Pharmacogenomics is of particular importance in oncology, a medical subspecialty characterized by rapidly lethal diseases and drugs with narrow therapeutic indices and significant toxicities. Identification of individuals likely to respond to or experience toxicity from a given chemotherapeutic agent, will have significant impact on outcomes, particularly in the field of oncology. Several models currently exist for discovery of pharmacogenomic markers in oncology. Phenotypic variations may range from variability in response as measured by survival or time to progression, to variability in toxicity in individuals treated with a particular agent. Measurements of toxicity can be a challenge to quantify in individuals because of interobserver variability. Lymphoblastoid cell lines (LCLs) and the NCI60 bank of tumor cell lines have been used as models for clinical phenotypes. To date, there are several examples of germline polymorphisms and somatic mutations that predict likelihood of response and/or toxicity from chemotherapeutic agents. A pattern of interethnic variability in response and toxicity has been observed for some chemotherapeutic agents, and the associated field of pharmacoethnicity is likely to contribute to our understanding of pharmacogenomics.

Pharmacogenomics has found extensive application in the field of oncology and is likely to remain an important tool in the race toward personalized medicine. Individualization of therapies is of particular importance in oncology because of several unique features of cancer treatment. First, most oncologic therapies have potential for organ toxicity and typically give rise to an array of potential life-threatening side effects. For example, taxanes are highly efficacious against malignancies of the lung, breast, ovary, and head and neck, but are also associated with significant toxicities such as myelosuppression and peripheral neuropathy. Identification of individuals unlikely to respond to taxane therapy a priori will be tremendously important in therapeutic decision making, because alternative therapies can be considered, thereby reducing the likelihood of unnecessary toxicity. Second, many oncologic diseases progress rapidly and are generally lethal in the absence of effective therapy. Consequently, prompt diagnosis and early institution of efficacious therapies is of paramount importance. In the absence of knowledge about predictors of response, individuals could be subjected to therapies to which their tumors might not respond, resulting in further disease progression. With more advanced disease and organ dysfunction, some therapies may no longer be given safely and may only serve a palliative rather than a curative role. For example, a five-year period of adjuvant tamoxifen therapy following successful treatment of early-stage estrogen receptor (ER)-positive breast cancer in a premenopausal woman is associated with a reduction in the rate of disease recurrence and mortality. A poor metabolizer phenotype results in insufficient conversion of tamoxifen to endoxifen and an increased risk of disease relapse and progression (1). Affected individuals may be better served by alternative antiestrogen maneuvers such as the combination of ovarian ablation and aromatase inhibitor therapy. Third, most chemotherapeutic agents have a fairly narrow therapeutic index (see Figure 10.1). The therapeutic index of a drug compares the dose that produces toxicity with the dose that produces the desired effect and, as such, provides a measure of the drug's safety. Given the significant likelihood of an adverse effect even within the therapeutic window, treatment with a particular agent is best reserved for individuals likely to respond, with the careful weighing of risks and benefits and informed decision making on the part of the patient. Finally, the expenses associated with oncologic therapies necessitate avoidance of therapy-related morbidity that further increases the likelihood of hospitalization and overall cost of care. For example, trastuzumab is an agent used in the treatment of HER2neu-positive breast cancer, is typically infused on a three-weekly schedule for at least one year, and may cost as much as $70,000 for a full course of therapy (2). Given all the aforementioned, it is not surprising that current pharmacogenomic research is dominated by investigation of variability in response to, and toxicity from, oncologic therapies (3).