Abstract
Colorectal cancer (CRC) is the third most common cancer type and the second cause of death worldwide. The advancement in understanding molecular pathways involved in CRC has led to new classifications based on the molecular characteristics of each tumor and also improved CRC management through the integration of targeted therapy into clinical practice. In this review, we will present the main molecular pathways involved in CRC carcinogenesis, the molecular classifications. The anti-VEGF and anti-EGFR therapies currently used in CRC treatment and those under clinical investigation will also be outlined, as well as the mechanisms of primary and acquired resistance to anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Targeted therapy has led to great improvement in the treatment of metastatic CRC. However, there has been variability in CRC treatment outcomes due to molecular heterogeneity in colorectal tumors, which underscores the need for identifying prognostic and predictive biomarkers for CRC-targeted drugs.
Highlights
Colorectal cancer (CRC) is considered the third most prevalent cancer and the second cause of death by cancer worldwide [1]
The 5-year overall survival (OS) rate of CRC is estimated at 64% for all stages in the United States, and this seems to decrease to nearly 12% for metastatic CRC [4, 5]
E CORRECT phase III trial showed that treatment with regorafenib conferred a significant improvement in OS compared with the placebo arm, for metastatic CRC (mCRC) that was refractory to standard therapy (6.4 vs. 5 months; hazard ratio (HR), 0.77; P 0.0052) [86]
Summary
Colorectal cancer (CRC) is considered the third most prevalent cancer and the second cause of death by cancer worldwide [1]. Developing other treatment options for CRC, especially for mCRC to increase its overall survival and reduce its severity, is highly needed. With the advancement in our understanding of carcinogenesis mechanisms and the underlying molecular pathways, treatment of CRC, especially mCRC, has evolved considerably over the past years, which was reflected by using many chemotherapy combinations and integrating novel targeted drugs into clinical practice. Cetuximab was the first targeted agent for CRC that has been approved by the Food and Drug Administration (FDA) in 2004, followed by bevacizumab in the same year. E advancement in understanding molecular pathways involved in CRC carcinogenesis has led to many molecular classification systems. E current review aims to provide an overview of molecular pathways involved in CRC carcinogenesis, as well as molecularly defined subtypes and their clinical implication. We will summarize available and future CRCtargeted agents and discuss anti-EGFR resistance mechanisms
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