Pharmacogenomics and colorectal cancer

The current methods of treating cancer patients with chemotherapeutics do not account for interpatient variability in the expression of particular target genes. This variability leads to unpredictable tumor responses and host toxicity. The approach we have taken is to determine gene expression levels in the metabolic pathways of drugs used in the treatment of gastrointestinal tumors. One of the main obstacles in the evaluation and determination of these markers has been the limitations of available technology. Many advances have been made in the development of more sophisticated techniques and the ability to perform these techniques on paraffin-embedded tumor tissue. In fact, with the identification of genetic polymorphisms, these markers may be obtained from peripheral blood specimens, thus making access to tissues a moot issue. An immediate goal is the application of this nascent technology and incorporation of these data in prospective clinical trials that would stratify patients according to their molecular profile. The ability to predict with a high degree of accuracy which patients are likely to respond to treatment and identify those who are not likely to respond will significantly influence the design of new treatment regimens with fluoropyrimidines and platinum. Tumors with high TS, TP, and DPD expression levels should be treated with such non-TS-directed anticancer drugs as irinotecan or oxaliplatin, or in combination with 5-FU. Patients with high expression of ERCC1 should be treated with nonplatinum-based regimens, whereas patients with low levels would be good candidates for cisplatin or oxaliplatin. We now understand that molecular determinants play an important role in response to 5-FU. With the development of new effective anticancer drugs such as irinotecan and oxaliplatin, it is important to gain a better understanding about the metabolism of these new active agents and mechanisms of resistance. It is essential to understand why some patients develop life-threatening toxicity and why some tumors are resistant to irinotecan or oxaliplatin. With the integration of novel-targeted therapies such as Erbitux and Avastin, molecular characterization and profiling will become more important for patient selection. Preliminary data suggest that germ line polymorphisms of cyclin D and gene expression levels of VEGF are associated with efficacy of Erbitux therapy.