Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

Abstract

A B S T R A C TPharmacogenomics is the study of genetic factors determining drug response or toxicity.The use of pharmacogenomics is especially desirable in oncology because the therapeutic index of oncology drugs is often narrow, the need for favorable drug response is often acute, and the consequences of drug toxicity can be life-threatening. In this review, we examine the state of pharmacogenomics in oncology, focusing only on germline pharmacogenomic variants. We consider several critical points when assessing the quality of pharmacogenomic findings and their relevance to clinical use, and discuss potential confounding factors limiting interpretation and implementation. Several of the most extensively studied drugegene pairs (irinotecan and UGT1A1; tamoxifen and CYP2D6; 5-fluorouracil and DPYD) are inspected in depth as illustrations of both the state of advancementdand the current limitations ofdpresent knowledge. We argue that there will likely soon be a critical mass of important germline pharmacogenomic biomarkers in oncology which deserve clinical implementation to provide optimal, personalized oncologic care.We conclude with a vision of how routine clinical testing of such germline markers could one day change the paradigm for cancer care.

Clinical Management of Head and Neck Cancer Cases: Role of Pharmacogenetics of CYP2 and GSTs

“…Such studies are based on a case-control approach wherein genetic markers or mutations across the genome are compared between persons affected by a complex disease or drug-response phenotype and those who are not [19]. Cancer pharmacogenomics has fast emerged for the identification of pharmacogenomic markers that predict drug response or toxicity, since chemotherapeutic drugs usually have narrow therapeutic indices resulting in potentially life-threatening toxicity or non-response to treatment [20]. Identifying genetic markers useful in the selection of optimal drugs, dose, and treatment duration on an individual basis could result in improved drug efficacy and decreased toxicity (fig.…”

The Human Genome Project: Where Are We Now and Where Are We Going?

“…In particular, genetic deregulations affecting genes coding for DPD, UGT1A1, TPMT, CDA, and CYP2D6 are now considered as critical issues for patients treated with 5-FU/capecitabine, irinotecan, mercaptopurine/azathioprine/thiopurine, gemcitabine/ capecitabine/AraC, and tamoxifen, respectively (Evans 2004;Marques and Ikediobi 2010;Yang et al 2011;O'Donnell and Ratain 2012). Examples like this serve to underscore the reality that the real clinical impact of pharmacogenetics will be in identifying those patients who are most likely to experience the desired therapeutic effect from the drug under consideration.…”

The challenge to bring personalized cancer medicine from clinical trials into routine clinical practice: The case of the Institut Gustave Roussy

“…One perspective could be to further evaluate the methods for target identification at the tumor level, and no longer the drugs. Several approaches are being developed to identify the right target at the sample level (Mani et al, 2008;Chen et al, 2011;Barabasi et al, 2011) (see also O'Donnel andRatain, 2012). We plan to develop a virtual cell that will map the main oncogenes and their interactions.…”