From the Departments of Medicine and Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Author's disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Hein-Josef Lenz, MD, FACP, Professor of Medicine and Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Ave, Los Angeles, CA 90033-1048; e-mail: lenz_h{at}ccnt.usc.edu
Overview: Progress in cancer biology has expanded our understanding of the molecular and cellular mechanisms of cancer development, cancer metastasis, and resistance of cancer cells to (radiotherapy) chemotherapy. Selection of the most beneficial treatment strategy in colorectal cancer (CRC) remains a challenge and is hindered by the lack of predictive and prognostic markers. Retrospective analyses of CRC patients revealed promising molecular markers in the metabolism and stress response to standard chemotherapeutic (5-fluorouracil, oxaliplatin, and irinotecan) and novel targeted (cetuximab, panitumumab, and bevacizumab) agents. Polymorphisms and gene expression levels of TS, ERCC1, and UGT1A1 have been the most widely investigated markers in determining clinical outcome in CRC patients treated with standard chemotherapeutic agents. The identification and association of the UGT1A1*28 polymorphism with impaired detoxification of irinotecan and increased risk for neutropenia has caused the U.S. Food and Drug Administration (FDA) to change labeling of the drug indicating these findings. Although the introduction of biologic agents and the development of associate molecular markers have shown promising results (K-ras, MSI, 18q del, TS, ERCC1, UGT1A1), only a few of these biomarkers have been accepted into routine clinical practice. It is becoming increasingly apparent that complex pathways largely drive disease progression; analysis of one single marker is unlikely to predict efficacy and outcome. Large prospectively designed and biomarker-embedded clinical trials are needed to determine conclusively their significance in tailored treatment modalities. However, a great deal of work remains. Ongoing and future clinical trials hold promise for further improvements in optimizing and specifying chemotherapy individually to prolong lives and optimize quality of life.
