5^th ESPT CONGRESS on Precision Medicine and Personalised Health Seville, Spain - 16/18 October 2019

PHARMACOGENETICS OF CUTANEOUS ADVERSE DRUG REACTIONS

M. Pirmohamed¹

¹Wolfson Centre for Personalised Medicine, Unviersity of Liverpool

Adverse drug reactions (ADRs) are a major clinical problem accounting for a great deal of morbidity, mortality and are a drain on healthcare resources. ADRs can generally be divided into on-target and off target reactions. Both types of ADRs have a genetic predisposition, but the quantitative contribution of genetic vs. non-genetic factors varies with the type of reaction, the drug implicated and the patient’s clinical co-morbidities. Cutaneous ADRs fit into the category of off-target reactions and are typically immune-mediated. They vary in phenotype from the relatively mild maculopapular exanthem to the very severe Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN), which can be associated with 10-30% mortality. The role of HLA in predisposing to cutaneous ADRs has been particularly fertile in identifying new associations, often through genome wide technologies. Many new HLA associations have been identified with cutaneous ADRs, two of which are in clinical practice (HLA-B*57:01 for abacavir hypersensitivity, and HLA-B*15:02 for carbamazepine-induced Stevens-Johnson Syndrome). Importantly, HLA associations even with the same drug can vary across different ethnic groups. For example, HLA-B*15:02 predisposes to carbamazepine-induced SJS/TEN, but only in patients from SE Asia. In Europeans, HLA-B*15:02 has a population prevalence of <0.01%, and another HLA allele, HLA-A*31:01, is more important, predisposing to a variety of cutaneous phenotypes (not just SJS/TEN). Investigation of the genomic basis of ADRs is not only important for development of predictive genetic testing, but can also provide insights into the mechanisms of ADRs, for example in determining how antigens derived from the drug/metabolites lead to recognition by the immune system as being foreign leading to T cell proliferation and the occurrence of a skin rash of varying severity.

PHARMACOGENETICS OF DRUG-INDUCED LIVER INJURY (DILI)

A. Daly ¹

¹Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

Drug-induced liver injury (DILI) is a rare but serious adverse reaction with certain widely prescribed drugs. It is also an important cause of drug attrition during drug development. Using genome-wide association studies, highly significant associations with particular HLA genotypes have been detected for idiosyncratic DILI with a number of specific drugs, for example flucloxacillin, co-amoxiclav and terbinafine. Examples of these associations and possible underlying mechanisms, including how these may relate to reported HLA associations for other types of adverse drug reactions, will be considered. Not all forms of idiosyncratic DILI show HLA gene associations. Genes relevant to the innate immune system and to drug disposition appear to represent additional risk factors for DILI but, as with the associations involving HLA, risk factors are mainly but not exclusively dependent on the individual drug. In particular, a nonsynonymous polymorphism in PTPN22 appears to be a more general risk factor for DILI but this does not extend to all drug causes, most notably flucloxacillin-related DILI. The genetic associations we have seen, involving both HLA and non-HLA genes, provide new insights into the underlying mechanisms for idiosyncratic DILI and may assist in the development of improved strategies for its prediction and diagnosis.

AN INITIATIVE FOR EARLY DRUG DISCOVERY WITH A PHARMACOGENOMIC PERSPECTIVE FROM GALICIA

A. Carracedo ², M. Loza ¹

¹Kaertor Foundation. Biopharma Group. University of Santiago de Compostela.

²Kaertor Foundation. Genomic Medicine Group. University of Santiago de Compostela.

Open Innovation has transformed early drug discovery into a highly multidisciplinary and delocalized scenario, by enabling all players integrated in the network to share knowledge in real time throughout the entire health ecosystem. Pharmaceutical companies now operate through open innovation departments in which the top experts worldwide connect research on the mechanisms of disease through these pipelines. It is a new world where the creation of ‘real’ innovation in drug discovery is possible.

This scenario represents a great opportunity for drug discovery R&D to connect biomedical research in disease mechanisms with drug development and patients.

Worldwide there are already several initiatives in Open Innovation in drug discovery, such as Apollo Therapeutics in the UK, FlandersBio in Belgium, the Centre for Drug Research and Development in Canada and the Medicon Valley Alliance in Denmark/Sweden. With the same idea our plataform Innopharma-Kaertor, part of the EU OpenScreen, was promoted 5 years ago. Its objective is to provide expert knowledge in drug discovery that contributes to transform, guide and accelerate research projects on new therapies for unmet medical needs. Also, it serves as an instrument to connect basic investigation in drug discovery with the pharmaceutical industry in an open innovation context. We regularly launch calls for projects of drug discovery where biomarkers for disease stratification and drug response are a priority for selection. An example is the I2D2 initiative (http://kaertorfoundation.org/en/i2d2/) that will be described in the presentation.

Genomics is offering new possibilities for drug discovery not only for the identification of new targets or for the advances in personalized medicine but also for the introduction of new tools such as DNA-encoded chemical libraries that are accelerating drug screening or the possibilities of CRISPR-Cas9 strategies that has been shown effective for genome-scale loss of function screens in mammalians cells and that has been used to identify genes required for drugs or toxins to trigger cell death.

TOWARDS THE IMPLEMENTATION OF PHARMACOGENOMICS IN PSYCHIATRY

D.J. Müller ¹

¹Department of Psychiatry, University of Toronto

Introduction

Antidepressants and antipsychotics are essential components in treatment of most psychiatric disorders. Unfortunately, lengthy trials are often required before the optimum medication treatment is found. The underlying reasons for this large inter-individual variability in terms of treatment response are not fully understood. Important factors that influence drug dose, response and adverse effects include age, gender, patient compliance, type of symptoms, co-morbidity, and to a significant extent: genetic factors.

Methods

This presentation will 1) review the clinical validity and utility of pharmacogenetic studies in psychiatry; 2) discuss current guidelines and recommendations (e.g., CPIC, DPWG); and 3) present results of own studies evaluating treatment outcome in psychiatric care after genetic information (e.g., CYP2D6 and CYP2C19) was provided to more than 350 physicians.

Results

There is growing consensus among experts that genetic information, when adopted thoughtfully, will result in improved treatment for many psychiatric gene-drug pairs. However, utility remains restricted to specific gene-drug pairs and multi-gene test require specific validation.

Our own research has shown that variation in genes - mainly involved in the metabolism of psychotropic drugs (pharmacokinetics) - are associated with plasma drug levels, treatment response, and onset of adverse effects.

With respect to our preemptive genetic testing program in more than 11,000 patients, we received supportive responses from physicians who enrolled patients in our study. Notably, the vast majority of patients reported improvement in patient treatment outcome.

Discussion

There is emerging evidence that preemptive genetic testing will improve treatment for numerous gene-drug pairs commonly used in psychiatry. While pharmacogenetic testing has become readily available and is offered routinely in many institutions of the world, both care providers and patients are poorly prepared to these new opportunities and proper education remains of utmost importance. This presentation will provide an important update in this regard and congress participants are encouraged to ask questions and to join the discussion.

G-NOMIC PHARMACOGENETICS SOFTWARE AND DRUG INTERACTIONS

A. Sabater ¹

¹Eugenomic

g-Nomic,is a pharmacogenetics interpretation software that analyzes globally a prescribed medication taking into account the personal background genetics, drug-drug interactions, lifestyle, nutritional supplements, inhibitors, inducers and other risks to analyze primary or secondary metabolism pathways. G-Nomic provides a set of recommendations describing the suitability of a given combination of drugs for each patient according to their genes and polymedication. G-Nomic is updated monthly. A query on the g-Nomic software begins with entering the medication by either their common or commercial name. Non-pharmacological substances can be also added or selected under “lifestyle habits”.

