DNA Damage and Immune Response Biomarkers May Predict Toxicity and Response to Radiation Therapy Using a Blood Based Test

Abstract

Radiation therapy is a critical part of cancer patient treatment regimens. While many patients respond to radiation therapy, others will not respond or will have toxicities that significantly reduce quality of life or outcome. Our objective was to create a gene expression assay from peripheral blood to predict radiation toxicity and/or response, thus allowing doctors to modify therapy based on the patient’s genetic background. A 302 gene Ampliseq RNA sequencing panel was developed to study radiation toxicity and response by performing Whole Genome Correlation Network Analysis (WGCNA) of publicly available radiation toxicity gene expression data sets in tissue, and radiation response (total body irradiation radiation biodosimetry data sets) in blood. To identify biological pathways of significance in therapy responders, KEGG and DAVID Analysis of the gene panel was performed on microarray data from the tissue of 71 prostate cancer and 318 glioblastoma patients in The Cancer Genome Atlas (TCGA). A targeted 31 gene assay was developed on a proprietary genomics platform. and a prospective study of 81 pelvic cancer patients representing 17 different cancer types was performed. This cohort included 34 patients reporting Grade 2 or Grade 3 acute radiation toxicity (3-month follow-up), and 12 rectal cancer patients with known tumor response. KEGG and DAVID analysis of the 302-gene radiation panel revealed a predominance of genes related to DNA repair, P53 signaling, Cell Cycle, Protein Ubiquitination, and Immune Response. In-silico analysis of the TCGA data revealed clear separation of responders and non-responders in the 71-patient prostate cancer data set, and clustering by survival after treatment in the 318-patient glioblastoma data set. Testing of pre-irradiation blood samples in the 81-patient prospective pelvic cancer study with the 31-gene assay showed 80.6% sensitivity and 90.7% specificity for predicting stage 2 or higher acute radiation toxicity, and 83.3% sensitivity and 85.7% specificity for predicting rectal cancer tumor response in the 12 rectal cancer patients with known Tumor Response Grading (TRG 0-4). A second IRB approved study is currently accruing additional patients to further validate these results. We were able to develop a gene expression signature from peripheral blood samples of cancer patients to predict radiation toxicity and response prior to the initiation of therapy. The blood based gene signature, comprised primarily of DNA damage and immune response genes, identified several genes also identified as biomarkers of radiation response/radiosensitivity from rectal cancer tumor samples. These results indicate that a gene expression based blood test may be developed to assist in radiation treatment decisions.