Knowledge and Skills Needs for Health Professions About Pharmacogenomics Testing Field

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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 reduce 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 educational 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 activity 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 andskillsneedsforhealthprofessions aboutpharmacogenomicstestingfield

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 Decreased enzyme activity Irinotecan Neutropenia toxicity MDR1 (C3435T) Low expression Various Drug resistance TYMS 3 tandem repeats Increased enzyme activity 5-FU, Metatrexate Drug resistance DPYD IVS14+1G Decreased enzyme activity 5-FU, Metatrexate Neutropenia toxicity DHFR T91C Increased enzyme activity Metatrexate Drug resistance MTHFR (C677T) (A1298C) Decreased enzyme activity 5-FU, Metatrexate Toxicity c-KIT D860 N567K Constitutive signal activation Imatinib desensitizes activity in GIST K-RAS G12x G13D Inhibition of the tyrosine Cetuximab Desensitizes activity in colon-rectum kinase domain-binding drug Panitumomab carcinoma B-RAF V600E Inhibition of the tyrosine Vemurafenib Good response in melanomas kinase domain-binding drug Gefitinib Good response in NSCLC EGFR L858R Inhibition of the tyrosine Erlotinib kinase domain-binding drug BCR/ABL fusion gene t(9;22) BCR/ABL Constitutive signal activation Imatinib Good response in CML Dasatinib Nilotinib ABL T315I, M351T Inhibition of the tyrosine Imatinib Drug resistance in CML kinase domain-binding drug PML/RARα fusion gene t(15;17) PML/RARα Block of myeloid lineage All Trans Retinoic Good response in AML-M3 subtypes cells acid (ATRA) ADRB1 ADRB2 R389G G-protein altered beta-bloccants Desensitizes activity MHC class B 1 Several SNPs including HLA-B~5701 aplotype Abacavir Hypersensitivity r codon K751Q VKORC1 Many, VKORC1 haplotypes Associated with a higher/low Warfarin Variable anticoagulant effect including codon G3673A warfarin dose

Abbreviations: TPMT: thiopurine methyltransferase; UGT1A1: UDP-glucuronosyltransferase 1A1; MDR1: multidrug resistance 1; TYMS: thymidylate synthase; DHFR: Dihy- drofolate reductase; MTHFR = 5,10-methylene tetra hydrofolate reductase; EGFR: Epidermal Growth Factor Receptor; 5-FU: 5-fluorouracil; 6-MP: 6-mercaptopurine; AML:Acute Myeloid Leukemia; NSCLC: Non-Small Cell Lung Cancer; CML: Chronic Myeloid Leukemia; ADRB: adrenergic b-receptors; VKORC1: Vitamin K epoxide reductase complex 1; The present list is not meant to be whole comprensive. aGenes are available for genotyping test or under consideration for clinical diagnostics. 783 R. Di Francia, D. Valente, O. Catapano, M. Rupolo, U. Tirelli, M. Berretta

