Clinical Biomarkers in Oncology Focus on Colorectal Cancer

103 1. Molecular Genetics of Colorectal Cancer . 105 2. Choosing Therapeutic Strategies in Colorectal Cancer . 105 2.1 Biomarkers Indicating Requirement for Adjuvant Therapy . 106 2.1. 1 Single Gene Markers . 106 2.1. 2 Genomic and Expression Profiling . 106 2.2 Choosing Chemotherapeutic Agents for Metastatic Disease . 108 2.2.1 Single Markers Predictive of Chemotherapy Efficacy . 108 2.2.2 Expression Profiling for Chemotherapy Efficacy . 109 3. Predictive Markers of Response to Targeted Therapy . 109 3.1 KRAS . 109 3.2 BRAF . 111 3.3 PI3K/PTEN/AKT . 111 4. Summary. 112 Abstract Rapidly growing insight into the molecular biology of colorectal cancer has led to high hopes for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on gene-specific biomarkers are contradictory in their findings, and no tests are currently used in clinical practice, with the exception of microsatellite instability (MSI) and guanylyl cyclase C (GCC) testing in the adjuvant setting, and in Europe KRAS mutation testing is used in the setting of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease. There are many reasons for the failure of the initial marker hypothesis-driven approach. Although supported by a good biologic rationale, single markers such as tumor protein p53 (TP53) gene mutations, when applied to a complex tumor type containing many synchronous alterations, do not perform well in predicting outcome. Many markers also suffer from technical shortcomings, resulting from the lack of quantitative techniques to capture the impact of the molecular alteration. The impact of markers obtained frommicroarray expression profiling needs to be further investigated in studies based on much larger cohorts, and cross-validation studies will be essential. Recently, mutations in theKRAS gene were shown to be strong negative predictors of response to EGFR inhibitors in metastatic disease. It has also been suggested that BRAF gene mutations may be predictive of EGFR inhibitor resistance, and there are some conflicting data regarding the role of thePIK3CA gene. Further studies are needed to help integrate the latest findings into clinically useful tools for personalized medicine.Rapidly growing insight into the molecular biology of colorectal cancer has led to high hopes for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on gene-specific biomarkers are contradictory in their findings, and no tests are currently used in clinical practice, with the exception of microsatellite instability (MSI) and guanylyl cyclase C (GCC) testing in the adjuvant setting, and in Europe KRAS mutation testing is used in the setting of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease. There are many reasons for the failure of the initial marker hypothesis-driven approach. Although supported by a good biologic rationale, single markers such as tumor protein p53 (TP53) gene mutations, when applied to a complex tumor type containing many synchronous alterations, do not perform well in predicting outcome. Many markers also suffer from technical shortcomings, resulting from the lack of quantitative techniques to capture the impact of the molecular alteration. The impact of markers obtained frommicroarray expression profiling needs to be further investigated in studies based on much larger cohorts, and cross-validation studies will be essential. Recently, mutations in theKRAS gene were shown to be strong negative predictors of response to EGFR inhibitors in metastatic disease. It has also been suggested that BRAF gene mutations may be predictive of EGFR inhibitor resistance, and there are some conflicting data regarding the role of thePIK3CA gene. Further studies are needed to help integrate the latest findings into clinically useful tools for personalized medicine. With our understanding of the molecular biology of colorectal cancer (CRC) growing rapidly, hopes have been raised for the identification of prognostic and/or predictive molecular markers to be used in optimizing treatment of this disease. CANCER Mol Diag Ther 2009; 13 (2): 103-114 1177-1062/09/0002-0103/$49.95/0 a 2009 Adis Data Information BV. All rights reserved.