UNRAVELING CYP2D6 GENOTYPING: THE OPTIMAL STRATEGY

C. Nofziger ¹

¹Pharmgenetix, Gmbh

Because a relatively high percentage (˜25%) of clinically prescribed drugs are substrates for CYP2D6, accurate determination of its genotype for phenotype prediction is essential. However, this is challenging due to its inherent genetic variation (at least 138 different star alleles have been catalogued to date, not including suballeles), copy number variation (duplications and deletions) and hybrid formation with its highly homologous pseudogene, CYP2D7. Consequent to its extensive polymorphic nature, there is no one single method to date that is able to accurately capture CYP2D6 diplotype. Rather, a combination of highly optimized techniques is required to determine i) CYP2D6 copy number, ii) the identity and allele specificity of any functionally relevant genetic variations within those copies and iii) the presence of hybrid structures and any genetic variation within them that may interfere with diplotype determination.

FUNCTIONAL CHARACTERISATION OF KNOWN AND UNKNOWN CYP2D6 VARIANTS USING A CELL-BASED IN VITRO SYSTEM

S. Vanoni ², G. Scantamburlo ², M. Paulmichl ¹, C. Nofziger ²

¹Department of Personalized Medicine, Humanomed / Klagenfurt, Austria.

²Pharmgenetix GmbH / Niederalm-Anif, Austria

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene that metabolizes around 25% of the currently marketed drugs. While more than 200 haplotypes have been reported for this gene, only around 75% of them have a defined function. Therapeutic drug monitoring is one way to determine CYP2D6 activity, but this technique is not specific for the enzyme. Moreover, it is near impossible to determine the activity of rare haplotypes since they usually occur in uninformative diplotypes. We have developed a cell-based in vitro functional assay which allows for the determination of individual CYP2D6 haplotype function.

ASPECTS OF MOLECULAR ANALYSIS FOR PERSONALIZED THERAPY

D. Kasper ¹

¹Agena Bioscience

The use of liquid biopsies to analyze circulating tumor cell (CTCs) and circulating tumor DNA (ctDNA) in the blood of patients with cancer has received enormous attention because of its obvious clinical implication for personalized medicine.

Tumor cells release cell-free DNA (cfDNA) into the blood, but the majority of circulating DNA is often not of cancerous origin. Therefore, the greatest technical challenges are a) the identification of very low amounts of ctDNA in blood samples with variable excessive amounts of cfDNA, b) the detection sensitivity and c) the relevant panel of cancer-specific genomic aberrations. These aspects will be discussed.

LIQUID BIOPSY TO PERSONALIZE LUNG CANCER TREATMENT: OVERCOMING THE CHALLENGES

P. Lamy ¹

¹Imagenome-Génétique des Cancers, Institut d’Analyse Génomique, Inovie, Montpellier, France

Non-Small-Cell Lung Cancer (NSLC) is an iconic example of the generalization of somatic mutation detection in tumor DNA for patient’s treatment personalization. At time of diagnosis, if the testing has shown epidermal growth factor receptor (EGFR) mutations (reflex testing), then treatment with EGFR inhibitors could be prescribed. However, reflex testing for EGFR of NSCLC patients is not always done. There are also some issues about the best way to get sample between endoscope biopsy, core biopsy and fine needle aspiration Moreover all biopsies are not always informative due to small samples or samples with a low percentage of tumor cells. Finally, some patients cannot be biopsied because of bad condition. In the IFUM study, it has been shown EGFR mutation was not determined in 19% of patients for all these reasons.

In patients treated by EGFR tyrosine-kinase inhibitors EGFR-TKIs, disease will progress in most patients around 10 months of treatment. At the time of progression, 60% of patients present an EGFR T790M mutation. The presence of this variant reduces binding of first and second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, and thereby reduces EGFR pathway inhibition. In this setting the number of patients that can be biopsied is even more low. The results of the AURA3 trial (a trial comparing the efficacy of osimertinib (a third generation EGFR-TKI binds irreversibly EGFR mutants) and standard therapy in patients with T790M-positive advanced non–small-cell lung cancer) confirm the feasibility of detection EGFR T790M mutation from plasma circulating tumor DNA (ctDNA) samples.

With the development of multiplex genomic analysis, and the discovery a DNA test from a simple blood draw give results that are highly accurate and specific to a given patient, cell-free ctDNA analyses are now routinely used in clinical setting and thereby can radically change a patient’s course of care. This approach, less invasive than a tissue biopsy, could give important information on the tumor genetic content if pre-analytical and analytical conditions are controlled. Here we present the challenges we must face to analyze ctDNA in clinical laboratories.

PERSONALIZING TAXANE TREATMENT: FROM GENETIC VARIANTS TO CONCOMITANT MEDICATION

C. Rodriguez-Antona ¹

¹Spanish National Cancer Research Centre (CNIO)

Technologic advancements in genomics are contributing to a better understanding of human genetics and to the identification of variants associated with drug response, which can provide the basis for a more efficient and personalized medicine. In oncology, intrinsic and acquired resistance to systemic therapies and severe drug-induced toxicities are common, representing major obstacles for improving the survival and quality of life of cancer patients. Here, using taxanes as an example in cancer, genetic markers of drug toxicity will be discussed together with the study approaches applied and challenges found. Current knowledge derived from GWAS and next generation sequencing will be presented, and results regarding the role of CYP3A4 defective variants and EPHA gene variation as risk factors for taxane-induced neuropathy will be discussed. However, genetic markers cannot fully explain the toxicity observed in patients. Drug-drug interactions are an important source of drug response variation; data regarding the impact of concomitant medication on taxanes toxicity will also be presented. On the whole, technology advancements in genomics support pharmacogenetic progress, however, combination of genetic and environmental factors will be crucial for an accurate prediction of drug toxicity and response and for the advance of personalized medicine.

UPDATE ON DPYD TESTING FOR SAFER FLUOROPYRIMIDINE THERAPY

L.M. Henricks ¹

¹Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands

Fluoropyrimidines, including 5-fluorouracil and capecitabine, have been in use for over sixty years and are among the most commonly used anticancer agents, used by approximately two million patients worldwide yearly. While these drugs are highly valuable treatment options, fluoropyrimidine-related toxicity remains a major clinical problem.

Risk of fluoropyrimidine-related toxicity is significantly increased in patients with reduced activity of the metabolic enzyme dihydropyrimidine dehydrogenase (DPD). This (partial) DPD deficiency is often the result of single nucleotide polymorphisms (SNPs) in DPYD, the gene encoding DPD.

In a large prospective trial, performed in seventeen hospitals in the Netherlands, we included 1100 patients about to start with fluoropyrimidine-based chemotherapy. All patients were screened for four DPYD SNPs before start of treatment. Carriers of a DPYD SNP received a fluoropyrimidine dose reduction of 25-50%, with the aim to reduce risk of severe toxicity in these DPD deficient patients. We showed that this prospective DPYD screening improved patient safety. Next to this, DPYD screening was also shown to be cost-saving, as dose-individualization based on DPYD genotype reduces costs for hospitalization and treatment of side effects.

Based on the findings of this study, we recommend implementation of DPYD screening as standard of care in all fluoropyrimidine-treated patients.