Current genotyping technologies can be divid- achievable by fully integrated systems using 96- ed into two major categories, depending upon or 384-well plate robotic processing such as 1G their ability to screen for new mutations or to Genetic analyzer by Illumina/Solexa (Cam- identify known mutations. In general, all geno- bridge, UK), SOLiD by Applied Biosystems typing platforms must fulfill two requirements: (Foster City, CA, USA) and Genome Sequencer 1) discrimination between alternative alleles (i.e. FLX by Roche Diagnostics (Brandfort, CT, mutant vs. wild type) and 2) detection of both al- USA). These new types of ultrafast DNA se- leles (i.e. mutant and wild type) in a DNA sam- quencers provide a consensus base accuracy of ple. The only platform able to fulfill both tasks in 99.99%. In almost all homogeneous assays, a single step assay is the Matrix-Assisted Laser DNA amplification is required. Non-PCR-based Desorption/Ionization Time of Flight (MALDI technologies such as the Ligase chain reaction, TOF). However, the technological platforms may Rolling Circle Amplification (RCA) and be “homogeneous” if based on a single tube reac- Invader® assays (Third Wave Technologies, tion, or “heterogeneous” when involving both a Madison, WI, USA) are able to genotype direct- liquid and a solid phase (i.e. DNA Chip). The ly from genomic DNA. most-used platforms for the detection of known Heterogeneous methods such as DNA chip- SNPs can be operatively classified into two ma- based microarray, Golden Gate® assay and mass jor categories (Table II): 1) homogeneous; 2) het- spectrometry genotyping technologies, are the erogeneous. latest development in the genotyping arena, but The advantages of homogeneous methods in- these newer technologies are currently less wide- clude reduced risk of cross-contamination, time- ly used in the clinical laboratory setting than effectiveness and practicability. Traditional tech- cheaper PCR-based methods. Additionally, costs niques for SNPs genotyping detection such as for DNA chip assay are projected to be high and Single-Strand Conformational Polymorphism results interpretation will remain strictly depen- (SSCP) and Restriction Fragment Length Poly- dent on the availability of highly qualified and morphism (RFLP) have now been largely re- well-trained personnel. Here, we highlight some placed by high-throughput methods that are able of the most popular technologies currently used to generate higher numbers of data, and are easi- in specialized laboratories, focus on the transition er to automate. High-throughput processing is from research setting to clinical laboratory as previously discussed by other Authors12. In conclusion, no single genotyping platform Table II. Current methods for genotyping at molecular level. stands out as ideal; the methods listed in Table II Methods for detection and screening for show that many overlaps and attempts to com- unknown mutations pare them may result difficult and unproductive. Detection and screening Conventional sequencing Ethical, Social and Denaturing-HPLC Economics Competencies Denaturing gradient gel electrophoresis (DGGE) As genomics-based technologies are widely Heteroduplex DNA assay (melting curve) introduced in clinical laboratories testing setting, High throughput sequencing Single strand conformation polymorphism (SSCP) the risks of mishandling or misinterpreting data from patient’s sample analyses becomes a signif- Methods for detection of known mutations icant consideration with especially dramatic con- Homogenous sequences where the test becomes commercially Fluorescent probe by Allelic Discrimination available to the public13 (Hyb Probe® TaqMan®, Beacons® Scorpions®) Generally, genotyping is performed either High Resolution Melting (HRM) by custom service laboratories or academic Invader® assay Locked Nucleic Acid (LNA) probe referenced laboratories, as well as by using Peptide nucleic acid-mediated Clamping PCR commercial kits (when available). In the USA, Pyrosequencing diagnostics products are regulated by the Food Heterogenous and Drug Administration (FDA), whereas di- Gene Chip technology agnostic services are under the rules of the Golden Gate® assay Clinical Laboratory Improvement Act (CLIA). Maldi-TOF Mass Spectroscopy Oligo ligation assay (SNPlex®) In Europe this field is covered by in vitro Di- agnostic (IVD) directive, without a distinction

