P2.05-058 Blood Biomarkers of Inflammation, Tumor Burden and Proliferation Predict Radiotherapy Response and Toxicity in Lung Cancer: Topic: Toxicities

Abstract

There is an unmet need to develop non-invasive biomarkers that can be used to tailor radiotherapy and select patients for future mechanism-based therapy-radiotherapy combination trials. The aim of this study is to assess blood biomarkers of radiotherapy response and toxicity in patients with lung cancer. This is a prospective exploratory study conducted at the Christie NHS Foundation Trust (Manchester, UK). Blood samples were collected prior, during and post-radiotherapy and at the time of relapse. A panel of 26 biomarkers were evaluated; M30 and M65 (apoptosis/ cell death), CA-IX and Osteopontin (hypoxia), Ang-1, Ang-2, FGFb, IL-8, PDGFb, PIGF, Tie-2, VEGFA, VEGFC, VEGFR-1 and VEGFR-2 (angiogenesis), E-selectin, IL-1b, IL-6, IL-10, IL-12 and TNFα (inflammation), CYFRA 21-1, EGF, KGF and VCAM-1 (tumor burden, proliferation and invasion) and HGF (multiple processes). Clinical, demographic and treatment data as well as routine haematology and biochemistry test results were collected. Blood sampling and analysis were performed in a good clinical practice-compliant laboratory. Univariate analysis was performed on patients with small-cell and non-small cell lung cancer (NSCLC) while multivariate analysis focused on patients with NSCLC. All statistical analyses were performed in R v3.1.1. Between March 2010 and February 2012, blood samples form 78 patients were analysed. Forty eight (61.5%) were treated with sequential chemo-radiotherapy, 61 (78.2%) harboured NSCLC while 66 (84.6%) had stage III disease. TNFα, IL-1b, KGF and IL-12 accounted for the bulk of the variability between patients at baseline. Of these, high TNFα (hazard ratio (HR); 2.27, 95% confidence interval (CI); 1.22-4.23, log-rank p=0.008) and IL-1b (HR; 4.02, 95% CI; 2.04-7.93, log-rank p<0.001) were the strongest covariates of survival. Of routinely-collected laboratory tests, neutrophil count was a significant covariate of survival (HR; 1.07, 95% CI; 1.02-1.11, log-rank p=0.017). A multivariate survival predication model for NSCLC was created by combining baseline IL-1b and neutrophil count. The addition of early-treatment (week 3) CYFRA 21-1 to this model modestly improved the survival prediction concordance probability (0.75; p=0.029 to 0.78; p=0.004). Chemotherapy was strongly correlated with acute oesophagitis (p<0.001) while KGF was weekly correlated (p=0.019). The addition of KGF did not improve a multivariate toxicity prediction model based on chemotherapy. None of the tested variables correlated with acute pneumonitis. Blood biomarkers of inflammation and proliferation and early-treatment tumor burden could provide additional information about radiotherapy response and toxicity in patients with lung cancer. Following independent validation, the proposed biomarkers could be integrated within future mechanism-based therapy-radiotherapy combination trials.