European Review for Medical and Pharmacological Sciences 2012; 16: 781-788 Knowledge and skills needs for health professions about pharmacogenomics testing field R. DI FRANCIA1, D. VALENTE2, O. CATAPANO2, M. RUPOLO3, U. TIRELLI3, M. BERRETTA3 1Hematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione “G. Pascale” IRCCS, Naples (Italy) 2Italian Association of Pharmacogenomics and Molecular Diagnostics, Caserta (Italy) 3Department of Medical Oncology; National Cancer Institute, Aviano, Pordenone (Italy) Abstract. – Background: Promise in the Introduction future, a disease could be ranked into genetic categories, allowing bespoke tailoring of medi- Advances in genetics and molecular biology cine to maximize therapeutic effects and to re- duce the potential for adverse drug response. technologies have led to many changes in phar- This new feature requires for health profession- maceutical sciences. In particular, with the devel- als to have competencies not only for the basic opments in pharmacogenetics and pharmacoge- skills of their discipline, but also for the under- nomics (PGx), detailed information about human standing on why, when, and how that knowl- genome made available and the genetic basis for edge should be applied to improve personalized success/failure of pharmacotherapy have being therapies for their patients. Current opinion on studied1. basic competences of health professions in- cludes knowledge and skills on two fundamen- Pharmacogenetic knowledge is rapidly devel- tal features: (1) genetics of disease, to allow the oping and changing; it is imperative that health- understanding and the identification of dis- care professionals keep abreast of advances and eases associated to genetic variations, and to clinical indications. The current knowledge of facilitate the development of new genomic health professions regarding PGx is still low. tests; and (2) ethical, social and economical im- There exists an acute lack of education of both plications that are fundamental to identify those physicians and pharmacists regarding pharmaco- factors that might contribute to a successful in- 2 tegration of pharmacogenomics into interna- genetics and personalized care . Academic cur- tional health and public policy. ricula are slowly including teaching of this field Aim: Briefly, we described (1) current knowl- in their courses. Healthy institutions and academ- edge on genetic variations that interact with ic organizations must play a central role in edu- therapies and the need to detect them; (2) the cating health professionals on the best use for ap- most common available methods for detecting plications of advancing pharmacogenomics re- mutations; and (3) ethical, social and economic issues related to pharmacogenetic testing and search, and in articulating on the role of physi- recording of genetic information (e.g., critical cians and pharmacists in the development and evaluation of the development of new tests, pri- use of gene-based therapies, as well as in making vacy, the current absence of public reimburse- treatment choices as the result of available pa- ment, etc). tient-specific genetic information3. Conclusions: These could be useful recom- The large number of drug options also means mendations for academic institutions and edu- cational programs to prepare health profession- that physicians are often spoilt for choice, and als with the necessary abilities for their future have a low threshold to consider alternative ther- practice. apies when toxicity becomes unmanageable. The need to evaluate the genetic basis for side effects Key Words: becomes less clinically relevant in such circum- stances. Pharmacogenomics, Health profession education, However, it is often forgotten that genetic testing Genotyping methods, Genetic knowledge base. is not only predictive for treatment related toxicity Corresponding Author: Raffaele Di Francia, Ph.D.; e-mail: [email protected] 781 R. Di Francia, D. Valente, O. Catapano, M. Rupolo, U. Tirelli, M. Berretta or allows for dose adjustment, but also determines less/low toxicity in comparison with conventional response or lack thereof. It is frequently imperative chemotherapies; therefore, these drugs represent a that must be done before treatment, as giving inap- new and promising approach to targeted cancer propriate treatment may result in an outcome poor- therapy. These new drugs are designed to interfere er than the alternative1. A “treat-and-see” approach with a specific molecular target, usually a protein has ethical and legal implications in this era where with a critical role in tumour growth or progres- genetic testing is readily available. It delays and sion (i.e. tyrosine kinase). There are multiple types even potentially deprives