Background : Prasugrel and clopidogrel require transformation into active metabolites by cytochrome P450 (CYP) enzymes. Variants in CYP genes, particularly CYP2C19 , are associated w/ reduced levels of metabolite and platelet inhibition w/ clopidogrel but not prasugrel. We investigated the impact of variants in CYP genes on clinical outcomes. Methods : TRITON-TIMI 38 randomized ACS patients w/ planned PCI to prasugrel (60 mg load, 10 mg qd) or clopidogrel (300 mg, 75 mg qd) for 6–15 mos. DNA was available in 2943 subjects who were genotyped for functional polymorphisms in CYP2C19 , 2C9 , 3A4/5 , 2B6 , and 1A2 and classified for each gene as carriers or non-carriers of ≥1 reduced function allele. Results : Among subjects treated with clopidogrel, CYP2C19 reduced function allele carriers (27% of population) had a 53% increased risk of the primary efficacy endpoint of CV death, MI, or stroke (HR 1.53, P=0.007, Fig ) and a 3-fold increased risk of ARC-defined definite or probable stent thrombosis (HR 3.09, P=0.038) compared w/ non-carriers. In contrast, with prasugrel CYP2C19 reduced function allele carriers were not at increased risk of CV death, MI, or stroke (HR 0.89, P=0.86) or stent thrombosis (HR 0.60, P=0.57). No association between genotype and bleeding was observed w/ either treatment. There were no statistically significant associations between any other tested CYP genotypes and outcomes. Conclusions : CYP2C19 genetic variants identify patients at significantly higher risk for CV death, MI, or stroke and for stent thrombosis among those treated with clopidogrel but not among those treated with prasugrel. CYP2C19 genotyping offers the potential to help tailor antiplatelet therapy.
Introduction: Current lymphoma response criteria rely on metabolic imaging with moderate predictive value. Prior studies showed prognostic utility of circulating tumor DNA (ctDNA) early during therapy. However, accurate MRD detection at the end of therapy (EOT) is difficult using 1st-generation assays with plasma detection limits of ∼1e-4. We tested performance of phased variant enrichment and detection by sequencing (PhasED-Seq), an ultrasensitive ctDNA MRD method (LOD ∼1e-6), focusing on EOT disease detection. Methods: We integrated PhasED-Seq MRD from LBCL studies using curative intent 1st-line regimens. We considered 6 prospective trials including investigational combinations of CHOP or EPOCH with rituximab, acalabrutinib, lenalidomide, obinutuzumab, polatuzumab, and/or tafasitimab [ACTRN12609001077257;NCT04002947;NCT00398177;NCT02529852;NCT04231877;NCT04134936]. Samples were profiled by PhasED-Seq at Foresight Diagnostics or Stanford University. Tumor or pretreatment plasma samples were used to identify Phased Variants, which were tracked at MRD timepoints (C2D1, C3D1, C4D1, and EOT). Results: 407 specimens from 151 pts were evaluable, with 148 pts (97%) successfully genotyped. Plasma samples were available from 119 pts pretreatment, 52 at C2D1, 53 at C3D1, 51 at C4D1, and 93 at EOT. While MRD clearance during therapy stratified PFS, persistent MRD at EOT identified highest risk (p < 0.0001, HR = 90, Figure A). EOT MRD+ had 95% Sn for predicting future PFS events, with lead times up to 30 mo before radiologic PD. In total, 23 cases (25%) were MRD+ at EOT, with 18/23 experiencing PFS events to date. Among 5 pts without PFS events to date, 1 received subsequent RT for FDG-avid residual disease, while 2 others have <1-yr follow-up. In contrast, 70 cases were MRD-neg at EOT, with 99% (69/70) remaining alive without progression to date. The 1 MRD-neg case at EOT that experienced later progression presented with isolated CNS relapse at 10 mo. MRD status predicted PFS in multivariate models after adjusting for regimen and ctDNA profiling lab (p < 0.01). Clinical Sn, Sp, PPV, and NPV of EOT MRD for subsequent events were 95.0%, 94.5%, 83%, and 99%, respectively. While analytical Sn of 1e-4 has been used in CLL and myeloma for MRD, detection below this threshold was needed for adequate clinical Sn in DLBCL. When using a threshold of 1e-4 for MRD-detection, performance deteriorated, with clinical Sn dropping to 60% (Figure B), and corresponding degradation in PFS stratification ([email protected], HR = 16; MRD-Full, HR = 90). Although EOT PET/CT response also predicted PFS (p < 0.0001, HR = 8.5), PhasED-seq showed higher