784 Knowledge and skills needs for health professions about pharmacogenomics testing field , ient care .php/NCHPEG- esign, ogenetic fits and potential fits e, education, and resources and tools such as OMIM ih.gov/Genbank/index.html); and iii) ih.gov/Genbank/index.html); enomic information in their labels are many of these database and an attempt many mics/default.htm) and European Medicine mics/default.htm) ge of aims and scopes including: i) those pre- data resource used in Pharmacogenetic testing recommendations based on the results studies and its impact at the societal level as well that of the studies and its impact at the societal level patient individual • drug therapy Interpret the results of pharmacogenetic testing, and make Knowledge Skills Issues listed derives, in part, from National Coalition for Health Professional Education Genetics (//wikigenetics.org/index Issues listed derives, testing and recording of genetic information (e.g., privacy, the potential fortesting and recording of genetic information (e.g., privacy, genetic discrimination in health insurance and employment)patient information language Adopt a code of conduct in patient treatment that is free racial • • by professional organizations, Identify appropriate resources offered and communities services, including potential risks of discrimination and risks of pharmacogenetic information for individuals, family members, family and risks of pharmacogenetic information for individuals, risks of using health insurance for payment pharmac along with other clinical information • identify the epidemiologic implications of pharmacogenetic/genomic identification of genetic predispositionidentification and uncovereddrug response are investigate rather is used but 100 percent reliability, testing it will not have and data interpretation that will influence pat technology, team of health professionals interdisciplinary • information obtained from pharmacogenetic/ Critically evaluate • Understand the increased liability that accompanies access to detailed and security of patient health records• Maintain the confidentiality ethnic, and religious bias disciplines, or institutions • and social issues related to pharmacogenetic Appreciate the ethical, legal • information and services to patient cultur Tailor • limitations, Understand the potential physical and/or psychosocial benefits, • Discuss costs of pharmacogenetic services, bene • Basic concepts • Nomencalature (genetic glossary)• respons to drugs Most recently SNPs causing intervariability • disease in preventing The role of genetic factors between clinical diagnosis of disease andThe difference • in specialized laboratories• Genomic tests available • to detect pharmacogenomics tests Current methods available • information about Pharmacogenomics to find where/how Know • and association between genomic variation Understand how • in Explain basic concepts of probabilities genetic factors • all other clinical Understand that pharmacogenetic testing is like • Seek coordination and collaboration with an • problems that may be related to genetic Identify drug therapy test is not repeated unnecessarily the past so that a specific in of disease maintenance of health and development • when a pharmacogenetic test has not been done even pharmacogenetic testing undergone Identify patients who have variability, genomic clinical trials and identify limitations in study d clients and colleagues • Current information about pharmacogenomics for self, Basic competencies (in terms of knowledge and skills) in Pharmacogenomics for health profession. Basic competencies (in terms of knowledge implications and economic Ethical, social Genetics Table III. Table Agency (www.emea.europa.eu/pdfs/human/ich/43798606en.pdf); ii) those provide a genetic row data such as Genbank (www.ncbi.nlm.n a genetic row ii) those provide (www.emea.europa.eu/pdfs/human/ich/43798606en.pdf); Agency drugs with pharmacog The table lists of FDA-approved or Orphanet. (www.orpha.net). (www.ncbi.nlm.nih.gov/sites/entrez?db=omim/) Appendix to Table III: Table Appendix to Principles_of_Genetics_for_Health_Professionals) and in part from, databases available to the genetic community with a wide ran Principles_of_Genetics_for_Health_Professionals) and in part from, databases available Administration (www.fda.gov/cder/geno and drug such as Food policy senting guidelines on pharmacogenomics related to government Other types of large-scale (www.sanger.ac.uk/Software/Pfam). structure and annotation such as Pfam higher level those providing and disease/gene information Base (www.pharmgkb.org/index.jsp) include publication databases such as Pharmacogenomics Knowledge between Clearly there are overlaps at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. available and unproductive. may be difficult detailed degree them to any at categorize

