Publications by authors named "Ron H N van Schaik"

Aligned with the mission of the Dutch Pharmacogenetics Working Group (DPWG) to promote the implementation of pharmacogenetics (PGx), this guideline is specifically designed to optimize pharmacotherapy of cholesterol lowering medication (statins) and glucose lowering medication (sulfonylureas). The SLCO1B1 c.521 T > C variant reduces the activity of the SLCO1B1 transporter involved in statin transport out of the blood into the liver.

View Article and Find Full Text PDF
Article Synopsis
  • Alectinib is a treatment for ALK+ non-small cell lung cancer, but many patients experience drug-related toxicity requiring dose adjustments, potentially linked to genetic variants.
  • In a study of 215 patients, 47% had severe toxicity, with females being more affected and having higher drug levels. Additionally, specific genetic variants like PPAR-α 209G>A were associated with increased toxicity.
  • Identifying these genetic factors could help tailor treatments and reduce adverse effects, suggesting the need for pre-treatment genetic testing and possible dose modifications.
View Article and Find Full Text PDF

Aims: A genotype-guided P2Y12-inhibitor de-escalation strategy, switching acute coronary syndrome (ACS) patients without a CYP2C19 loss-of-function allele from ticagrelor or prasugrel to clopidogrel, has shown to reduce bleeding risk without affecting effectivity of therapy by increasing ischemic risk. We estimated the cost-effectiveness of this personalized approach compared to standard dual antiplatelet therapy (DAPT; aspirin plus ticagrelor/prasugrel) in the Netherlands.

Methods And Results: We developed a one-year decision tree based on results of the FORCE-ACS registry, comparing a cohort of ACS patients who underwent genotyping with a cohort of ACS patients treated with standard DAPT.

View Article and Find Full Text PDF

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice.

View Article and Find Full Text PDF
Article Synopsis
  • Hypertensive disorders of pregnancy (HDP) are major contributors to complications in pregnancy, prompting research into the role of maternal tryptophan metabolites in placental health and development.
  • The study involved 911 women and assessed serum tryptophan metabolites early in pregnancy, analyzing their relationships with placental volume and vascular development, as well as odds of developing HDP.
  • Findings showed that higher kynurenine levels negatively impacted placental development, while increased levels of 5-hydroxytryptophan were linked to higher risks of early pregnancy hypertension and preeclampsia.
View Article and Find Full Text PDF
Article Synopsis
  • - The study looks at whether stress hormones in pregnant women, called maternal vulnerability, can affect their baby's growth in the first trimester.
  • - Researchers found that higher levels of certain stress hormones in hair were linked to slower growth of the baby, while another substance called tryptophan was lower when stress was higher.
  • - The study used data from 132 pregnant women over a year to create a risk score for how vulnerable they are to stress and how it impacts their pregnancies.
View Article and Find Full Text PDF
Article Synopsis
  • The study investigated whether using CYP2C19 genetic testing to guide medication choices improves outcomes for patients with acute coronary syndrome (ACS) compared to standard treatment.
  • Out of 5,321 ACS patients, those who were genotyped and had their medications tailored showed significantly lower bleeding rates while maintaining a similar risk of ischemic events compared to those on standard therapy.
  • The findings suggest that a personalized approach to antiplatelet therapy based on genetic markers can enhance safety without compromising efficacy in managing ACS.
View Article and Find Full Text PDF

Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.

View Article and Find Full Text PDF
Article Synopsis
  • The Association for Molecular Pathology's Pharmacogenomics Working Group aims to establish key attributes and a standard set of genetic variants for clinical pharmacogenetic testing.
  • The document outlines two tiers of recommended genetic variants, which will guide clinical laboratories in creating pharmacogenomics assays.
  • Focused on dihydropyrimidine dehydrogenase (DPYD) testing, the recommendations encourage standardization while serving as a flexible reference rather than strict rules.
View Article and Find Full Text PDF

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented.

View Article and Find Full Text PDF

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g.

View Article and Find Full Text PDF

Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed. This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-β (TGF-β) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies.

