P. Koh

Targeted agents in non-small cell lung cancer (NSCLC): Clinical developments and rationale for the combination with thoracic radiotherapy

In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions.

Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value

Lung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived > 18 mo were compared to the same time points from patients who survived < 14 mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment.

Cell-death, inflammation, tumor-burden and proliferation blood biomarkers predict lung cancer radiotherapy response and correlate with tumor volume and proliferation imaging

Micro‐Abstract In this study we evaluated, to our knowledge, the largest blood biomarker panel ever reported. Baseline interleukin‐1b and neutrophil count and early‐treatment cytokeratin‐19 antigen predicted lung cancer radiotherapy response. Baseline angioprotein‐1 and hepatocyte growth factor (HGF) significantly correlated with the gross tumor volume. Changes in vascular cell adhesion molecule 1 (VCAM‐1) correlated with proliferation imaging, highlighting for the first time a potential role of blood biomarkers as imaging surrogates. Introduction There is an unmet need to develop noninvasive biomarkers to stratify patients in drug‐radiotherapy trials. In this pilot study we investigated lung cancer radiotherapy response and toxicity blood biomarkers and correlated findings with tumor volume and proliferation imaging. Patients and Methods Blood samples were collected before and during (day 21) radiotherapy. Twenty‐six cell‐death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor‐burden biomarkers were evaluated. Clinical and laboratory data were collected. Univariate analysis was performed on small‐cell and non–small‐cell lung cancer (NSCLC) whereas multivariate analysis focused on NSCLC. Results Blood samples from 78 patients were analyzed. Sixty‐one (78.2%) harbored NSCLC, 48 (61.5%) received sequential chemoradiotherapy. Of tested baseline biomarkers, undetectable interleukin (IL)‐1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04‐7.93; P < .001) was the only significant survival covariate. Of routinely collected laboratory tests, high baseline neutrophil count was a significant survival covariate (HR, 1.07; 95% CI, 1.02‐1.11; P = .017). Baseline IL‐1b and neutrophil count were prognostic for survival in a multivariate model. The addition of day‐21 cytokeratin‐19 antigen modestly improved this models survival prediction (concordance probability, 0.75‐0.78). Chemotherapy (P < .001) and baseline keratinocyte growth factor (P = .019) predicted acute esophagitis, but only chemotherapy remained significant after Bonferroni correction. Baseline angioprotein‐1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F‐fluorothymidine (FLT) positron emission tomography (PET). Conclusion Select biomarkers are prognostic after radiotherapy in this lung cancer series. The correlation between circulating biomarkers and 18F‐FLT PET is shown, to our knowledge for the first time, highlighting their potential role as imaging surrogates.