Genetic testing in cancer therapeutics.

A major challenge to physicians administering drugs with a low therapeutic index, such as chemotherapeutic agents, is the variability in drug disposition and clearance. This variability accounts for the wide interpatient response to conventional doses of antineoplastic agents. Currently, most dosing regimens are based on body weight or surface area, with the decision for dose modifications typically being made after the appearance of toxicity. Furthermore, the use of these potentially toxic agents with individuals who are unlikely to receive any benefit makes the blind use of these drugs undesirable. The goal, thus, becomes to select the drug that will likely be most efficacious in an individual patient (see Fig. 1), emphasizing the need for better methods of predicting outcome and response to treatment (1). Over the past two to three decades, clinical cancer researchers have shown an increasing interest in the role of genetic pathways encoding drug-metabolizing enzymes. The main focus has been on developing genetic tests for abnormalities in pathways potentially influencing response to treatment, particularly inherited polymorphisms affecting drug metabolism and disposition (2–4). The interest in predicting response to treatment or reducing the risk of an adverse drug reaction (ADR) has been driven by pharmacogenetic investigations linking an individual’s DNA blueprint with drug toxicity and more recently efficacy. These pharmacogenomic studies have suggested that response to treatment is, in essence, genetically associated and could be predicted by a phenotypic/genotypic test. To date, the effect of pharmacogenetic testing on drug response and ADR remains modest. This is despite the fact that ADR ranks between the 4th and 6th cause of death in the United States for all therapeutic agents (5). For safety reasons, several drugs have been withdrawn from the U.S. market in the past several years (6). Annually, more than two million hospitalized patients suffer severe ADR, even following the administration of conventional (standard) doses of chemotherapy (5, 7). Opportunities to reduce or prevent ADR or toxicity due to genetic variations in drug-metabolizing enzyme(s) are now possible as a result of increased genetic knowledge from the Human Genome Project and other pharmacogenetic studies (8, 9). Pharmacogenetic approaches in cancer therapeutics aim at identifying patients at risk of developing severe toxicity before the administration of a chemotherapeutic agent. This approach should ultimately allow individualizing therapy through tailored dosing or using treatment modification strategies, thereby avoiding genetically altered drug metabolic pathways. In a systematic review by Phillips et al. (7), it was suggested that in >50% of drugs examined in ADR studies, genetic variability, at least in one of the enzymes associated with altered metabolism, was responsible for the development of such ADR.