PGX AND TAMOXIFEN THERAPY IN BREAST CANCER: AN UPDATE

M. Schwab ¹

¹Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and Department Clinical Pharmacology, University Hospital Tuebingen, Germany

Variation in drug disposition and response among breast cancer patients is a major concern. Estrogen-receptor (ER)-positive breast cancer accounts for 75% of diagnosed breast cancers worldwide. There are currently two major options for adjuvant treatment: tamoxifen and aromatase inhibitors. Breast cancer pharmacogenomics (PGx) research has led to fundamental discoveries in the last years regarding the question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome of tamoxifen in patients with early postmenopausal (ER)-positive breast cancer. Tamoxifen PGx is an excellent example to demonstrate (i) the clinical impact of pharmacokinetic alteration of metabolites by genetic polymorphisms with consequences on patient outcome, (ii) pitfalls of PGx research through missing consideration of the germline and tumor genome, and (iii) challenges in translation of PGx recommendations into clinical practice. Using strict clinical and genotype eligibility requirements, CYP2D6 genotype is associated with a higher risk of recurrence in postmenopausal women with breast cancer and tamoxifen therapy, therefore indicating up front testing for the CYP2D6 genotype prior tamoxifen therapy in postmenopausal women. In summary, based on the well-known metabolism and drug action, tamoxifen has been in the spotlight of PGx investigations within the past decade. Future goal is to identify additional biomarkers that can predict tamoxifen outcome and facilitate personalized treatment schemes in order to avoid drug failure.

PERSONALISED MEDICINE OF PROSTATE CANCER: IMPACT OF GENOMIC BIOMARKERS

C. Sipeky ¹

¹University of Turku

Prostate cancer (PC) is globally the second most common cancer in men (GLOBOCAN 2018). In PC research one of the biggest current challenges is assessing risk of developing PC during lifetime (1). The second challenge is differential diagnosis and prognosis of aggressive versus non-aggressive PC (2). The third and most important challenge is to optimize existing treatments and develop new treatments for advanced disease (3). Applicability of emerging genetic biomarkers in these three key areas will be discussed.

(1) Susceptibility to PC is likely to be due to a mixed model of rare variants with moderate effect size (e.g. BRCA1/2, HOXB13, CHEK2, PALB2) and common risk loci with small effect size (GWAS hits). In addition, combining the identified over 160 PC risk hits into a polygenic risks core offers the opportunity for accurate prediction of PC life-time risk, especially combined with age and prostate-specific antigen (PSA).

(2) Limited number of clinically actionable genomic biomarkers are known that can predict risk of aggressive PC at the time of diagnosis. New ways of understanding synergistic genetic interactions result in discovery of innovative compound genetic biomarker for aggressive PC. Another approach is to look beyond genes and explore regulatory elements of the intergenic regions, which in turn promote oncogenesis and result in biomarkers for aggressive PC.

(3) Metastatic castration resistant prostate cancer (mCRPC) is one of the most common causes of male cancer deaths. Although docetaxel chemotherapy is used for more than 15 years to treat mCRPC, genomic biomarkers to optimize treatment efficacy, toxicity are still not well understood. Current state-of-the-art of pharmacogenomic biomarkers in docetaxel treatment of PC will be highlighted. Newest clinical markers for personalized treatment of PC are the genes in DNA damage repair (DDR) pathway targeted by Poly (ADP-ribose) Polymerase (PARP) inhibitors. Rationale to use PARP inhibitors to treat PC is to target the dependence of DDR gene mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. Ongoing phase 3 trials are expected to shed more light on the applicability of DDR gene mutations as predictive markers of response to PARP inhibitors.

LIQUID BIOPSY: A NEW DIAGNOSTIC CONCEPT IN ONCOLOGY

K. Pantel ¹

¹Institute of Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg Eppendorf, Hamburg, Germany

The analysis of circulating tumor cells (CTCs) and tumor-derived products (DNA, RNA, proteins) in blood may provide clinically relevant information as “liquid biopsy” and provide new insights into tumor biology. Various technologies have been developed over the past 10 years which include label-dependent assays based on the expression of tumor-associated cell surface antigens and label-independent assays based on physical properties of tumors cells distinct from the surrounding leukocytes (Pantel & Alix-Panabieres, Nature Rev Cancer 2019). After detection CTCs can be further analyzed at the DNA, RNA and protein level to obtain global information on tumor biology and targets relevant to cancer therapy (Pantel & Alix-Panabieres, Nature Rev. Clin. Oncol. 2019). In particular, microRNAs control various genes and pathways that impact the biology of tumor cells (Anfossi, Bababayan, Pantel, Calin, Nature Rev. Clin. Oncol. 2018).

Liquid biopsy analyses with validated platforms provides reliable information on prognosis and may serve to identify therapeutic targets or mechanisms of resistance on metastatic cells. Metastatic cells might have unique characteristics that can differ from the bulk of cancer cells in the primary tumor currently used for stratification of patients to systemic therapy. Moreover, monitoring of blood samples before, during and after systemic therapy (e.g., chemotherapy or targeted therapy) might provide unique information for the future clinical management of the individual cancer patient and might serve as surrogate marker for response to therapy.

In conclusion, the analysis of CTCs can be used to improve the management of individual cancer patients and contribute to the vision of personalized medicine. CTCs are complementary to other liquid biopsy biomarkers such as ctDNA or exosomes (Alix-Panabieres & Pantel, Cancer Discovery, 2016; Bardelli & Pantel, Cancer Cell 2017). Validation of liquid biopsy assays is essential and currently performed by the EU/IMI consortium CANCER-ID (www.cancer-id.eu).

EGFR AND LUNG CANCER

R. Danesi ¹

¹University of Pisa

EGFR is mutated in 20-25% of non-small cell lung carcinoma (NSCLC) patients; common and rare mutations involve exon 19 deletion and insertion, exon 20 insertion, L858R, T790M, C797S, L861Q, S768I, G719A/C/S/D, E746_A750del, E746_E749del, and S752_I759del. While the role of activating (i.e., exon 19 deletion and L858R) and resistance mutations (i.e., T790M and C797S) has been defined and associated to specific drug treatments, the impact of rare mutations on the clinical course of the disease is less clear. For these reasons, the molecular profiling of tumors is imperative and the use of mini-invasive procedures to support diagnosis and perform disease monitoring is clearly expanding. Liquid biopsy has emerged as an alternative to tissue specimens as a source of nucleic acids for the diagnosis and management of EGFR-mutant NSCLC patients. The use of circulating free DNA (cfDNA) has been recently introduced in clinical practice owing to the improvement in molecular diagnostic platforms and the availability of quality control programs, improving the identification of EGFR druggable mutations for diagnosis and monitoring the response to target therapy. EGFR-dependent (T790M, C797S) and independent (MET amplification, KRAS, PI3KCA, BRAF) mechanisms of resistance to EGFR-tyrosine kinase inhibitors (TKIs) can be evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e. digital droplet PCR, NGS), allowing the switch to other therapy. Therefore, the value of liquid biopsy in EGFR-mutated NSCLC has received clinical validation as a non-invasive method able to detect the molecular dynamic changes produced by the selective pressure of treatments and to capture tumor heterogeneity better than tissue biopsy and may be used to guide treatment strategy.

CIRCULATING PREDICTIVE BIOMARKERS OF RESPONSE TO IMMUNOTHERAPY

M. Del Re ¹

¹University Hospital of Pisa

Immunotherapy has improved the clinical outcome of several tumours, including cancers poorly responsive to chemotherapy. PD-L1 assessment in tumour tissue (i.e., NSCLC) allows to identify a patient population with higher likelihood of response with respect to chemotherapy. However, changes in the activity of signal transduction patways (i.e., MAPK) may affect PD-L1 levels, thus impairing its predictive value if assessed on a single-tissue biopsy. For these reasons, the interest of the scientific community is turning towards other potential biomarkers. Moreover, the biomarkers assessment in primary tumour at the time of diagnosis may not inform on changes which will occur during clonal evolution and selective pressure of treatments. Studies on circulating biomarkers are increasing in number because they can provide important information on dynamic response to treatment. Although they are not aimed at selecting patients for the administration of anti-PD-1/PD-L1 treatments, they have the potential to provide relevant information on clinical outcome.

