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The combinatorial complexity of cancer precision medicine

Precision medicine approaches have recently been developed that offer therapies targeting mainly single genetic alterations in malignant tumors. However, next generation sequencing studies have shown that tumors normally harbor multiple genetic alterations, which could explain the so far limited suc...

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Main Authors: Klauschen, Frederick (Author) , Andreeff, Michael (Author) , Keilholz, Ulrich (Author) , Dietel, Manfred (Author) , Stenzinger, Albrecht (Author)
Format: Article (Journal)
Language:English
Published: July 23, 2014
In: Oncoscience
Year: 2014, Volume: 1, Issue: 7, Pages: 504-509
ISSN:2331-4737
DOI:10.18632/oncoscience.66
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.18632/oncoscience.66
Verlag, lizenzpflichtig, Volltext: https://www.oncoscience.us/archive/v1/i7/
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Author Notes:Frederick Klauschen, Michael Andreeff, Ulrich Keilholz, Manfred Dietel and Albrecht Stenzinger

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520 |a Precision medicine approaches have recently been developed that offer therapies targeting mainly single genetic alterations in malignant tumors. However, next generation sequencing studies have shown that tumors normally harbor multiple genetic alterations, which could explain the so far limited successes of personalized medicine, despite considerable benefits in certain cases. Combination therapies may contribute to a solution, but will pose a major challenge for clinical trials evaluating those therapies. As we discuss here, reasons include the low abundance of most of the relevant mutations and particularly the combinatorial complexity of possible combination therapies. Our report provides a systematic and quantitative account of the implications of combinatorial complexity for cancer precision medicine and clinical trial design. We also present an outlook on how systems biological approaches may be harnessed to contribute to a solution of the complexity challenge by predicting optimal combination therapies for individual patients and how clinical trial design may be adapted by combining and extending basket and umbrella design features. 
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