A Six-Gene Prognostic and Predictive Radiotherapy-Based Signature for Early and Locally Advanced Stages in Non-Small-Cell Lung Cancer

SIMPLE SUMMARY: The search for prognostic and/or predictive gene signatures of the response to radiotherapy treatment can significantly aid clinical decision making. These signatures can condition the fractionation, the total dose to be administered, and/or the combination of systemic treatments and radiation. The ultimate goal is to achieve better clinical results, as well as to minimize the adverse effects associated with current cancer therapies. To this end, we analyzed the intrinsic radiosensitivity of 15 NSCLC lines and found the differences in gene expression levels between radiosensitive and radioresistant lines, resulting in a potentially applicable six-gene signature in NSCLC patients. The six-gene signature had the ability to predict overall survival and progression-free survival (PFS), which could translate into a prediction of the response to the cancer treatment received. ABSTRACT: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, generating an enormous economic and social impact that has not stopped growing in recent years. Cancer treatment for this neoplasm usually includes surgery, chemotherapy, molecular targeted treatments, and ionizing radiation. The prognosis in terms of overall survival (OS) and the disparate therapeutic responses among patients can be explained, to a great extent, by the existence of widely heterogeneous molecular profiles. The main objective of this study was to identify prognostic and predictive gene signatures of response to cancer treatment involving radiotherapy, which could help in making therapeutic decisions in patients with NSCLC. To achieve this, we took as a reference the differential gene expression pattern among commercial cell lines, differentiated by their response profile to ionizing radiation (radiosensitive versus radioresistant lines), and extrapolated these results to a cohort of 107 patients with NSCLC who had received radiotherapy (among other therapies). We obtained a six-gene signature (APOBEC3B, GOLM1, FAM117A, KCNQ1OT1, PCDHB2, and USP43) with the ability to predict overall survival and progression-free survival (PFS), which could translate into a prediction of the response to the cancer treatment received. Patients who had an unfavorable prognostic signature had a median OS of 24.13 months versus 71.47 months for those with a favorable signature, and the median PFS was 12.65 months versus 47.11 months, respectively. We also carried out a univariate analysis of multiple clinical and pathological variables and a bivariate analysis by Cox regression without any factors that substantially modified the HR value of the proposed gene signature.