”MOLECULAR CHARACTERIZATION OF CIRCULATING TUMOR CELLS: AN UPDATE ON TECHNOLOGIES AND CLINICAL POTENTIAL”

E. Lianidou ¹

¹Professor of Analytical Chemistry – Clinical Chemistry, Analysis of Circulating Tumor Cells lab, Dept of Chemistry, University of Athens, 15771, Athens, Greece

Liquid biopsy provides a valuable source of biomarkers through simple and minimally invasive serial blood draws and represents a highly dynamic diagnostic, prognostic and theranostic tool for the management of cancer patients. Circulating tumor cells (CTCs) are major players in liquid biopsy and their presence has been linked to worse prognosis and early relapse in numerous clinical studies. CTC enumeration and molecular characterization offers an exciting approach to monitor the efficacy of systemic therapies in real-time, unravel the biology of cancer cell dissemination, understand resistance to established therapies and identify gene targets and signaling pathways relevant to therapeutic interventions. Single-cell CTC analysis is a powerful tool to understand tumor heterogeneity and the mechanisms involved in cancer progression with potential implications for improving treatment strategies. This overview is focused on the latest developments in the detection and molecular characterization of CTCs, and their clinical applications in many types of cancer.

GRAFT-DERIVED CELL-FREE DNA AS A MARKER FOR DETECTION OF REJECTION AND GRAFT INJURY AFTER SOLID ORGAN TRANSPLANTATION

M. Oellerich ¹

¹Institute for Clinical Pharmacology, University Medicine Göttingen, Germany

Biomarkers are needed in organ transplantation to achieve personalized immunosuppression and reduce premature graft loss. The 10-year survival rates for kidney, liver and heart transplants are only 55-58%, at least in part due to the lack of reliable noninvasive rejection biomarkers. Immunosuppressive drug monitoring can reduce toxicity but is a poor predictor of graft damage. In kidney transplant patients, increased plasma creatinine may also be due to exsiccation or the use of ACE inhibitors. By the time a rejection-related increase in plasma creatinine is evident, a significant degree of kidney tissue damage has already occurred. The current standard of care is to confirm rejection episodes by biopsies; with uncommon but potentially serious complications. The fact that organ transplants are also genome transplants allows for the use of graft-derived cell-free DNA (GcfDNA) as a liquid biopsy to perform repeated, noninvasive monitoring for allograft injury; the clinical validity of which has been documented in more than 48 independent studies. GcfDNA has been shown to detect acute or chronic rejection episodes at an early, actionable stage; including asymptomatic graft injury which can lead to irreversible damage. GcfDNA may also be useful to guide changes in immunosuppression, to monitor immunosuppression minimization (e.g. drug tapering), and prevent immune activation. The high negative predictive value of GcfDNA is the reason why this test can be useful to avoid unnecessary biopsies. It has also been shown that GcfDNA can be useful to detect subclinical, e.g. clinically unsuspected, graft damage triggered by underimmunosuppression. Earlier diagnosis of subclinical antibody-mediated rejection may improve outcomes after kidney transplantation. The combination of absolute quantification of GcfDNA (cp/mL) and GcfDNA fraction (%) may provide additional clinically useful diagnostic information in kidney transplantation. In summary, GcfDNA monitoring can allow more personalized treatment that shifts emphasis from reaction to prevention.

”PHARMACOGENETICS FOR GUIDING SOLID ORGAN TRANSPLANTATION THERAPY: THE BAROTAC STUDY”

N. Lloberas ⁴, L. Elens ³, D.A. Hesselink ², T. Van Gelder ², R. Van Schaik ², H. Colom ¹, F. Andreu ⁴, O. Bestard ⁴, J. Torras ⁴, A. Vidal-AlabrÓ ⁴, P. Fontova ⁴, J.M. Cruzado ⁴, J.M. GrinyÓ ⁴

¹Biopharmaceutics and Pharmacokinetics Unit, School of Pharmacy, University of Barcelona, Barcelona, Spain

²Erasmus Medical Center. Rotterdam, The Netherlands

³Louvain Centre for Toxicology and Applied Pharmacology, Catholic University of Louvain, Brussels, Belgium

⁴Nephrology Department. Bellvitge University Hospital. Barcelona, Spain

Tacrolimus (TAC) is the cornerstone of immunosuppresion in solid organ transplantation. Its pharmacokinetics is characterized by high inter and intra-individual variability showing a narrow therapeutic interval. Currently, the limiting step for TAC monitoring is the inability to individualize the dose during the first early days post-transplant period, when optimal exposure is crucial for adequate immunosuppressant. Implementation of pharmacogenetics may refine TAC assessment.

In the BAROTAC study we showed that the CYP3A4*22 and CYP3A5*3 alleles are all associated independently with TAC exposure during the first year after transplantation. CYP3A4*1/*22 and CYP3A5*3/*3 genotyping showed lower dose requirements to achieve the target concentrations. Our study provided arguments for implementation of the combined CYP3A genotype status when deciding on the initial TAC dose. Also the impact of these genetic polymorphisms on lesions in different compartments of kidney protocol biopsies has been studied. More TAC exposure in the CYP3A5 non-expressers genotype recipients lead to higher tubule-interstitial damage and i-IFTA in kidney protocol biopsies.

Furthermore, the true clinical benefit remained to be tested in appropriately designed prospective randomized trials to determine the influence of genotype combinations on clinical outcome. Therefore, with these results, a population pharmacokinetic model was performed, identifying CYP3A4*22 and CYP3A5*3 polymorphisms as a factors that explain the observed variability. According to the PPK model, the percentage of patients not achieving the target pre-dose concentration (Co) range after is 40%.

A prospective, randomized superiority study in renal transplant patients is actually ongoing. Patients are randomized in two groups: A Group where patients are dosage according to the conventional strategy and, B Group where patients receive the first dose estimated from the population model and subsequent doses are adjusted by using the Bayesian approach levels doses. The aim of the study was dose optimization of TAC considering CYP3A polymorphisms for guiding solid organ transplantation therapy to increase the number of patients achieving target from the start of treatment and during the immediate post-transplant period.

USING THERAPEUTIC DRUG MONITORING IN OPTIMIZING TACROLIMUS-PERSONALIZED THERAPY AND PATIENTS CARE IN SOLID ORGAN TRANSPLANTATION: THE IATDMCT CONSENSUS REPORT

M. Brunet ¹

¹Pharmacology & Toxicology. Biochemistry & Molecular Genetics. Biomedical Diagnostic Center. Hospital Clinic of Barcelona. University of Barcelona.

Currently the evolution of graft and patient clinical outcomes early and long term after transplantation remains unsatisfactory. Our understanding of immunosuppression to achieve personalized therapies, modulating the immune system response according to each patient needs, is still evolving.

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology decided to issue an updated consensus report on the optimization of tacrolimus considering the most relevant advances in tacrolimus pharmacokinetics (the best practice for therapeutic drug monitoring,TDM), pharmacogenetics, pharmacodynamic and immunologic biomarkers, with the aim to provide analytical and drug exposure recommendations. In addition, the quality of evidence and the strength of recommendations for the monitoring of some of these biomarkers is provided considering their role in the selection of initial immunosuppression, target concentrations to be achieved, identification of good candidates to minimize immunosuppression, as well as in the improvement of clinical outcome and long-term graft survival.

