Have we Made Progress in Pharmacogenomics? the Implementation of Molecular Markers in Colon Cancer

Abstract

For the last 40 years, 5-fluorouracil (5-FU) has remained the treatment of choice in both the adjuvant and advanced treatment of colorectal cancer (CRC). However, 5-FU monotherapy produces response rates of only 10-20% in the advanced setting. 5-FU has been combined with newer agents, such as oxaliplatin and irinotecan, and this has significantly increased response rates to 40-50% in the advanced setting. More recently, novel biological agents, such as the monoclonal antibodies targeting either the epidermal growth factor receptor or vascular endothelial growth factor, have shown to provide additional clinical benefit for patients with metastatic CRC. A number of predictive markers have been identified for CRC to date. However, their usefulness as individual markers of response has led to somewhat inconclusive results. Therefore, there is a need to identify panels of predictive markers of response to therapy for advanced CRC, in order to improve these disappointing response rates. The advent of high-throughput methodologies, such as microarrays, enables tumor samples to be profiled on a global scale. This technology has been utilized to develop predictive markers for a wide range of tumor types to date, and hopefully this technology can be translated into the CRC setting with the hope of predicting the response of each individual tumor to chemotherapy.

Targeted therapy of cancer: new roles for pathologists in colorectal cancer

“…As a result, these enzymes have been studied extensively at the DNA, RNA, and protein levels, and high levels of expression by immunohistochemistry and mRNA associated with poor outcome. 1,[8][9][10][19][20][21][22] Recently, additional enzymes important in 5-FU effects have been identified, including mRNA expression of TNFRSF1B, SLC35F5, and orotate phosphoribosyltransferase. [23][24][25] At the DNA level, a tandem repeat of 28 bp is present in the 5 0 -untranslated region of the TS gene and is linked to its expression and enzymatic activity in tumors.…”

“…Predictive markers address the issue of how to treat a patient and have potential applicability in both the adjuvant and advanceddisease settings. [8][9][10][11][12] These markers would improve patient management by permitting the use of effective agents from the outset of therapy and the avoidance of the toxicities of ineffective agents that are ultimately discontinued due to lack of efficacy after exposure of the patient to potential adverse events. Markers to predict response and, even more importantly, survival would make major changes in patient management.…”

“…Somatic alterations at the DNA, RNA, and protein levels in tumors are well studied, and comprehensive approaches in characterizing the pharmacogenomics of tumors are being pursued actively. 1,[8][9][10][11][12]14 The germline constitution of patients has also received attention in the discipline of pharmacogenetics with recognition of numerous single-nucleotide polymorphisms in genes that are important in tumor biology. 8,15 Less effort has been directed at understanding the interaction of environmental and lifestyle exposures and factors such as diet and physical activity with the effects of therapeutic agents, but intriguing results have emerged that western diet and low physical activity have adverse effects on survival after chemotherapy.…”

The role of pharmacogenetics in making treatment decisions in colorectal cancer

“…This apparent inconsistency may be due to the fact that TP is an angiogenic factor, also known as platelet-derived endothelial cell growth factor. The angiogenic role of TP is likely to be more relevant in vivo where higher TP levels may be markers of more aggressive tumors with higher invasive and malignant potential [11]. Dihydropyrimidine dehydrogenase (DPD) is a crucial enzyme in the catabolism of 5-FU as it degrades more than 80% of 5-FU in the liver [12].…”

Prognostic significance of Cytokeratin 20-positive lymph node vascular endothelial growth factor A mRNA and chromodomain helicase DNA binding protein 4 in pN0 colorectal cancer patients

“…Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the Western world [ 1 ]. Despite curative surgery, approximately 40% of patients still experience disease relapse leading to morbidity and eventual mortality [ 2 ]. The main cause of death among patients with CRC is metastasis that can occur in regional lymph nodes (LNs) [ 3 ] or via blood to other distant organs [ 4 ].…”