A GENE EXPRESSION MODEL OF INTRINSIC TUMOR RADIOSENSITIVITY: PREDICTION OF RESPONSE AND PROGNOSIS AFTER CHEMORADIATION

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

来源：International Journal of Radiation Oncology, Biology, Physics, 2009, 75(2): 489-496.

DOI：10.1016/j.ijrobp.2009.06.014

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

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.

• 出版日期2009-10-1