The Expert Committee concludes that the combined knowledge of pharmacokinetics, with pharmacogenetics together with pharmacodynamics and immunologic biomarkers, could provide further predictive/prognostic information regarding the risk of rejection and graft outcome at earlier time points and allow personal therapy adjustment to prevent drug-related adverse events and graft injury. There is a need to re-evaluate how we monitor tacrolimus exposure/effect and graft outcomes by incorporating these potential biomarkers into multidisciplinary, prospective, randomized and interventional clinical trials to support evidence for patient stratification and immunosuppression guidance.

THE 100,000 GENOMES PROJECT: TRANSFORMING HEALTH INITIATIVE

M. Caulfield ¹

¹Genomics England and Queen Mary University of London

The UK 100,000 Genomes Project has focussed on transforming genomic medicine in the National Health Service using whole genome sequencing in rare disease, cancer and infection. Genomics England partnering with the NHS established 13 Genomic Medicine Centres, the NHS whole genome sequencing centre and the Genomics England Clinical Interpretation Partnership (3250 researchers from 24 countries). We sequenced the 100,000th genome on the 5th December 2019 will complete an initial analysis for all participants by the end of July 2019. Alongside these genomes we have assembled a longitudinal life course dataset for research and diagnosis including 1.6 billion clinical data points for the 3000 plus researchers to work on to drive up the value of the genomes for direct healthcare. In parallel we have partnered the NHS to establish one of the world’s most advanced Genomic Medicine Service where we re-evaluated 300,000 genomic tests and upgraded 25% of tests to newer technologies with an annual review. The Department of Health have announced the ambition to undertake 5 million genome analyses over the next 5 years focused on new areas tractable to health gain.

PERSONALISED MEDICINE BASED ON COMMON AND RARE GENETIC VARIANTS IN ESTONIA

L. Milani ¹, K. Krebs ¹, S. Reisberg ², K. Läll ¹, L. Leitsalu ¹, N. Tõnisson ¹, T. Esko ¹, K. Fischer ¹, J. Vilo ², R. Mägi ¹, A. Metspalu ¹

¹Estonian Genome Center, Institute of Genomics, University of Tartu

²Institute of Computer Science, University of Tartu

The Estonian Biobank was founded in 2000 as a volunteer-based biobank. Today, it contains a collection of health and genetics data of close to 200 000 individuals, approximately 20% of the adult population of the country. The Human Genes Research Act (passed in 2000) and the broad consent form signed by all participants allows regular updating of data through linking to national electronic health databases and disease registries. This enables long-term follow-up of the cohort, including diagnoses, drug prescriptions, lab tests and medical procedures. To date, 152 000 individuals have been genotyped with Illumina’s Global Screening Array, and the genomes of 3,000 individuals and exomes of 2500 individuals have been sequenced. This serves as a population-based imputation reference for rare and common genetic variants.

I will present three pilot projects of personalized medicine in Estonia. By re-contacting biobank participants with specific high-risk mutations, we were able to prove the utility of a “genetics first approach” for familiar hypercholesterolemia and breast cancer and evaluate the response of participants who consented to receiving results and counseling. This has led to the next level of validation projects run by the two major hospitals in Estonia, in collaboration with primary care physicians, testing the implementation of high-risk mutations and polygenic risk scores for breast cancer and cardiovascular disease.

We have also developed and tested algorithms for translation of preexisting genotype data of biobank participants into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants.

Overall, the expectations for personalized medicine are very high in Estonia, and several implementation projects will be launched in the national healthcare system within the next few years.

QUALITY ASPECTS OF PHARMACOGENOMIC TESTING FROM A REGULATORY PERSPECTIVE

M. Paulmichl ¹

¹Humanomed Maria Hilf Privat Clinic

For pharmacogenomics testing, two different approaches are chosen, (i) genotyping and (ii) phenotyping. The latter is not commonly used because of the complex nature of the procedure, as well as the fact that the result can only be extrapolated in a very restricted way beyond the drug used for testing (exemptions are signature drugs for different metabolic pathways). As such, a focus has been placed on genotyping and the consecutive prediction of the related phenotype. In September of 2018, the European Medicines Agency issued a guideline for good pharmacogenomics practice, summarizing all the critical points of the molecular analytics involved for providing a clinically meaningful report for the physician. In short, the guideline requests (i) that all DNA variants should be tested for which functional data is available, (ii) allele specificity should be given when necessary, (iii) copy numbers should be determined where necessary, (iv) hybrids should be diligently examined for the relevant genes and (v) allele drop-outs should be avoided depending on the chemistry used for the analytical process. Despite the clear guidance given by the regulatory authority, reporting by a considerable number of laboratories does not comply with the mentioned requirements. The focus of the presentation will be on two disturbing issues, i.e. the use of *1 in the reporting and the use of the allele specific nomenclature when no direct allele specificity was used in the analytical approach.

CYP3A GENOTYPING - WORTH TO CONSIDER IT CLINICALLY?

I. Cascorbi ¹

¹Institute of Experimental and Clinical Pharmacology, University of Kiel, Germany

Cytochrome P450 (CYP) enzymes metabolize more than 70% of drugs for clinical use. Among them, CYP3A4 is quantitatively the most important P450 enzyme in adults. It is expressed to a major extent not only in the human liver, but also in the small intestine, thus contributing to the pre-systemic and systemic metabolism of ˜30% of all drugs. In addition, CYP3A5 contributes to the metabolism of certain drugs, in particular of immunosuppressants such as tacrolimus. Phenotyping using probe drugs such as midazolam revealed broad interindividual differences in enzyme activity; however, there is no clear distinction between groups of CYP3A4 slow or rapid metabolizers. In contrast CYP3A5 is expressed only in a minor proportion of individuals, i.e. only 20% of Caucasians. Both CYP3A enzymes underlie strong induction through interactions with the pregnan X-receptor (PXR) and constitutive androstan receptor (CAR) and are regulated by various cytokines and their downstream signaling cascades. Moreover, due to its broad substrate spectrum, manifold pharmacokinetic drug interactions may occur, having potentially severe clinical consequences. The contribution of common genetic variants to CYP3A4 activity is only modest, but the CYP3A5 expresser status and CYP3A4*22 is associated with significant pharmacokinetic changes of compounds having a narrow therapeutic windows such as tacrolimus. However there is lack of evidence so far that the consideration of genotypes to optimize tacrolimus dosage led to an improvement of the overall clinical outcome. More recent findings indicate that rare variants in the CYP3A4 gene may lead to loss of activity, implying tremendous consequences for patients. Therefore the increasing progress in genome sequencing technologies discovering rare variants in single individuals may change the current situation in the future. In any case, both, drug-drug-interactions and eventually possible loss of function variants should both be considered in order to optimize the dosage of CYP3A substrates.

