Clinical biomarkers in oncology: focus on colorectal cancer.
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 from microarray expression profiling needs to be further investigated in studies based on much larger cohorts, and cross-validation studies will be essential. Recently, mutations in the KRAS 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 the PIK3CA gene. Further studies are needed to help integrate the latest findings into clinically useful tools for personalized medicine.
De Roock
Wendy
W
Digestive Oncology Unit, Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
Biesmans
Bart
B
De Schutter
Jef
J
Tejpar
Sabine
S
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins