Serum MicroRNA Signature Predicts Response to High-Dose Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer

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

Research output: Contribution to journalArticle

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Abstract

Purpose To assess the utility of circulating serum microRNAs (c-miRNAs) to predict response to high-dose radiation therapy for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials Data from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiation therapy for stages II-III NSCLC as part of 4 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) after high-dose versus standard-dose radiation therapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross-validation. The 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. Results Eleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiation therapy was associated with significantly improved OS compared to treatment with standard-dose radiation therapy (hazard ratio 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 (hazard ratio 0.78). The DRS did not correlate with treatment-related toxicity. Conclusions Using 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 radiation therapy. This DRS may guide dose escalation in a patient-specific manner.

Original languageEnglish (US)
Pages (from-to)107-114
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume100
Issue number1
DOIs
StatePublished - Jan 1 2018

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MicroRNAs
Non-Small Cell Lung Carcinoma
serums
lungs
radiation therapy
Radiotherapy
cancer
signatures
dosage
Serum
toxicity
regression analysis
Survival
metastasis
Neoplasm Metastasis
progressions
hazards
grade
Survival Rate
logistics

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Serum MicroRNA Signature Predicts Response to High-Dose Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer. / Sun, Yilun; Hawkins, Peter G.; Bi, Nan; Dess, Robert T.; Tewari, Muneesh; Hearn, Jason W.D.; Hayman, James A.; Kalemkerian, Gregory P.; Lawrence, Theodore S.; Ten Haken, Randall K.; Matuszak, Martha M.; Kong, Feng Ming; Jolly, Shruti; Schipper, Matthew J.

In: International Journal of Radiation Oncology Biology Physics, Vol. 100, No. 1, 01.01.2018, p. 107-114.

Research output: Contribution to journalArticle

Sun, Y, Hawkins, PG, Bi, N, Dess, RT, Tewari, M, Hearn, JWD, Hayman, JA, Kalemkerian, GP, Lawrence, TS, Ten Haken, RK, Matuszak, MM, Kong, FM, Jolly, S & Schipper, MJ 2018, 'Serum MicroRNA Signature Predicts Response to High-Dose Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer', International Journal of Radiation Oncology Biology Physics, vol. 100, no. 1, pp. 107-114. https://doi.org/10.1016/j.ijrobp.2017.08.039
Sun, Yilun ; Hawkins, Peter G. ; Bi, Nan ; Dess, Robert T. ; Tewari, Muneesh ; Hearn, Jason W.D. ; Hayman, James A. ; Kalemkerian, Gregory P. ; Lawrence, Theodore S. ; Ten Haken, Randall K. ; Matuszak, Martha M. ; Kong, Feng Ming ; Jolly, Shruti ; Schipper, Matthew J. / Serum MicroRNA Signature Predicts Response to High-Dose Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer. In: International Journal of Radiation Oncology Biology Physics. 2018 ; Vol. 100, No. 1. pp. 107-114.
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abstract = "Purpose To assess the utility of circulating serum microRNAs (c-miRNAs) to predict response to high-dose radiation therapy for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials Data from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiation therapy for stages II-III NSCLC as part of 4 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) after high-dose versus standard-dose radiation therapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross-validation. The 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. Results Eleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiation therapy was associated with significantly improved OS compared to treatment with standard-dose radiation therapy (hazard ratio 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 (hazard ratio 0.78). The DRS did not correlate with treatment-related toxicity. Conclusions Using 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 radiation therapy. This DRS may guide dose escalation in a patient-specific manner.",
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AU - Dess, Robert T.

AU - Tewari, Muneesh

AU - Hearn, Jason W.D.

AU - Hayman, James A.

AU - Kalemkerian, Gregory P.

AU - Lawrence, Theodore S.

AU - Ten Haken, Randall K.

AU - Matuszak, Martha M.

AU - Kong, Feng Ming

AU - Jolly, Shruti

AU - Schipper, Matthew J.

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N2 - Purpose To assess the utility of circulating serum microRNAs (c-miRNAs) to predict response to high-dose radiation therapy for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials Data from 80 patients treated from 2004 to 2013 with definitive standard- or high-dose radiation therapy for stages II-III NSCLC as part of 4 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) after high-dose versus standard-dose radiation therapy. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross-validation. The 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. Results Eleven predictive miRNAs were combined with clinical factors to generate a DRS for each patient. In patients with low DRS, high-dose radiation therapy was associated with significantly improved OS compared to treatment with standard-dose radiation therapy (hazard ratio 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 (hazard ratio 0.78). The DRS did not correlate with treatment-related toxicity. Conclusions Using 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 radiation therapy. This DRS may guide dose escalation in a patient-specific manner.

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