THE ROLE OF RARE GENETIC VARIANTS FOR INTERINDIVIDUAL DIFFERENCES IN DRUG METABOLISM, TOXICITY AND RESPONSE

M. Ingelman-Sundberg ¹

¹Karolinska Institutet

Pharmacogenomic biomarkers for prediction of drug metabolism, toxicity and response are currently approved by FDA and EMA and are to some extent implemented into clinical work. These mainly identify common genetic variations in genes encoding enzymes, transporters and targets. However, recent results from analyses of WGS and WES sequencing efforts of large populations reveal that about 20-30 % of all loss of function (LOF) and missense mutations of importance for prediction of drug response are rare. Pharmacokinetic analyses in twins also reveal that 50 % of the interindividual inherited variation in metoprolol and toresimide pharmacokinetics might be caused by mutations not routinely analysed in the pharmacogenetic platforms currently used. This forms a problem for specific individualized drug therapy when the patient specific mutations have to be taken into consideration. The talk will consider the genes and drugs of importance where NGS based sequencing data would substantially add information beyond the current platforms to facilitate individualized drug therapy. This includes the description of complex genetic loci, algorithms able to predict the functionality of missense mutations in the pharmacogenes and protocols for streamline analyses in personalized medicine where the whole genome sequence is taken into consideration.

INTERINDIVIDUAL VARIABILITY OF CYP2D6, CYP3A4, AND CYP7A1: UNDERLYING CAUSES AND CLINICAL IMPLICATIONS

W. Sadee ¹

¹Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus OH, USA

The CYP family of oxidative enzymes assumes critical functions in the metabolism of xenobiotics and endogenous substrates. As a result, most CYP genes are under considerable evolutionary selection pressure to balance enzymatic activity under demands of a changing environment, leading to negative and positive selection – the latter characterized by frequent variants in long LD blocks, multiple functional variants interacting with each other, gene duplications, and complex genomic domain regulation. We have addressed these predictions by studying the genetic variations in CYP2D6, CYP3A4, and CYP7A1 (Danxin Wang et al.), finding examples of these predicted conditions in each. In CYP2D6 and CYP7A1, two frequent alleles with considerable distance between each other are in strong LD so that only the resultant haplotypes accurately represent the genetic effect. CYP3A4 resides in a gene cluster with several homologous genes, a genomic region regulated by long-range DNA looping interactions, some decorated with regulatory variants, and by a network of transcription factors. Consideration of evolutionary pressures therefore guides the discovery of genetic variant panels that impact enzyme activity in the individual patient, required for optimizing personalized therapeutics.

IMPLEMENTING CLINICAL PHARMACOGENETIC PROGRAMS: PERSPECTIVES FROM A SERVICE PROVIDER

H. Hachad ¹, D. Rule ¹

¹Translational Software

Despite an increasing enthusiasm for implementing clinical pharmacogenetic (PGx) testing across several institutions, stakeholders are still facing hurdles for service expansion and sustainability. Moreover, a growing interest by consumers in genomics is challenging implementers to develop patient-accessible programs. Drawing from our experience in providing PGx services, we discuss characteristics that shape the current implementation landscape.

MEDEA: A GLOBAL IMPLEMENTATION INITIATIVE OF PERSONALIZED MEDICINE IN A PUBLIC HEALTH CARE SERVICE BASED ON E-HEALTH

A. Llerena ¹

¹INUBE Instituto de Investigación Biosanitaria de Extremadura - SES Servicio Extremeño de Salud - UEX Universidad de Extremadura

Among the useful information to increase the efficiency of drug prescription are clinical (personal, family background of drug), pathophysiology of the disease, clinically relevant (drug / food / medicinal plants etc.) interactions; plasma levels of drugs and metabolites, genetic and other biochemical biomarkers, clinical routine analytical data (biochemistry/hematology/microbiology, etc.), and genetic biomarkers.

Although some of this information is available in the electronic medical record, its management is done manually, therefore a guided drug prescription tool that allows a rapid increase in the choice of drug in a context of polytherapy and multiple pathology is required. This system will be evaluated to establish a cost/effectiveness analysis that allows decision-making regarding its implementation in the National Health Service.

The project for the clinical Implementation of Personalized Medicine in Health Services consists of a program of health innovation that seeks the involvement of private companies using public procurement of innovation to boost research, development and innovation in companies, within the frame of open innovation created by Extremadura Healthcare Services (SES) and the Spanish Ministry of Economy and Competitiveness.

The innovation consists of the development of a Prescription Supporting Tool for the personalized drug prescription at the e-Medical Record. For that purpose, data from 1-genetic biomarkers will be integrated with other relevant data for drug response (i.e. 2-personal and family medical antecedents, 3-information from Biochemistry, Hematology data, and 4-Drug-drug interactions, and other factors). All this information will be used to develop computerized clinical decision support tool to help in individualized drug prescribing.

The project will generate a clinical decision support system for personalized drug prescribing based on learning algorithms to interpret all the above mentioned patient’s information, this Personalized Prescription System will validated in “real world” clinical conditions connected to the electronic medical record.

BIOINFORMATICS AND THE ANDALUSIAN INITIATIVE FOR PERSONALIZED MEDICINE

J. Dopazo ¹

¹Clinical Bioinformatics Area, Fundacion Progreso y Salud, CDCA, Hospital Virgen del Rocio, Sevilla

Data is becoming more and more important in medicine, which has became a de facto Big Data discipline. Specifically, the advancement in personalized medicine relies on the capability of data management the health system has. Contrarily to other regions that focus on the production of genomic data, Andalucía, which already experimented with genomic data production back in 2011 with the Medical Genome Project, is more focused on the importance of linking the genomic data to the clinical data for further prospective health Big Data exploitation for knowledge generation. Thus, the Andalusian Population Health Database, which contains data on more than 12.5 million users, is starting to be populated with genomic data coming from the Rare Diseases diagnostic pilot project and soon from the pilot project on cancer treatment recommendation. Bioinformatics and machine learning will play a key role in the process of knowledge generation from the analysis of these clinical Big Data that will produce more precise diagnostic, prognostic and treatment recommendation biomarkers, will improve hospital processes and, in general, will increase the degree of precision and personalization within the health system.

INNOVATIVE PURCHASE IN ANDALUSIA FOR LIQUID BIOPSY

M.J. Serrano ⁴, J. Exposito-Hernandez ⁶, E. De Alva ⁷, I. Castillo ³, J.R. Delgado ⁵, J.A. Lorente ¹, J.J. Diaz-Mochon ¹, J.M. De La Higuera ², J.L. Garcia-Puche ¹

¹Centre GENyO. Granada

²Public Innovativion Purchase Coordinator. Consejeria de Salud. Sevilla

³Univesity Hospital San Cecilio. Granada

⁴Univesity Hospital Virgen de las Nieves. Centre GENyO . Granada

⁵Univesity Hospital Virgen de las Nieves. Granada

⁶Univesity Hospital Virgen de las Nieves.Centre GENyO. Granada

⁷Univesity Hospital Virgen del Rocio. Sevilla

The Andalusian Health Service (SAS), within the framework of the innovation policies developed by the Ministry of Health of the Andalusian Government, has developed a corporate initiative for Public innovative purchase (PIP) in the field of precision medicine focused in the liquid biopsy area and Cancer”.

This initiative is supported by an agreement signed by the SAS together with the Ministry of Knowledge, Innovation and Universities, in the context of the Program for the Promotion of Innovation from Demand in the Health Sector (FID-Health), which aims to develop innovative solutions from the industrial sector based on the needs and priorities of the public health system.

One of the lines of this initiative pursues the development of non-invasive solutions for the diagnosis, monitoring and control of cancer patients, through the detection of peripheral blood biomarkers: liquid biopsy (LB).

Defined the needs in a generic way as biomarkers (Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, etc. for breast, colon, lung and prostate cancer, it has been estimated as relevant by part of the promoters of the initiative (General Secretary of R+D+i of the Andalusian Ministry of Health, Direction Management of the SAS, Direction of the Oncology Plan and the Local Group of Research and Clinical Development constituted by the UGC of Oncology of the Hospitals of Granada and the GENyO Center) holding a Consensus Meeting of experts, of international scope and external to the SAS, on development priorities according to the state of the art and the needs identified by the care system.

