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Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment
Alessia Bignucolo1, Elena De Mattia2, Erika Cecchin3
1Clinical and Experimental Pharmacology, CRO-National Cancer Institute, via Franco Gallini 2, 33081 Aviano (PN), Italy. alessia.bignucolo@cro.it.
Abstract:
The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient.
Insights
Targeted therapies improve metastatic colorectal cancer (CRC) outcomes. Pharmacogenomics and advanced sequencing identify predictive markers, enabling precision medicine by detecting drug resistance early.
Area of Science:
- Oncology
- Pharmacogenomics
- Molecular Biology
Background:
- Targeted agents, including anti-epidermal growth factor receptor (anti-EGFR) and antiangiogenic drugs, have advanced metastatic colorectal cancer (CRC) treatment.
- Additional pathways like MAPK, PI3K-AKT, mTOR, HER-2/3, and BRAF are targets for novel CRC therapies.
- A significant challenge in targeted therapy is predicting and overcoming primary or secondary drug resistance.
Purpose of the Study:
- To review the role of pharmacogenomics in identifying predictive markers for targeted therapies in metastatic colorectal cancer (CRC).
- To discuss the integration of genetic profiling, such as RAS/RAF pathway mutations, for optimizing anti-EGFR and antiangiogenic treatments.
- To explore the potential of next-generation sequencing and circulating tumor DNA analysis for real-time monitoring and personalized medicine in CRC.
Main Methods:
- Review of current literature on targeted agents and pharmacogenomic markers in metastatic colorectal cancer (CRC).
- Analysis of genetic profiling requirements for anti-EGFR therapy (RAS/RAF pathway).
- Evaluation of emerging technologies like next-generation sequencing (NGS) and circulating tumor DNA (ctDNA) for predictive marker discovery.
Main Results:
- Pharmacogenomic studies have identified tumor mutations that can predict response to targeted therapies in CRC.
- RAS/RAF pathway genetic status is crucial for anti-EGFR agent selection; EGFR pathway mutations are also investigated for antiangiogenic therapy response.
- Immunotherapy has introduced new predictive markers, including comprehensive tumor genetic landscape analysis.
Conclusions:
- Pharmacogenomics is essential for predicting drug resistance and guiding targeted therapy selection in metastatic colorectal cancer (CRC).
- Next-generation sequencing and ctDNA analysis promise real-time pharmacogenomic monitoring, facilitating precision medicine for all CRC patients.
- Continued research into genetic markers will further refine personalized treatment strategies for colorectal cancer.
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