Abstract
The treatment scenario of colorectal cancer (CRC) has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease. An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices. Pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities. The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers, while supporting the rationale for the development of new drugs and treatment combinations. Clinical validation of promising biomarkers, however, is often an issue. More recently, a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field. This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC, in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach, comprising genomics and epigenetics.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the western world and ranks third among the most frequent malignancies in both men and women[1]
Moving from early studies exploring the genetic bases of individual predisposition to severe toxicities from chemotherapy agents [i.e. 5-fluorouracil (5-FU) or irinotecan] in metastatic CRC (mCRC) patients, the introduction of targeted agents such as anti-epidermal growth factor receptor (EGFR) drugs, has prompted the discovery of predictive molecular biomarkers (i.e. RAS mutational status) which are tested as part of routine clinical practice[5]
We present an overview of current pharmacogenomic biomarkers validated in clinical practice and future perspectives of pharmacogenomics in CRC [Tables 1 and 2], in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach, comprising genomics and epigenetics
Summary
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the western world and ranks third among the most frequent malignancies in both men and women[1]. Patients with any RAS mutation in their tumors showed a worse outcome when treated with panitumumab [hazard ratio (HR) for progression free survival (PFS) = 1.31 (P = 0.008, P for interaction < 0.002); HR for OS = 1.21 (P = 0.04, P for interaction = 0.001)][24] Following this evidence, results of all recent randomized trials with anti-EGFR-based therapies were retrospectively re-evaluated according to the extended RAS mutational status[25,26,27] and several meta-analyses were performed. Primary tumor right-sidedness was found to be associated with resistance to anti-EGFRs, confirming recent literature evidence, and the combined evaluation of PRESSING panel and primary tumor location demonstrated the best predictive accuracy These results open promising perspectives on the clinical application of a more comprehensive molecular characterization of RAS/BRAF WT mCRCs to further improve and refine patients selection. New strategies are currently under study to develop miRNA based inference methods to extensively infer drug-disease causal relationship (miRDDCR) to assist in experimental design for drug discovery and disease treatment[196]
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