The final objetive of this PIP is the inclusion in the clinical routine inside SAS ´s hospitals of new methodos of precision medicine based on LB . The development of this PIP includes transferability of biological information from laboratory to clinicians through updates of the digital services including the information provided by these new platforms.

“NAGEN PROYECTO GENOMA 1000 NAVARRA”: AN EXAMPLE OF A REGIONAL PILOT PROJECT FOR THE IMPLEMENTATION OF PERSONALISED GENOMIC MEDICINE IN THE HEALTHCARE

S. Pasalodos ³, J. Salgado ³, M. Miranda ³, E. Calero ³, P. Brennan ⁴, I. Gut ², J. Dopazo ¹, I. Lasa ³, A. Alonso ³

¹Bioinformatics Platform CIBERer, Área de Bioinfromática Clínica. Fundación Progreso y Salud. Seville

²Centro Nacional de Análisis Genómicos CNAG, Barcelona

³Genomic Medicine, Navarrabiomed, Complejo Hospitalario de Navarra (CHN)-Universidad Pu?blica de Navarra (UPNA), IDISNA, Pamplona, Spain

⁴NENC NHS Genomic Medicine Centre, Newcastle upon Tyne, UK

Recent advances in precision technologies herald a new era of Personalised Medicine, although the actual implementation has proved to be challenging. “NAGEN 1,000” is a Spanish regional pilot study incorporating cutting edge genomic research technology (Whole Genome Sequencing) into the real clinical practice.

Initially intended to elucidate undiagnosed rare diseases in 1,000 patients and their relatives, NAGEN is producing complex genomic diagnoses for one third of the participating families, and strong candidate findings, potentially explaining additional cases, in 40% of the cohort, which delivers the promise of new diagnoses to come through collaborative research projects in the future. Interestingly, NAGEN is also contributing very useful information on secondary findings, mainly related to personal risk in 1 out of 20 enrolees, but also on pharmacogenetics, showing that 100% of participants carry at least 1 PharmGKB® Clinical Annotation Level of Evidence 1A or 1B variant, with a mean of 3.5 actionable variants per person. The project also recognises limitations for genomic medicine progression at different levels, and provides original solutions to overcome barriers in dissemination, optimisation of available resources, big data and ICT innovations, and ELSI regulations, for the use of genomic information in the clinical setting.

“NAGEN 1,000”, which was awarded as the Best Practice in Personalised Medicine by ICPerMed in 2018, illustrates how translational research and innovation in the field of genomics and personalised medicine is ready to deliver benefit to real patients.

PGX AND DRUG TRANSPORTERS

M. Niemi ¹

¹Department of Clinical Pharmacology and INDIVIDRUG research program, University of Helsinki

Variability in genes involved in drug pharmacokinetics can profoundly affect the absorption and disposition of drugs and drug response. Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) facilitates the uptake of its substrates from portal blood into the liver. Several clinically used drugs, eg many statins and angiotensin receptor antagonists, and endogenous compounds, eg bilirubin and certain bile acids, are substrates of OATP1B1. A common single nucleotide variation (rs4149056, c.521T>C, p.V174A) in SLCO1B1 impairs OATP1B1 activity and reduces the hepatic uptake and increases the plasma concentrations of many OATP1B1 substrates. For example, the plasma AUC of active simvastatin acid is increased more than 3-fold in individuals homozygous for the c.521T>C variant, increasing the risk of simvastatin-induced myopathy. This variant also affects the pharmacokinetics of most other statins and, e.g., those of the antidiabetic drug repaglinide. Moreover, genetically impaired OATP1B1 activity also reduces the hepatic uptake of methotrexate, decreasing the risk of gastrointestinal toxicity during high-dose intravenous methotrexate therapy in children with leukemia. On the other hand, the SLCO1B1*14 and/or *1B alleles are associated with reduced plasma concentrations of certain OATP1B1 substrates. The efflux transporter breast cancer resistance protein (BCRP, encoded by ABCG2) also shows significant genetic variability. A common single nucleotide variation (rs2231142, c.421C>A, p.Q141K) in ABCG2 impairs BCRP activity and is associated with increased systemic exposure to some BCRP substrates, eg rosuvastatin. Genome wide association studies have demonstrated that ABCG2 variants affect the lipid-lowering efficacy of rosuvastatin and also the antihyperuricemic efficacy allopurinol. Further to the common variants, both SLCO1B1 and ABCG2 harbor rare loss-of-function variants. In addition to explaining interindividual differences in drug response within ethnic populations, SLCO1B1 and ABCG2 variants may explain interethnic differences, as their frequencies differ markedly between populations.

WHAT IS THE IMPACT OF PHARMACOGENOMICS TO PREDICT SINUSOIDAL OBSTRUCTIVE SYNDROME IN PEDIATRIC STEM CELL TRANSPLANTATION

P. Huezo-Diaz Curtis ¹, T. Nava ¹, C.R. Uppugunduri Satyanarayana ¹, M. Ansari ¹

¹Geneva University Hospital, Onco-Hematology Unit, Geneva Medical School, CANSEARCH Research Laboratory, Geneva University, Geneva, Switzerland

Sinusoidal obstruction syndrome (SOS) is a potentially severe complication of hematopoietic stem cell transplantation (HSCT). It arises from endothelial cell damage and hepatocellular injury due to the pre-transplant treatments. It occurs in approximately 20% of pediatric patients depending on the intensity of the conditioning regimen. In patients undergoing allogeneic HSCT, SOS is the third most common cause of transplant-related death, with reported mortality rates of up to 50%. Besides the elements composing the conditioning regimens, the risk of SOS associated with specific drugs such as busulfan (Bu, an alkylating agent) depends on the extent of the exposure to the drug, indeed the reason why Therapeutic Drug Monitoring is recommended, especially in children, where Bu exposure comes with a high variability and pharmacogenetics is hypothesized to help.

This condition usually develops as early as day 15 post HSCT, although it can occur +50 days, especially in children. Diagnosis of SOS and incidence varies from that of adults thus the biological mechanisms that cause it may also be different. The aim of this presentation is to summarize the evidence on SOS risk factors with special focus on genetic biomarkers. As the primary mechanism of injury in SOS is thought to be conditioning-related injury most effort has focused in understanding the pharmacokinetics and pharmacodynamics of the drugs that are used in the conditioning regimen, thus many retrospective studies have identified potential markers via the candidate gene approach. However, recently a whole-exome sequencing approach has identified additional potential markers. From these studies current genetic markers for SOS risk include variants within; GSTA1, GSTM1, CTH, MTHFR, HPSE and UGT2B10 genes.

The next stage is to proceed with prospective cohort studies composed by patients with homogenous diagnostics and treatments to confirm the usefulness of these markers. This information might then be incorporated into an algorithm that includes other clinical and epidemiological risk factors to SOS. Ultimately, these algorithms will assist clinicians to choose the safest conditioning regimen and/or to consider prophylactic measures in patients identified as being at high risk of SOS.

