Perspectives and challenges of clinical pharmacogenomics in cancer.

Lessons from the past For the purposes of this editorial, clinical pharmacogenomics is defined as research that uses high-throughput gene expression profiling of human cancer tissues to discover new diagnostic and predictive markers. The technology platforms that enable this research are novel and they may even be considered as revolutionary analytical tools. However, many of the practical challenges of clinical pharmacogenomics are old and have plagued prognostic and predictive marker research since its inception. It is thought provoking that after 30 years of modern tumor marker research, clinically useful cancer markers are still rare. For example, the most recent recommendations of the American Society of Clinical Oncology (ASCO) only included estrogen receptor (ER), progesterone receptor (PR) and HER-2 (human epidermal growth factor receptor) measurements for routine use in the management of breast cancer [1]. Other professional organizations adopted very similar guidelines [101]. This is in spite of the inclusion of tens of thousands of breast cancer samples in various retrospective tumor marker studies that have examined a large number of potential biomarkers over the past 20 years [2,3]. During the same 20-year period, the US Food & Drug Administration (FDA) approved at least seven new drugs specifically for the treatment of breast cancer and many more for the treatment of other cancers. One cannot help but ask if it is more difficult to develop a clinically useful prognostic or predictive marker for cancer than it is to develop a clinically useful anticancer drug. Most cancer treatments approved by the FDA tend to be rapidly accepted and adopted by the medical community. This is not surprising since the approval process requires the demonstration of some form of clinical benefit from the new drug. Such benefit could represent improvement in survival compared to an existing standard therapy, or new, at least partially effective treatment for a clinical situation where older treatments have minimal or no activity. Improvements in quality of life, prolongation of cancer progression-free period and development of less toxic but equally effective alternative treatments, may also be considered as clinical benefits. In contrast, many of the FDA-approved prognostic or predictive diagnostic reagents and kits, and a large number of molecular markers offered by the Clinical Laboratory Improvement Amendment (CLIA) [102] – certified diagnostic laboratories – have not been shown to provide clinical benefit. This lack of proof for clinical benefit from using a particular test is reflected in the conservative recommendations of the ASCO and other medical organizations. Of course, all of the cancer markers available through clinical diagnostic laboratories have been shown, at least by some studies, to be associated with a particular clinical outcome. However, what is missing is the unequivocal demonstration that using a new marker in clinical decision making improves patient outcome compared to not using it. Figure 1 illustrates the differences in the therapeutic drug development process and the current clinical evaluation process of putative predictive or prognostic markers.