785 R. Di Francia, D. Valente, O. Catapano, M. Rupolo, U. Tirelli, M. Berretta between commercial products (used by labora- and the patients themselves. One can predict, tories) and diagnostics service. In both circum- however, that health insurance companies will be stance, a voluntary list of international labora- very interested in patient PGx testing to docu- tories (with CLIA certification in the US and ment the proper dosing of expensive prescription CE mark in Europe) that perform genetic tests drugs and hence reduce the occurrence or risks of can be found on the National Institute of adverse drug reactions. It will be interesting to Health-funded website named GeneTests™ see whether insurers will consider PGx testing to [http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab be a cost-effective alternative to the current trial- ?db=GeneTests], although only a small minority and-error approach to dosage regulation. Howev- of genetic tests listed on this site are PGx tests. er, if the detection of these genetic variants is Clinical laboratories may develop and validate routinely incorporated either into clinical practice tests in-house (“home-brew”) and perform them or large clinical trials, knowledge concerning the as a laboratory service; which may further reduce predictive value of PGx which will eventually the cost of analysis11,14. enable the individualization of optimized therapy Pharmaceutical and Biotech companies fre- could be gained17. However, we still need a pre- quently develop their own clinical pharmacoki- cise demonstration that PGx tests offer an added netic and pharmacodynamic tests for new drug value, in terms of relative cost and benefit. studies. They are required to have validated as- Furthermore, trials evaluating the pharma- says for human clinical phase III trials complying coeconomic impact of genotyping testing before with current Good Clinical Practice guidelines therapy will likely provide answers for policy for FDA or EMEA submission purposes. This in- making in the merging of PGx testing into clini- volves testing patients as a potential recipients cal practice. The primary aim of a cost-effective- before the administration of the drug. This differ- ness analysis is to provide sufficiently robust in- ence poses an ethical dilemma for pharmaceuti- formation for decision-makers to allocate re- cal companies, especially if inadequate testing sources to healthcare interventions. Overviews of excludes some patients who might benefit from cost-effectiveness studies on PGx technologies receiving the drug or, conversely, long-term dos- are now available18. A relevant example is the ing continues with a treatment that does not have National Institute for Health and Clinical Excel- good clinical efficacy15. Pharmaceutical compa- lence (NICE). NICE forms a Diagnostic Adviso- nies should be involved with the initial develop- ry Committee, which is willing to stimulate Phar- ment of PGx assays because they have the prima- ma and Academic communities to produce a ro- ry data and information necessary for this stage bust set of data, including design and data source of assay development. However, this assay devel- in economic models of healthcare19. Only few opment activity should be transferred to outside studies have addressed the cost-effectiveness of referenced laboratories, clinical core laboratories pharmacogenomics testing implication in clinical in academic health centers, or established Clini- practice18. For example van den Akker et al, in- cal Research Organizations when research and cluded thiopurine S-methyltransferase (TPMT) development transit into clinical application be- genotyping prior to 6-mercaptopurine treatment cause these independent external sites are able to in paediatric Acute Lymphoblastic Leukaemia handle this function16. (ALL); the mean calculated cost from 4 Euro- Drug selection based on genetic assessment pean countries was € 2100,00 per life-year con- may be considered confidential information. Cur- sidering low myelosuppression-related hospital- rently, PGx testing may provide detailed genetic ization; the cost for genotyping of TMPT muta- information necessary for health professions to tion averaged around € 150,0020. Early outline of prescribe the correct drug and its dose. The skills genotyping cost for “home brew” pharmacoge- of health operator must be orientated to maintain nomic tests averaged about € 20,00 per SNP14. the confidentiality and security of patient’s health records. In this field, the clinical laboratories could be the most proficient means to protect pa- Conclusions tient/physician confidentiality. Reimbursement or payment for genetic testing The potential is enormous for pharmacoge- is another topic of considerable consequence that nomics to yield a powerful set of molecular diag- is already creating controversy among health nostics that will become routine tools by which maintenance organizations, healthcare providers, pharmacists and physicians select the proper

786 Knowledge and skills needs for health professions about pharmacogenomics testing field medications and doses for each individual pa- future implementation of the methods for geno- tient. Instead of starting patients on the “average typing of variants influencing therapy will result dose” that was found to be safe and effective in in personalized treatments and eventually, in most patients in large clinical trials, pharmacoge- shifting the clinical benefit from disease relapse nomics has the potential to provide patient-spe- towards disease eradication. Therefore, it is fun- cific data upon which the selection of drugs and damental that pharmaceutical and biotechnology doses can be individualized and optimized. Using companies join together, in order to develop an the amount of DNA that can be isolated from just extensive study the standardization method to few milliliters of blood, it is possible to deter- validated tests suitable for routine diagnostics in mine thousands of genotypes, even with current pharmacogenomics. technology, described above. So, taken together, In summary, with the increasing number of the process will be to collect a single blood sam- novel genetic markers being identified and vali- ple from each patient, submit an aliquot of the dated, pharmacogenomics will make the practice sample to a reference laboratory for analysis of a of health profession and medicine should be less panel of genotypes, and test for those established an art and more a science. to be important determinants of drug disposition and effects. The results of this specific panel of –––––––––––––––––––– genetic variants would be electronically deposit- Acknowledgements ed into a secured database, into and out of which data can be accessed only with the patient’s au- The Authors are grateful to Dr. O. Barletta from the thorization (to her/his health care professionals). “Italian Association of Pharmacogenomics and Molec- ular Diagnostics” for the invaluable bibliography re- The results of these tests will not be simply a list search and Mrs. Paola Favetta for her expert assistant of gene SNPs, but rather a report formatted and in the preparation and correction of the manuscript. interpreted according to the patient’s diagnosis and treatment options. For example, the report could be a recommended algorithm for the selection of anticoagulation, starting with those most References likely to be effective and well tolerated, based on the patient’s genotypes for the panel of genes 1) BEAULIEU M, DE DENUS S, LACHAINE J. 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