and rna genomic profiles from phase-ii clinical trial nct03398694

Abstract BACKGROUND With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising. Treatment varies based on presentation, however, for patients with < 4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence, and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1-4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor. METHODS Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. RESULTS/CONCLUSIONS Our initial data analyses show that pre-treatment with SRS results in significant genomic changes at DNA and RNA levels throughout the tumor when compared to non-radiated tumors. In matched center and peripheral samples DNA damage levels, measured by high impact mutation load, were similar indicating no evidence of radiation dose fall off effect on DNA damage. However, differing DNA damage locations and RNA expression profiles between center and matched samples are present, which may indicate unequal DNA repair processes between the center and periphery of tumors. Furthermore, global DNA mutation and RNA expression profiles differed significantly between the metastasis of different primary cancers signaling the importance of the primary cancer location in determining viable therapeutic targets.