View Article and Find Full Text PDF

Introduction: For patients with KRAS-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression.

Methods: Patients with KRAS-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372).

View Article and Find Full Text PDF
Article Synopsis
  • The Dutch Pharmacogenetics Working Group (DPWG) is creating guidelines to improve the use of pharmacogenetics (PGx) in prescribing medications, focusing on genetic interactions with drugs like phenytoin, carbamazepine, oxcarbazepine, and lamotrigine.
  • Recommendations include adjusting phenytoin doses for patients with certain genetic markers (CYP2C9) and avoiding certain medications for patients with specific HLA alleles (like HLA-B*15:02) to reduce the risk of severe skin reactions.
  • The DPWG emphasizes the importance of genetic testing before starting these medications to help prevent adverse effects and promote safer drug use among at-risk populations.
View Article and Find Full Text PDF
Article Synopsis
  • - Higher levels of 5-hydroxytryptophan (5-HTP) in pregnant women are linked to lower embryonic and fetal growth, increasing the risk of being small-for-gestational age (SGA), while higher kynurenine (KYN) levels are associated with a lower risk of SGA.
  • - Maternal tryptophan (TRP) metabolism plays an important role in the growth of embryos and fetuses, affecting both immune response and blood vessel function; disruptions in this metabolism can lead to negative outcomes for both mother and baby.
  • - The study analyzed data from over 1,100 women using blood samples and advanced ultrasound techniques to track embryonic and fetal growth, employing various statistical models to
View Article and Find Full Text PDF

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible.

View Article and Find Full Text PDF

Background: Identification of tumor-derived variants in circulating tumor DNA (ctDNA) has potential as a sensitive and reliable surrogate for tumor tissue-based routine diagnostic testing. However, variations in pre(analytical) procedures affect the efficiency of ctDNA recovery. Here, an external quality assessment (EQA) was performed to determine the performance of ctDNA mutation detection work flows that are used in current diagnostic settings across laboratories within the Dutch COIN consortium (ctDNA on the road to implementation in The Netherlands).

View Article and Find Full Text PDF

Neutropenia is the major dose-limiting toxicity of irinotecan-based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan-induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan.

View Article and Find Full Text PDF

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date.

View Article and Find Full Text PDF
Article Synopsis
  • Two cases demonstrate that using a combination of osimertinib and sotorasib may work well for patients whose cancer has developed resistance to osimertinib due to KRAS G12C mutations.
  • This combination therapy provides a potential solution for overcoming the limitations associated with single-agent treatments.
  • The findings suggest a new avenue for improving outcomes in patients facing this specific type of cancer resistance.
View Article and Find Full Text PDF

The development of immune checkpoint inhibitors (ICIs) has a tremendous effect on the treatment options for multiple types of cancer. Nonetheless, there is a large interpatient variability in response, survival, and the development of immune-related adverse events (irAEs). Pharmacogenetics is the general term for germline genetic variations, which may cause the observed interindividual differences in response or toxicity to treatment.

View Article and Find Full Text PDF

Extragonadal androgens play a pivotal role in prostate cancer disease progression on androgen receptor signaling inhibitors (ARSi), including abiraterone and enzalutamide. We aimed to investigate if germline variants in genes involved in extragonadal androgen synthesis contribute to resistance to ARSi and may predict clinical outcomes on ARSi. We included ARSi naive metastatic prostate cancer patients treated with abiraterone or enzalutamide and determined 18 germline variants in six genes involved in extragonadal androgen synthesis.

View Article and Find Full Text PDF
Article Synopsis
  • A recent study analyzed genetic data from over 156,000 prostate cancer cases and 788,000 controls from diverse populations, significantly increasing the representation of non-European participants.
  • Researchers identified 187 new genetic risk variants for prostate cancer, bringing the total to 451, enhancing understanding of genetic factors across different ancestries.
  • The developed genetic risk score (GRS) showed varying risk levels for prostate cancer among different ancestry groups, highlighting its potential for better risk assessment, especially in men of African descent.
View Article and Find Full Text PDF