Interpreting disparate responses to cancer therapy: the role of human population genetics

Increasingly, investigators are recognizing differences in tumor biology, drug metabolism, toxicity, and therapeutic response among different patient populations receiving anticancer agents. These observations provide exciting opportunities to identify the factors most important for predicting individual variability in pharmacologically relevant phenotypes and consequently for personalizing the delivery of cancer therapy. Although pharmacogenomic differences may explain some of these disparities, rigorous investigation of both genetic and nongenetic differences is important to identify the variables most important for optimal selection and dosing of treatment for an individual patient. For example, pharmacogenetic tests currently used in cancer therapy, such as genotyping UGT1A1 to reduce the incidence of severe toxicity of irinotecan and sequencing epidermal growth factor receptor from tumors to identify somatic mutations conferring sensitivity to tyrosine kinase inhibitors, were developed without initial identification of interpopulation differences. Although interpopulation variability in toxicity and efficacy of these agents has been observed, the basis for these population differences remains only partially explained. Here, we review concepts of human population genetics to inform interpretations of disparate drug effects of cancer therapy across patient populations. Understanding these principles will help investigators better design clinical trials to identify the variables most relevant to subsequent individualization of a cancer therapy.