PGX IN DIABETES

E. Pearson ¹

¹University of Dundee

People are all different, and this is no different when we consider people with diabetes, yet the current approaches to management of diabetes tend to treat everyone the same. The field of precision medicine aims to recognise these differences – whether at the level of their phenotype or at the molecular level. Faced with multiple, and increasing, treatment options for diabetes as well as increasing healthcare costs there is a clear need to target therapy to maximise benefit and reduce harm for every patient with diabetes. This talk will discuss advances in precision medicine and pharmacogenetics in diabetes over the last decade. I will initially outline striking examples seen in monogenic diabetes: subtypes of Maturity Onset Diabetes of the Young and for Neonatal Diabetes caused by potassium channel gene mutations, where patients are often able to transfer off insulin injections onto oral treatment. However, patients with monogenic forms of diabetes are rare, and this lecture will move on to how we might begin to tailor treatment in more common forms of diabetes – such as type 2 diabetes. I will then provide an overview of our latest understanding of the genetics of type 2 diabetes, where >400 variants have been identified and where extremes of the polygenic risk score are associated with considerable differences in diabetes risk. Partitioning genetic risk into component pathophysiological processes also allows us to start to predict progression of diabetes or drug response based upon the individual underlying diabetes aetiology.

There is increasing evidence that genetic and other molecular and clinical characteristics will impact on treatment outcomes. The exciting challenge now is how we incorporate this information into clinical care and establish that this improves patient outcomes.

PHARMACOGENETICS AND PERSONALISED MEDICINE IN ANTICOAGULATION: LATEST DEVELOPMENTS

V. Manolopoulos ¹

¹ Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece

Anticoagulation pharmacogenomics (PGx) still mainly concerns the older coumarinic anticoagulants (COAs). For COAs, genotype-guided dosing has been assessed in randomized clinical trials (RCTs). Genotype-guided algorithms used in RCTs included genotype for CYP2C9 and VKORC1 genes (COAG and EU-PACT trials) and more recently CYP4F2 gene additionally to CYP2C9/VKORC1 (GIFT trial). Use of algorithms to predict initial COA dosing have given mixed results in RCTs. Despite the uncertainty concerning the value of genotyping prior to treating patients with COAs, evidence is positive pointing to a benefit in fixing dose if genotype data is available at the start of treatment. Additionally, it appears that ethnic-driven PGx algorithms should be developed and used in different populations.

Therapeutic options for non valvular atrial fibrillation now include a new class of anticoagulant drugs known as non-VKA oral anticoagulants (NOACs) that are directly inhibiting coagulation factors. NOACs have several advantages over COAs, such as uses of fixed-dosing with no need for monitoring, few interactions and a wider therapeutic window, however, disadvantages are not missing including much higher cost and lack of standardized test for NOAC monitoring.

Application of COA PGx has therefore a two-fold dimension, both predicting the optimal dosing of COAs and additionally identifying individuals who are at increased risk of bleeding with COAs and, consequently, would benefit with a NOAC rather than COAs.

Currently, NOAC PGx is scarcely studied. Notably, there is only one Genome Wide Association Study performed in patients treated with dabigatran. To date, only a few genes have been studied in association with NOAC response including CES1 and ABCB1 for dabigatran, ABCB1 and CYP3A4/5 for rivaroxaban, ABCB1, ABCG2 and CYP3A4/5 for apixaban, and factor X, ABCB1 and SLCO1B1 for edoxaban. NOAC PGx is still a naïve albeit emerging field of research; thus, firm conclusions have not been drawed yet.

Further developments for anticoagulation PGx and personalized medicine are expected for both COAs and NOACs. Could future developments of personalized medicine in anticoagulation lie within epigenetic modifications?

PRE-EMPTIVE PHARMACOGENOMICS IN CLINICAL PRACTICE

G.P. Patrinos ¹, M. Skokou ¹, E. Tsermpini ¹

¹University of Patras, School of Health Sciences, Department of Pharmacy, Laboratory of Pharmacogenomics and Individualized Therapy

Despite scientific and clinical advances in the field of pharmacogenomics, the application into routine care still remains limited. One of the main obstacles which currently limits the clinical application of pharmacogenomics, is the absence of evidence presenting the collective clinical utility of a panel of pharmacogenomics biomarkers, as evidence is currently limited to individual drug-gene pairs. There are only few implementation studies and programmes that have been initiated during the recent years. The Ubiquitous Pharmacogenomics Consortium (U-PGx) aims to address these unmet needs with a prospective, randomized, controlled clinical study (PREPARE), employing pre-emptive genotyping of a panel of clinically relevant pharmacogenomics biomarkers, for which dosing guidelines are available. The impact on patient outcomes and cost-effectiveness will be investigated in a multi-center, multi-gene, multi-drug, multi-ethnic, and multi-healthcare system approach in a variety of medical specialties, such as cardiology, oncology, psychiatry, neurology, making this a unique study to demonstrate clinical utility of pharmacogenomics worldwide.

PHARMACOGENOMIC IMPLICATIONS OF POPULATION ADMIXTURE IN LATIN AMERICA

G. Suarez-Kurtz ¹

¹Brazilian Pharmacogenetics Network, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

Research and clinical implementation of pharmacogenetics/genomics (PGx) in Latin America must take into account ethnic, cultural, socioeconomic, scientific, and technological disparities across the region, but also the diversity and genetic heterogeneity of its population. Although Native American (Amerindian), European, and sub-Saharan African biogeographical ancestries are common to all Latin American countries, the relative proportions of each ancestral root vary across nations, and, most importantly within each nation. The population diversity of Latin America offers opportunity for original PGx research but also creates additional challenges to the implementation of PGx-informed prescription. Thus, adoption of international guidelines may be hindered by the rarity/absence of genetic variants that guide the dosing recommendations (e.g. HLA-B*15.02 in the case of phenytoin and carbamazepine) and faces the caveat of extrapolating to admixed populations, proposals based on categorical variables, such as continental ancestry (e.g. updated CPIC warfarin guideline), “race” or ethnicity. Furthermore, cost-effectiveness assessments of the clinical utility of PGx testing performed in developed countries, can hardly be extrapolated to the clinical scenarios prevalent in most health care facilities in Latin America.

Latin America is under-represented in the PGx literature, accounting for <4% of Pubmed entries for PGx in the last ten years. Furthermore, Latin Americans are often lumped into a single category (e.g. Hispanics, Latinos, etc) which fails to recognize their rich and complex diversity, while large-scale genomic/PGx resources, such as the 1000 Genomes Project, do not provide data for some of the most populous countries in Latin America (e.g. Brazil and Argentina). Importantly, there is a paucity of PGx information for Native American peoples, although large divergence in the distribution of functional PGx polymorphisms among different groups has been reported (e.g. NUDT15 rs116855232, a major determinant of thiopurine dosing).

In my presentation I will show data from my lab to highlight some of the above points, and to emphasize the importance of expanding PGx research and knowledge in Latin America.

THE MICROBIOME AND RESPONSE TO DRUGS

M. Simmaco ¹

¹Sant’Andrea University Hospital, Sapienza University of Roma Italy

The advent of cost-effective next generation sequencing platform opened the way to detailed description of microbiota composition and function in human compartments. Even if still a young science, facing both methodological and conceptual challenges, the bulk of information derived from taxonomic, genomic and metabolic evaluation of human microflora is already shaping the medical approach to health and disease.

Among the many interesting aspects of the cross-talk between resident microorganisms and anatomical, physiological, and immunological functions, microbiota research is shedding light on a dark side of the biological processes underlying the inter-individual variation in response to medications. Indeed, the novel disciplines of pharmacomicrobiomics and toxicomicrobiomics born to explain how the individual microbiome (the combination of microbial communities and their genomes) can changes the expected kinetics of drug disposition, affecting drug’s efficacy and toxicity.

Thus, microbiota research represents a further piece to compose the “patient puzzle”, giving us further information to build ever more precise therapeutic intervention.

DISCUSSION AND FINAL REMARKS