Abstract
Over the past two decades, several protein and genomic markers have refined the prognostic information of colorectal cancer (CRC) and helped to predict which patient group may benefit most from systemic treatment or targeted therapies. Of all these markers, KRAS represents the first biomarker integrated into clinical practice for CRC. Microarray-based gene-expression profiling has been used to identify prognostic signatures and to a lesser degree predictive signatures in CRC; however, common challenges with these types of studies are clinical study design, reproducibility, interpretation and reporting of the results. We focus on the clinical application of a range of published prognostic and predictive protein and genomic markers in CRC and discuss the different challenges associated with microarray-based gene-expression profiling. While none of these genomic signatures is currently in routine clinical use in CRC, novel adaptive clinical trial designs that incorporate putative genomic prognostic/predictive markers in prospective randomized trials, will enable a clinical validation of these markers and may facilitate the implementation of these biomarkers into routine medical practice.
Key Points
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MSI-H in colorectal cancer (CRC) tumors is associated with a more favorable prognosis, which may be stronger in patients with stage II compared with stage III disease
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5-FU-based adjuvant therapy significantly reduces the recurrence risk in MSI-L/MSS, but not in MSI-H patients, who have a favorable prognosis and low recurrence risk
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Several randomized studies have shown the negative predictive value of KRAS mutations for response to EGFR monoclonal antibodies; KRAS represents the first biomarker integrated into clinical practice in CRC
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Patients with BRAF mutations have a poor prognosis; larger patient cohorts are needed to define the predictive role of BRAF, PIK3CA and PTEN for response to EGFR monoclonal antibodies
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High-throughput technologies have helped to define a detailed picture of multiple genomic alterations and may be powerful tools for biomarker discovery and validation
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Novel adaptive clinical trial design, incorporating putative genomic prognostic/predictive markers into prospective studies, will enable a clinical validation of these markers and their implementation in clinical practice
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S. Van Schaeybroeck and P. G. Johnston provided substantial contribution to the discussion of content, and reviewed and edited the manuscript before submission and after peer review. All authors researched the data to include in the manuscript and contributed to the writing of the manuscript.
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P. G. Johnston is a consultant for Chugai Pharmaceuticals, Roche Pharmaceuticals and Sanofi-Aventis. He receives grant and research support from Amgen and AstraZeneca. He is the Director of Almac Diagnostics and the Society for Translational Oncology, and is a shareholder for Almac and Fusion Antibodies. The other authors declare no competing interests.
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Van Schaeybroeck, S., Allen, W., Turkington, R. et al. Implementing prognostic and predictive biomarkers in CRC clinical trials. Nat Rev Clin Oncol 8, 222–232 (2011). https://doi.org/10.1038/nrclinonc.2011.15
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DOI: https://doi.org/10.1038/nrclinonc.2011.15
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