Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694 Showed Distinct Transcriptomic Profile for Patients With Local Failure

Abstract

INTRODUCTION: Stereotactic radiosurgery (SRS) has become a standard of care for brain metastasis (BM). In the setting of lesions needing surgical intervention, it is typically delivered to the resection cavity after surgical resection to strike a balance between adverse effect from the dose of radiation and tumor recurrence. Pre-operative SRS is now being examined because of its ability to deliver radiation to all cells before surgical disruption and dispersion with added advantage of treating larger lesions with radiation. METHODS: We designed a phase II trial for patients with up to 4 BM and at least one resectable lesion. All lesions were treated with SRS and symptomatic lesions were resected. We examined both the clinical and biological outcomes. RESULTS: We performed whole genome DNA and RNA sequencing of the center and periphery of the resected lesion from the first 35 patients. We found that SRS causes significant and biologically observable damage to the tumor. Radiation induced DNA damage is qualitatively different between center and periphery of the tumor. Functionally distinct genetic profiles exist between both center and peripheral tumor locations as well as between different primary tumor types. Center of the tumor has higher functional mutation burden while peripheral samples initiate DNA repair pathways. Peripheral samples may interact more with surrounding environment when compared to central samples. Different radiation delivery modality has differential transcriptomic profile and patients who failed locally also had a distinct transcriptomic profile. CONCLUSIONS: In conclusion, radiation dosing fall-off has differential effect on the genomic landscape of the tumor and cells from the periphery are most likely gaining DNA repair abilities and that might explain tumor recurrence. Also, Gamma knife and LINAC as different genomic signature.