Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling

Folkvord, Sigurd; Flatmark, Kjersti; Dueland, Svein

doi:10.1016/j.ijrobp.2010.04.036

Title: Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling

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Abstract

Purpose: Tumor response of rectal cancer to preoperative chemoradiotherapy (CRT) varies considerably. In experimental tumor models and clinical radiotherapy, activity of particular subsets of kinase signaling pathways seems to predict radiation response. This study aimed to determine whether tumor kinase activity profiles might predict tumor response to preoperative CRT in locally advanced rectal cancer (LARC). Methods and Materials: Sixty-seven LARC patients were treated with a CRT regimen consisting of radiotherapy, fluorouracil, and, where possible, oxaliplatin. Pretreatment tumor biopsy specimens were analyzed using microarrays with kinase substrates, and the resulting substrate phosphorylation patterns were correlated with tumor response to preoperative treatment as assessed by histomorphologic tumor regression grade (TRG). A predictive model for TRG scores from phosphosubstrate signatures was obtained by partial-least-squares discriminant analysis. Prediction performance was evaluated by leave-one-out cross-validation and use of an independent test set. Results: In the patient population, 73% and 15% were scored as good responders (TRG 1-2) or intermediate responders (TRG 3), whereas 12% were assessed as poor responders (TRG 4-5). In a subset of 7 poor responders and 12 good responders, treatment outcome was correctly predicted for 95%. Application of the prediction model on the remaining patient samples resulted in correct prediction for 85%.more »« less

Authors:

Folkvord, Sigurd ^[1]; Flatmark, Kjersti ^[1]; Dueland, Svein ^[2]

Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital (Norway)
Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital (Norway)

Publication Date:: Fri Oct 01 00:00:00 EDT 2010

OSTI Identifier:: 21436200

Resource Type:: Journal Article

Journal Name:: International Journal of Radiation Oncology, Biology and Physics

Additional Journal Information:: Journal Volume: 78; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2010.04.036; PII: S0360-3016(10)00619-X; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0360-3016

Country of Publication:: United States

Language:: English

Subject:: 62 RADIOLOGY AND NUCLEAR MEDICINE; COMBINED THERAPY; FORECASTING; NEOPLASMS; RADIOSENSITIVITY; RECTUM; BODY; DIGESTIVE SYSTEM; DISEASES; GASTROINTESTINAL TRACT; INTESTINES; LARGE INTESTINE; MEDICINE; ORGANS; SENSITIVITY; THERAPY

Citation Formats


                    Folkvord, Sigurd, Flatmark, Kjersti, Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital, and Dueland, Svein. Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling.  United States: N. p., 2010. 
        Web.  doi:10.1016/j.ijrobp.2010.04.036.

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                    Folkvord, Sigurd, Flatmark, Kjersti, Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital, & Dueland, Svein. Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling.  United States.  https://doi.org/10.1016/j.ijrobp.2010.04.036

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                    Folkvord, Sigurd, Flatmark, Kjersti, Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital, and Dueland, Svein. 2010.  
        "Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling".  United States.  https://doi.org/10.1016/j.ijrobp.2010.04.036.

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@article{osti_21436200,

  title        = {Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling},

  author       = {Folkvord, Sigurd and Flatmark, Kjersti and Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital and Dueland, Svein},

  abstractNote = {Purpose: Tumor response of rectal cancer to preoperative chemoradiotherapy (CRT) varies considerably. In experimental tumor models and clinical radiotherapy, activity of particular subsets of kinase signaling pathways seems to predict radiation response. This study aimed to determine whether tumor kinase activity profiles might predict tumor response to preoperative CRT in locally advanced rectal cancer (LARC). Methods and Materials: Sixty-seven LARC patients were treated with a CRT regimen consisting of radiotherapy, fluorouracil, and, where possible, oxaliplatin. Pretreatment tumor biopsy specimens were analyzed using microarrays with kinase substrates, and the resulting substrate phosphorylation patterns were correlated with tumor response to preoperative treatment as assessed by histomorphologic tumor regression grade (TRG). A predictive model for TRG scores from phosphosubstrate signatures was obtained by partial-least-squares discriminant analysis. Prediction performance was evaluated by leave-one-out cross-validation and use of an independent test set. Results: In the patient population, 73% and 15% were scored as good responders (TRG 1-2) or intermediate responders (TRG 3), whereas 12% were assessed as poor responders (TRG 4-5). In a subset of 7 poor responders and 12 good responders, treatment outcome was correctly predicted for 95%. Application of the prediction model on the remaining patient samples resulted in correct prediction for 85%. Phosphosubstrate signatures generated by poor-responding tumors indicated high kinase activity, which was inhibited by the kinase inhibitor sunitinib, and several discriminating phosphosubstrates represented proteins derived from signaling pathways implicated in radioresistance. Conclusions: Multiplex kinase activity profiling may identify functional biomarkers predictive of tumor response to preoperative CRT in LARC.},

  doi          = {10.1016/j.ijrobp.2010.04.036},

  url          = {https://www.osti.gov/biblio/21436200},
  journal      = {International Journal of Radiation Oncology, Biology and Physics},

  issn         = {0360-3016},

  number       = 2,

  volume       = 78,

  place        = {United States},

  year         = {Fri Oct 01 00:00:00 EDT 2010},

  month        = {Fri Oct 01 00:00:00 EDT 2010}

}

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