Pharmacogenomic‐Guided Therapy in Colorectal Cancer

Abstract

Approximately 20 drugs have been shown to be effective for the treatment of colorectal cancer (CRC). These drugs are from several classes of agents and include cytotoxic drugs, therapeutics that target cell signaling pathways at the extracellular and/or intracellular levels, and combination therapies that contain multiple targeted agents and/or cytotoxic compounds. Targeted therapeutics can include monoclonal antibodies, fusion proteins, and small molecule drugs. The first introduced into clinical use was 5‐fluorouracil in the early 1960s and remains the foundation for most CRC treatments in both adjuvant therapy and in advanced (metastatic) treatment regimens. As with other cancers, the consideration of biomarkers has the potential to improve CRC therapy through patient stratification. The biomarkers can include germline genetic markers, tumor‐specific genetic markers, immune markers, and other biomarkers that can predict antitumor efficacy or the likelihood of toxicity prior to administration of a specific drug. Consistent with the benefit of considering biomarkers in treatment, many newer targeted therapies are developed and approved simultaneously with a companion diagnostic test to determine efficacy. This review will focus on biomarkers that have demonstrated clinical utility in CRC treatment; however, it is noted that many additional biomarkers have been theorized to contribute to drug response and/or toxicity based on known biological pathways but thus far have not attained widespread use in the clinic. The importance of pretreatment biomarker testing is expected to increase as future drug development will likely continue to focus on the concurrent development of companion diagnostics.

Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer

“…2 Molecular profiling of RAS (KRAS, NRAS) and BRAF mutations has revolutionized the treatment of mCRC, as evidenced through guidelines by the National Comprehensive Cancer Network and several other professional societies. [3][4][5][6] Not surprisingly, therefore, recent studies have reported increasing trends in the use of molecular testing in patients with mCRC. 7,8 The presence or absence of certain variations informs the choice of targeted therapies by such agents as epithelial growth factor receptor (EGFR) inhibitors, which are effective in RAS wild-type (WT) left-sided mCRC tumors, and vascular endothelial growth factor (VEGF) inhibitors, used regardless of molecular subtypes.…”

“…Molecular profiling of RAS ( KRAS , NRAS ) and BRAF mutations has revolutionized the treatment of mCRC, as evidenced through guidelines by the National Comprehensive Cancer Network and several other professional societies . Not surprisingly, therefore, recent studies have reported increasing trends in the use of molecular testing in patients with mCRC …”

Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells

“…From 1950 to 1990, virtually the only drug for the treatment of colorectal cancer was 5-fluorouracil and its derivatives, cytotoxic agents, which are still among the main first-line drugs. Later, other cytotoxic drugs, such as irinotecan (SN-38) and platinum compounds (oxaliplatin), were included in the treatment regimens, and a number of target inhibitors, such as cetuximab, bevacizumab, BRAF inhibitors, and others were discovered somewhat later [ 3 ]. Despite the apparent diversity of drugs and treatment regimens, there are a number of problems associated with these approaches.…”

Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent

“…5-Fluorouracil (5-FU) is a nonselective chemotherapeutic agent against many types of cancers, including colorectal cancer, , breast cancer, pancreatic cancer, gastric cancer, and head & neck cancer. − Especially in the treatment of colorectal cancer, 5-FU is still the first-line chemotherapeutic drug. , However, its short plasma half-life and high incidences of adverse side effects, such as hematological, gastrointestinal, cardiac, neural, and dermatological toxicities, limit wider clinical applications. − Evidently, the full anticancer potential of the drug can only be profitably and safely harnessed with much improvement. In the past few decades, two main strategies have emerged.…”

“…5-Fluorouracil (5-FU) is a nonselective chemotherapeutic agent against many types of cancers, including colorectal cancer, 1,2 breast cancer, pancreatic cancer, gastric cancer, and head & neck cancer. 3−6 Especially in the treatment of colorectal cancer, 5-FU is still the first-line chemotherapeutic drug.…”