Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
Aims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study... Show moreAims/hypothesis Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.Methods One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.Results Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAF(Afr)]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9x10(-9)); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAF(Afr)=0.0536), was associated with a reduced response to metformin (p=2.4x10(-8)), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA(1c) of 0.08% and non-carriers had an HbA(1c) increase of 0.01% after 1 year of treatment (p=3.3x10(-3)). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6x10(-5)), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.Conclusions/interpretation We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Show less
Rheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs,... Show moreRheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs, heart and blood vessels. Therefore, to prevent (potential) damage with a more favorable course of the disease, it is important to intervene both early and agressively with medication in the treatment of RA. Typically, methotrexate is used as the first treatment, possibly in conjuction with other disease-modifying antirheumatic drugs, or with prednisolone to reduce inflammation rapidly. While the treatment of RA has improved considerably in recent decades, drug treatment does not work for everyone due to toxicity or lack of responsiveness. Therefore, it is suspected that genetics plays a major role in the both efficacy and toxicity of current RA medication. The goal of this thesis is to identify the genetic factors that influence the effectiveness or toxicity of the drugs used in RA. Show less
Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study,... Show moreAim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Claassens, D.M.F.; Gimbel, M.E.; Bergmeijer, T.O.; Vos, G.J.A.; Hermanides, R.S.; Harst, P. van der; ... ; Berg, J.M. ten 2021
Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients,... Show moreBackground: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically.Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding).Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively.Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and pa-tients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in pa-tients using clopidogrel.(c) 2021 Published by Elsevier B.V. Show less
For more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide... Show moreFor more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide variability in response to therapy is still observed since disease recurrence happens in nearly 30 % of breast cancer patients. Tamoxifen has a complex metabolism and it is mainly metabolized by CYP2D6 enzyme, among others, into endoxifen, the most active metabolite of tamoxifen.In the search of a manner in order to individualize endocrine therapy with tamoxifen, CYP2D6 genotyping and therapeutic drug monitoring based on endoxifen serum concentrations were proposed as potential manners to individualize tamoxifen efficacy. Both approaches have been an ongoing discussion and many studies have been published claiming both negative and positive associations. This thesis mainly focusses on CYP2D6 genotyping and endoxifen concentrations and their impact on clinical survival outcome in early breast cancer patients treated with tamoxifen. Show less
Hulshof, E.C.; Deenen, M.J.; Guchelaar, H.J.; Gelderblom, H. 2020
Background: Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the... Show moreBackground: Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the available evidence and to assess the potential value of genotyping of UGT1A1*28 and UGT1A1*6 in patients before starting treatment with irinotecan to reduce the risk of severe toxicity.Methods: The literature was selected and assessed based on five pre-specified criteria: 1) the level of evidence for associations between UGT1A1 polymorphisms and irinotecan-induced severe toxicity, 2) clinical validity and utility of pre-therapeutic genotyping of UGT1A1, 3) safety and tolerability of irinotecan in carriers of UGT1A1 polymorphisms, 4) availability of specific dose recommendations for irinotecan in carriers of UGT1A1 polymorphisms, 5) evidence of cost benefits of pre-therapeutic genotyping of UGT1A1.Results: On all five criteria, study results were favourable for pre-therapeutic genotyping of UGT1A1. A high level of evidence (level I) was found for a higher incidence of irinotecan-induced severe toxicity in homozygous carriers of UGT1A1*28 or UGT1A1*6. The clinical validity and utility of this genetic test proved to be acceptable. Dose-finding studies showed a lower maximum tolerated dose in homozygous variant allele carriers, and most of the drug labels and guidelines recommend a dose reduction of 25-30% in these patients. In addition, pre-therapeutic genotyping of UGT1A1 is likely to save costs.Conclusion: Pre-therapeutic genotyping of UGT1A1 in patients initiating treatment with irinotecan improves patient safety, is likely to be cost-saving, and should, therefore, become standard of care. (C) 2020 The Author(s). Published by Elsevier Ltd. Show less
The primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis... Show moreThe primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis is divided in two parts: pharmacogenetics related with drugs used in RA and pharmacogenetics of rituximab used in SLE and other autoimmune diseases. Part 1: Pharmacogenetics of drugs used in RA MTX is the most common DMARD used in RA. However, its use is hampered by frequent adverse drug events among which gastrointestinal toxicity is most frequent. Hepatotoxicity is a relatively rare but serious adverse event related to the use of MTX and is largely unpredictable. In chapter 2 an overview is presented of the previously performed studies concerning pharmacogenetic predictive biomarkers for MTX-induced hepatotoxicity. Treatment with anti-TNF agents results in a reduction of disease activity in most RA patients. However, a substantial part of patients does not respond to this therapy for unknown reasons. It would be highly beneficial to be able to predict whether or not an individual patient responds to treatment. Chapters 4 and 5 describe the investigations on the role of different candidate SNPs related to the efficacy of the treatment with different anti-TNFs in RA. In addition, in chapter 3 a replication study is presented based on 4 polymorphisms that were found associated with anti-TNF response in RA in a previously published genomewide association study. Part 2: Pharmacogenetics of rituximab used in SLE and other autoimmune diseases In chapters 6–8 the role of different genetic variants related to the pharmacodynamics of the drug or of the diseases are evaluated to study the contribution to differences in the response to rituximab in patients with SLE and other systemic autoimmune diseases. In chapter 6, the possible involvement of the -174 IL-6 polymorphism in the clinical response to rituximab in different systemic autoimmune diseases is assessed. In chapter 7, the aim is to investigate the possible involvement of the FCGR3A-158F/V polymorphism in the clinical response to rituximab in Spanish patients with different systemic autoimmune diseases. In chapter 8, the role of G/T polymorphism at the IL2–IL21 region in the rituximab response in a cohort of SLE patient and different autoimmune disorders is analyzed. Chapter 9 provides a summary of this thesis, chapter 10 the Dutch summary (Nederlandse samenvatting), and chapter 11 the general discussion and future perspective of this thesis. Show less
Pharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare... Show morePharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare professionals (HCPs) to guide dose and drug selection before drug initiation in an effort to optimize drug therapy through precision medicine. Despite both the promise of and the progress in the field of PGx to achieve precision medicine, it is still not routinely applied in patient care. As such, a number of barriers preventing implementation have been identified. These include the undetermined model for delivering PGx, the lack of evidence supporting a PGx panel approach and the lack of tools supporting implementation. Therefore, the work of this thesis aims to support the implementation of precision medicine using PGx panel testing. It reports on generating evidence for PGx panel testing (Part I) and the development of tools facilitating implementation (Part II), evaluates the implementation process utilizing these tools (Part III) and quantifies the impact of PGx implementation on patient outcomes and cost-effectiveness (Part IV). Show less
This thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is... Show moreThis thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is investigated. SNPs related to the pharmacokinetics and pharmacodynamics of imatinib and sunitinib have been associated to survival and to toxicity. SNPs in VEGFA and SLCO1B3 have been associated to worse progression free survival during imatinib treatment of advanced GIST. SNPs in ABCG2 and CYP1A2 have been associated with the need for dose reduction in patients receiving imatinib for GIST. A SNP in POR was associated with better progression free survival during sunitinib treatment of advanced GIST . In part II the usage of trabectedin is soft tissue sarcomas (STS) in the Netherlands is studied. Trabectedin as second line treatment of soft tissue sarcoma was compared to ifosfamide monotherapy. The Incremental Cost-Effectiveness Ratio for leiomyosarcomas and liposarcomas was at the top end of what is considered acceptable in the Netherlands. For other soft tissue sarcomas subtypes, ifosfamide dominated trabectedin. The venous access related adverse events of trabectedin have been described. The research in this thesis contributes towards personalised treatment for advanced soft tissue sarcomas. Show less
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD... Show moreFluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or capecitabine. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care.With this thesis we improved knowledge on different aspects of DPYD genotyping and DPD phenotyping, in order to better predict DPD deficient patients and personalize their therapy. In addition, we improved clinical implementation of DPYD genotyping, and reduced the risk of severe fluoropyrimidine-induced toxicity in DPYD variant allele carriers. Show less
This thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis... Show moreThis thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis on statin-induced HDL-C response by the Genomic Investigation of consortium, which identified CETP as a loci of interest, and two-sample Mendelian randomization studies utilizing summary level data from the GIST and other GWAS consortia on fasted blood lipids and type 2 diabetes. We additionally examine the issue of survival bias in Mendelian randomization studies. Finally, we show that intra-individual lipid variability associates with worse neurocognitive outcomes in older individuals at high risk for vascular disease, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. Show less
The aim of this thesis is to investigate the adoption of PGx and the integration of genotype guided dosing in the workflow of physicians and pharmacists in primary care. This thesis is divided into... Show moreThe aim of this thesis is to investigate the adoption of PGx and the integration of genotype guided dosing in the workflow of physicians and pharmacists in primary care. This thesis is divided into five parts. The first part provides an overview of answers to frequently asked questions by clinicians related to the implementation of PGx. The second part of this covers investigates whether genotype guided dosing in primary care is feasible in a pilot study where 200 patients with an incident prescription for a subset of 10 drugs and historical use are genotyped in a panel based approach for 8 pharmacogenes and received genotype guided dosing based on recommendations of the DPWG guidelines and covers an assessment of the clinical impact of PGx in primary care in the Netherlands is provided to predict how many patients that start with a drug currently described in the guidelines of the DPWG require an optimization of therapy. Part III covers the harmonization of PGx-test interpretation and therapeutic recommendations. Part IV investigates the knowledge, experience and attitudes towards PGx among (future) healthcare professionals. The thesis is concluded with a general discussion. Show less
Sunitinib has been approved by FDA in 2006 and became the first-line treatment for patients with clear cell metastatic renal cell carcinoma (cc-mRCC) due to its dramatic improvement in... Show moreSunitinib has been approved by FDA in 2006 and became the first-line treatment for patients with clear cell metastatic renal cell carcinoma (cc-mRCC) due to its dramatic improvement in progression-free survival (PFS) and overall survival (OS) and affordable toxicity. However, the inter-individual variability of sunitinib outcomes is large. Some clinical factors, such as blood pressure, can partly predict sunitinib efficacy, but they are not enough. More insight into the genetic factors underlying sunitinib outcome could also be helpful to improve optimization of treatment. In this thesis, the relevance of single nucleotide polymorphisms (SNPs) to sunitinib treatment in (cc)-mRCC patients was investigated with regard to efficacy and toxicity.We identified SNPs in IL8,IL13, VEGFR, CYP3A5 and CTLA-4 were associated with efficacy, toxicity and clearance.Further validation in independent cohorts is need before the implementation of these genetic biomarkers into clinical practice. Show less
