Serum microRNA Signature Predicts Response to High-dose Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer

Publication date: Available online 4 September 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yilun Sun, Peter G. Hawkins, Nan Bi, Robert T. Dess, Muneesh Tewari, Jason W.D. Hearn, James A. Hayman, Gregory P. Kalemkerian, Theodore S. Lawrence, Randall K. Ten Haken, Martha M. Matuszak, Feng-Ming Kong, Shruti Jolly, Matthew J. Schipper
PurposeWhile efforts to improve control of locally-advanced non-small-cell lung cancer (NSCLC) by escalating radiation dose in unselected patients have been unsuccessful, we hypothesized that a subset of patients may derive benefit. Circulating serum microRNAs (c-miRNAs) have shown promise as prognostic and predictive biomarkers. We assessed the utility of c-miRNAs to predict response to high-dose radiotherapy.Methods and MaterialsData from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiotherapy for stages II-III NSCLC as part of four prospective institutional clinical trials were evaluated. Pretreatment serum levels of 62 miRNAs were measured by quantitative reverse-transcription polymerase chain reaction array. We combined miRNA data and clinical factors to generate a Dose Response Score (DRS) for predicting overall survival (OS) following high-dose versus standard-dose radiotherapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross validation. DRS was also correlated with local progression, distant metastasis, and grade 3 or higher cardiac toxicity using Cox regression; and grade 2 or higher esophageal and pulmonary toxicity using logistic regression.ResultsEleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiotherapy was associated with significantly improved OS compared to treatment with standard-dose radiotherapy (HR 0.22). In these patients, high-dose radiation also conferred lower risk of distant metastasis and local progression, although the latter association was not statistically significant. Patients with high DRS exhibited similar rates of OS regardless of dose (HR 0.78). DRS did not correlate with treatment-related toxicity.ConclusionsUsing c-miRNA signature and clinical factors, we developed a DRS that identified a subset of patients with locally-advanced NSCLC who derive an OS benefit from high-dose radiotherapy. This DRS may guide dose-escalation in a patient-specific manner.

Teaser

Escalation of radiation dose has not been beneficial in unselected patients with locally-advanced non-small-cell lung cancer. We hypothesized that a subset of patients may derive benefit and sought to identify a dose-response biomarker by analyzing patients treated with varying doses of radiotherapy on four institutional clinical trials. We identified a micro-RNA signature that, when combined with clinical factors, identified a subset of patients who exhibited an overall survival benefit following high-dose radiotherapy.


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