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Pharmacogenomic-Guided Therapy in Colorectal Cancer
Robert B Diasio1,2, Federico Innocenti3, Steven M Offer1
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
Approximately 20 drugs have been shown to be effective for the treatment of colorectal cancer (CRC). These drugs are from several classes of agents and include cytotoxic drugs, therapeutics that target cell signaling pathways at the extracellular and/or intracellular levels, and combination therapies that contain multiple targeted agents and/or cytotoxic compounds. Targeted therapeutics can include monoclonal antibodies, fusion proteins, and small molecule drugs. The first introduced into clinical use was 5-fluorouracil in the early 1960s and remains the foundation for most CRC treatments in both adjuvant therapy and in advanced (metastatic) treatment regimens. As with other cancers, the consideration of biomarkers has the potential to improve CRC therapy through patient stratification. The biomarkers can include germline genetic markers, tumor-specific genetic markers, immune markers, and other biomarkers that can predict antitumor efficacy or the likelihood of toxicity prior to administration of a specific drug. Consistent with the benefit of considering biomarkers in treatment, many newer targeted therapies are developed and approved simultaneously with a companion diagnostic test to determine efficacy. This review will focus on biomarkers that have demonstrated clinical utility in CRC treatment; however, it is noted that many additional biomarkers have been theorized to contribute to drug response and/or toxicity based on known biological pathways but thus far have not attained widespread use in the clinic. The importance of pretreatment biomarker testing is expected to increase as future drug development will likely continue to focus on the concurrent development of companion diagnostics.
Insights
Biomarker testing is crucial for improving colorectal cancer (CRC) treatment by stratifying patients. Pretreatment biomarker evaluation enhances drug efficacy and predicts toxicity, guiding personalized CRC therapy.
Area of Science:
- Oncology
- Pharmacogenomics
- Cancer Therapeutics
Background:
- Colorectal cancer (CRC) treatment involves approximately 20 drugs, including cytotoxic agents, targeted therapies (monoclonal antibodies, fusion proteins, small molecules), and combination regimens.
- 5-fluorouracil, introduced in the 1960s, remains a cornerstone for both adjuvant and advanced CRC treatment.
- Biomarkers, including germline, tumor-specific, and immune markers, are increasingly important for stratifying patients and predicting treatment response or toxicity.
Purpose of the Study:
- To review biomarkers that have demonstrated clinical utility in guiding colorectal cancer (CRC) treatment decisions.
- To highlight the growing importance of companion diagnostics in the development and application of targeted CRC therapies.
- To emphasize the potential of pretreatment biomarker testing for optimizing patient stratification and therapeutic outcomes in CRC.
Main Methods:
- Literature review focusing on biomarkers with established clinical utility in colorectal cancer (CRC) treatment.
- Analysis of the role of biomarkers in patient stratification for both established and novel CRC therapies.
- Examination of the trend towards concurrent development of targeted therapeutics and companion diagnostic tests.
Main Results:
- Several biomarkers have demonstrated clinical utility in predicting efficacy and/or toxicity for specific CRC drugs, enabling patient stratification.
- Many targeted therapies are now approved with companion diagnostics to ensure appropriate patient selection.
- Numerous other biomarkers show theoretical potential but have not yet achieved widespread clinical use in CRC treatment.
Conclusions:
- Biomarker testing is essential for improving the efficacy and safety of colorectal cancer (CRC) treatment.
- The development of targeted therapies increasingly involves companion diagnostics, underscoring the importance of pretreatment biomarker evaluation.
- Future CRC drug development will likely continue to prioritize the concurrent development of drugs and companion diagnostics for personalized treatment strategies.
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