Sn (95% vs. 50%, p = 0.008). Keywords: aggressive b-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, minimal residual disease The research was funded by: Grants from the NCI/NIH, Foresight Diagnostics. Conflicts of interests pertinent to the abstract D. M. Kurtz Other remuneration: Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Genentech: Consultancy. J. Westin Other remuneration: Research funding: Genentech, Kite, BMS, Novartis, Morphosys/incyte, AstraZeneca, ADC Therapeutics; Consulting: Genentech, Kite, BMS, Novartis, Morphosys/Incyte, AstraZeneca, ADC Therapeutics, Monterosa, AbbVie, Seagen, Foresight R. C. Lynch Other remuneration: Research Funding: TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt; Consultant/Advisory: Cancer Study Group, SeaGen, Foresight Diagnostics C. Kuffer Other remuneration: MorphoSys AG: Current Employment, Current equity holder in publicly-traded company G. J. Hogan Other remuneration: Foresight Diagnostics: Current Employment; Freenome: Other: Equity holder. A. Schultz Other remuneration: Foresight Diagnostics: Current Employment, Current holder of stock options in a privately-held company. S. Close Other remuneration: Foresight Diagnostics: Current Employment, Current holder of stock options in a privately-held company. J. J. Chabon Other remuneration: Foresight Diagnostics: Current Employment, Current holder of stock options in a privately-held company. D. Rossi Other remuneration: Gilead: Other: honoraria, advisory board fees, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; BeiGene: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD: Other: advisory board fees; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding. S. Opat Conflicts of interests pertinent to the abstract Other remuneration: Pharmacyclics, LLC an AbbVie Company: Research Funding; Antegene: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Belgene: Research Funding. R. Hicks Conflicts of interests pertinent to the abstract Stock ownership: Telix Pharmaceuticals M. S Hertzberg Other remuneration: Beigene: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria M. Diehn Other remuneration: Foresight Diagnostics: Consultancy, Current equity holder in private company. W. Wilson Other remuneration: Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Syncopation: Current equity holder in private company, Patents & Royalties; Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties. A. A Alizadeh Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Syncopation: Current equity holder in private company, Patents & Royalties; Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties.
Drug metabolism is a multistep process by which the body disposes of xenobiotic agents such as therapeutic drugs. Genetic variation in the enzymes involved in this process can lead to variability in a patient's response to medication.We used molecular-inversion probe technology to develop a multiplex genotyping assay that can simultaneously test for 1227 genetic variants in 169 genes involved in drug metabolism, excretion, and transport. Within this larger set of variants, we performed analytical validation of a clinically defined core set of 165 variants in 27 genes to assess accuracy, imprecision, and dynamic range.In a test set of 91 samples, genotyping accuracy for the core set probes was 99.8% for called genotypes, with a 1.2% no-call (NC) rate. The majority of the core set probes (133 of 165) had < or = 1 genotyping failure in the test set; a subset of 12 probes was responsible for the majority of failures (mainly NC). Genotyping results were reproducible upon repeat testing with overall within- and between-run variation of 1.1% and 1.4%, respectively-again, primarily NCs in a subset of probes. The assay showed stable genotyping results over a 6-fold range of input DNA.This assay generates a comprehensive assessment of a patient's metabolic genotype and is a tool that can provide a more thorough understanding of patient-to-patient variability in pharmacokinetic responses to drugs.
Background— Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. Methods and Results— The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested ( CYP2C19 , CYP2C9 , CYP2B6 , CYP3A5 , and CYP1A2 ). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. Conclusions— Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.