patients of appropriate of targeted therapies available, including mono- treatment, and deterioration is often rapid without clonal antibodies, antisense inhibitors, and in- it. Moreover, we think that genetic testing could hibitors of tyrosine kinase. Obviously, many of have a key role for the treatment choice in the so these new drugs set up a selective pressure for tu- called frail patients (i.e. elderly and HIV-positive mour cells that can survive and proliferate in its patients) for whom the efficacy and especially the presence. The same basic principle seems to be toxicity profile are important aspects4,5. true for protein kinase inhibitors. The best under- However, one should keep in consideration standing of this problem at a molecular level that it will not be feasible to conduct randomized comes from studies on imatinib resistance in trials on each and every diagnostic test, and the Chronic Myelogeneous Leukaemia (CML) pa- economic value of such tests can be modelled us- tients carrying BCR/ABL fusion gene. These ima- ing decision analysis techniques tinib-resistant clones, consisting a single nu- The goal of this review is to provide informa- cleotide mutation in ABL Kinase domain (with tion (in terms of knowledge-base in genetics, eth- consequent amino acid substitution), are success- ical, social and economic) for the health profes- fully suppressed by second-generation Tyrosine sion about the genetic variations implicate in kinase inhibitors (i.e. Dasatinib, Nilotinib), still pharmacotherapy and the most commonly avail- active on almost all imatinib-resistant mutants8. able methods for their molecular detection. Similarly to imatinib, other two biological drugs (Gefitinib and Erlotinib) showed clinical ac- tivity in a subset of patients affected by Non Small Genetics Competencies Cell Lung Cancer (NSCLC). The mechanism of action for both drugs is the selective inhibitions of Needs to Detect Genetic Variations the kinase activity of epidermal growth factor re- in Pharmacotherapy ceptor (EGFR)9. Recently, it has been reported in Pharmacogenomic approaches have been ap- NSCLC patients that specific point mutation of plied to many existing therapeutic agents in an EGFR gene in tumour cells select Gefitinib-re- effort to identify relevant inherited variations that sponders’ patients (EGFR mutated), from non-re- may better predict patients’ response to treat- sponders (EGFR wild type)10. The availability of ment. Genetic variations, which can alter the pro- this kind of biomarkers is currently useful tool for tein expressions and/or amino acid sequence of predicting resistance to specific drug therapy. the encoded proteins, include nucleotide repeats, insertions, deletions, translocations and Single Current Genotyping Methodology Nucleotide Polymorphisms (SNPs). The technology platform needed for genotyp- Such genetic polymorphisms in drug metaboliz- ing is different; it does depend from type of mu- ing enzymes like the Cytochrome P450 family6; tation, acquired genetic change, or the analysis of transporters like Multidrugs Receptors-17; and inherited SNPs. This is due to the heterogeneity molecular targets, have been actively explored of the sample source. Either the tumour itself or with regard to functional changes in phenotype the sample may contain a large excess of wild (altered expression levels and/or activity of the en- type DNA, therefore, highly specific and sensible coded proteins) and their contribution to variable techniques are required to detect mutant tumour drug response. The following Table I describes genomes in a background of normal DNA. some clinically relevant examples of genetic de- Whereas, for inherited SNPs there is a copious of fects illustrating the relevance of PGx in optimiz- suitable methods for genotyping able to detect ing pharmacotherapy, as a way to enhance efficacy mutant allele either in heterozygosis or homozy- and safety. For example the new generation of an- gosis cells. Rational selection of the best meth- ticancer drugs have high specificity toward tumour ods to detect them is dependent from the cells, provide a broader therapeutic window with specifics aims of different laboratories11. 782 Knowledge and skills needs for health professions aboutpharmacogenomicstestingfield Knowledge andskillsneedsforhealthprofessions Table I. Most significative known genetic variants and their effect in pharmacotherapy. Polymorphism GENEa (nucleotide translation) Molecular effect Drug Effect on therapy Cytochrome P450 family Various polymorphism Decreased enzyme activity Various Inter-individual variability inpharmacokinetics TPMT2, 3A, 3C Various polymorphism Decreased enzyme activity 6-MP Thioguanine Hematopoietictoxicity UGT1A 28 TA repeats in 5’ promoter