A Gene Expression Model of Intrinsic Tumor Radiosensitivity: Prediction of Response and Prognosis After Chemoradiation

Steven A. Eschrich, Jimmy Pramana, Hongling Zhang, Haiyan Zhao, David Boulware, Ji Hyun Lee, Gregory Bloom, Caio Rocha-Lima, Scott Kelley, Douglas P. Calvin, Timothy J. Yeatman, Adrian C. Begg, Javier F. Torres-Roca

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Purpose: Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients. Methods and Materials: Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12). Results: Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05). Conclusions: We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Original languageEnglish (US)
Pages (from-to)489-496
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume75
Issue number2
DOIs
StatePublished - Oct 1 2009

Keywords

  • Chemoradiation
  • Gene expression
  • Intrinsic radiosensitivity
  • Predictive assay
  • Systems biology

ASJC Scopus subject areas

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

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    Eschrich, S. A., Pramana, J., Zhang, H., Zhao, H., Boulware, D., Lee, J. H., Bloom, G., Rocha-Lima, C., Kelley, S., Calvin, D. P., Yeatman, T. J., Begg, A. C., & Torres-Roca, J. F. (2009). A Gene Expression Model of Intrinsic Tumor Radiosensitivity: Prediction of Response and Prognosis After Chemoradiation. International Journal of Radiation Oncology Biology Physics, 75(2), 489-496. https://doi.org/10.1016/j.ijrobp.2009.06.014