Journal
ANNALS OF TRANSLATIONAL MEDICINE
Volume 6, Issue 9, Pages -Publisher
AME PUBL CO
DOI: 10.21037/atm.2018.03.27
Keywords
Colorectal cancer (CRC); genomics; targeted therapies
Categories
Funding
- National Institutes of Health Memorial Sloan Kettering Cancer Center Core Grant [P30 CA 008748]
- NATIONAL CANCER INSTITUTE [P30CA008748] Funding Source: NIH RePORTER
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The widespread use of next generation sequencing (NGS) has led to a refined understanding of the genomics of colorectal cancer (CRC). However, progress in the use of molecular biomarkers in standard practice has been slow, and there is no approved targeted therapy for CRC based on a positive predictive marker yet. In this review, we will first summarize biomarkers with clinical utility in standard practice or targeted therapy trials and then consider how to rationally design clinical trials to more effectively target CRC. Specifically, we will discuss current clinical applications of genomic information consisting of the use of the MAPK (mitogen-activated protein kinase) pathway genes KRAS, NRAS, and BRAF as prognostic and predictive biomarkers for standard treatment, risk stratification by primary tumor site and consideration of tumor laterality in patient selection for epidermal growth factor receptor (EGFR) antibody treatment, and the evaluation for genomic biomarkers, including BRAF V600E, HER2 amplification, and gene rearrangements, for targeted therapies in clinical trials. Applying lessons from targeted therapy trials in CRC, we now appreciate that both tumor genomics and tissue of origin affect targeted therapy response and that the development of resistance to targeted therapies is dynamic and often subclonal. Based on these understandings, we propose the design of adaptive clinical trials that evaluate real-time pharmacodynamic markers and monitor tumor subpopulations during the course of treatment to overcome challenges targeting genetic drivers in CRC.
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