Abstract
Cancer drug development is a time and resources consuming process. Around 90% of drugs entering clinical trials fail due to lack of efficacy and/or safety issues, more often after conspicuous research and economic efforts. Part of the discarded drugs might be beneficial only in a subgroup of the study patients, and some adverse events might be prevented by identifying those patients more vulnerable to toxicities. The implementation of pharmacogenomic biomarkers allows the categorization of patients, to predict efficacy and toxicity and to optimize the drug development process. Around seventy FDA approved drugs currently present one or more genetic biomarker to keep in consideration, and with the progress of Precision Medicine tailoring therapies on individuals’ genomic landscape promises to become a new standard of cancer care. In the current article we review the role of pharmacogenomics in cancer drug development, underlying the advantages and challenges of their implementation.
Highlights
Since the development and approval of the first targeted agents, oncology care has moved from a onesize-fits-all paradigm with pure histology-oriented approach toward a tailored treatment, selected upon www.cdrjournal.comTarantino et al
Classically considered the main factors influencing the therapeutic decision, where integrated by a large number of new identified prognostic and predictive biomarkers. Some of these where found to predict response or resistance to certain drugs (e.g., Estrogen receptor expression for Tamoxifen[1], HER2 amplification for trastuzumab[2]), some others predicted instead a propensity in experimenting side effects from the treatments (e.g., UGT1A1 polymorphisms and irinotecan toxicity[3]). Both of these types of biomarkers are today studied by the discipline of pharmacogenomics (PGx), which evolved from a pre-existing branch of pharmacology called pharmacogenetics
Frequency-based and function-based approaches are being applied to individuate driver mutations, and have recently lead to the publishing by ESMO of a scale of actionability of molecular targets (ESCAT scale)[46] based on the strength of the evidence supporting them, which will serve as a base to interpret PGx findings and improve clinical trials, as well as clinical practice
Summary
Since the development and approval of the first targeted agents, oncology care has moved from a onesize-fits-all paradigm with pure histology-oriented approach toward a tailored treatment, selected upon www.cdrjournal.comTarantino et al. At least three of the 5 Rs (right safety, right target determination and right patient identification) can be improved by the implementation of PGx principles in cancer drug development, making it a main determinant of the success rate in clinical trials.
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