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One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0–5.3), P P P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials. more...

Introduction: IMbassador250 was a prospective phase III international multicenter trial enrolling 759 men with mCRPC who had prior progression on abiraterone, with or without prior taxane, randomizing to enzalutamide +/- atezolizumab. For this retrospective biomarker study, we hypothesized that decreases in ctDNA after 6 weeks of therapy, as measured from a novel low-pass, whole genome methylation sequencing assay from Foundation Medicine, will have greater discriminatory power to distinguish overall survival (OS) than PSA alone in a post-abiraterone mCRPC setting. Methods: Pre-treatment and C3D1 plasma samples from IMbassador250 were sequenced using a novel research assay that examines global copy number changes and methylation patterns through low pass, whole genome sequencing from Foundation Medicine. Kinetic changes in ctDNA were estimated between pre-treatment and C3D1 timepoints and patients were dichotomized into significant decreases vs. not using a predefined cutoff. PSA was examined as both 50% reduction from baseline to disease progression as well as a cutoff that matched the prevalence captured by the ctDNA reduction group at C3D1. Cox proportional hazards were calculated from Kaplan-Meier survival plots of overall survival between the reduction vs. no reduction groups. Results: Stratifying OS according to PSA 50% reduction from baseline to disease progression yielded an HR = 2.71 (95%CI:2.04-3.62). 370 patients (48%) had available ctDNA at both C1D1 and C3D1, and the median OS (mOS) in the reduction vs. non-reduction groups were 17.4 vs. 9.1 months, respectively (HR of 3.01; 95%CI:1.96-4.64). Evaluation of PSA reduction at C3D1 in the patients with available ctDNA yielded mOS of 16.3 and 9.5 months in the reduction vs. non-reduction groups, respectively (HR=2.70; 95%CI:1.77-4.12). Spearman’s correlation of ctDNA fold change between the research assay and an orthogonal FDA approved liquid biopsy assay was 0.95. Discussion: In this study, early ctDNA kinetic changes provided numerically superior estimation of overall survival compared to PSA in mCRPC patients receiving enzalutamide +/- atezolizumab in the post-abiraterone setting. Furthermore, ctDNA kinetic changes through C3D1 were apparent mostly prior to both PSA 50 and radiographic progression (6 weeks vs mean 3.3 months), providing a non-invasive strategy that is independent of PSA for monitoring therapy response when the disease is less AR dependent. Citation Format: Christopher Sweeney, Chang Xu, Jie He, Amanda Young, Alexander Robertson, Russell Petry, Daniel Zollinger, Alexander Fine, Neil Peterman, Eliana Polisecki, Tyler Warner, Kobe Yuen, Yanmei Huang, Zoe Assaf, Ryon Graf, Sanjeev Mariathasan, Priti Hegde, David Fabrizio, Thomas Powles. Evaluation of circulating tumor DNA kinetics as a prognostic biomarker for overall survival in metastatic castrate resistant prostate cancer using a novel methylation sequencing research assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3362. more...

We assessed secondary and genetic causes of severe HDL deficiency in 258,252 subjects, of whom 370 men (0.33%) and 144 women (0.099%) had HDL cholesterol levels G; 2) LCAT (12.4%): 1 homozygote, 3 compound heterozygotes, 13 heterozygotes, and 8 heterozygotes with variant rs4986970/p.S232T; 3) APOA1 (5.0%): 1 homozygote and 9 heterozygotes; and 4) LPL (4.5%): 1 heterozygote and 8 heterozygotes with variant rs268/p.N318S. In addition, 4.5% had other mutations, and 46.8% had no mutations. Atherosclerotic cardiovascular disease (ASCVD) prevalence rates in the ABCA1,LCAT,APOA1, LPL, and mutation-negative groups were 37.0%, 4.0%, 40.0%, 11.1%, and 6.4%, respectively. Severe HDL deficiency is uncommon, with 40.1% having secondary causes and 48.8% of the subjects sequenced having ABCA1,LCAT,APOA1, or LPL mutations or variants, with the highest ASCVD prevalence rates being observed in the ABCA1 and APOA1 groups. more...

International audience; Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5alpha-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5alpha-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs. more...

Background and aims: Marked hypercholesterolemia, defined as low density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL, may be due to LDLR, APOB, and PCSK9 variants. In a recent analysis, only 1.7% of cases had such variants. Our goal was to identify other potential genetic causes of hypercholesterolemia. Methods: In a total of 51,253 subjects with lipid testing, 3.8% had elevated total cholesterol >300 mg/dL and/or LDL-C≥190 mg/dL. Of these, 246 were further studied, and 69 without kidney, liver, or thyroid disease and who met Dutch Lipid Clinic Network criteria of ≥6 points had DNA sequencing done at the LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1, ABCG5, ABCG8, CYP27A1, LIPA, LIPC, LIPG, LPL, and SCARB1 gene loci and also had 10 SNP analysis for a weighted high LDL-C genetic risk score. Results: In the 69 subjects with genetic analyses, the following variants were observed in 37 subjects (53.6%): LDLR (n = 20, 2 novel), ABCG5/8 (n = 7, 2 novel), APOB (n = 3, 1 novel), CYP27A1 (n = 3, 1 novel), LIPA (n = 2, 1 novel), APOE (n = 2), LIPC (n = 1, novel), LIPG (n = 1, novel), and SCARB1 (n = 1); 14 subjects (20.3%) had a high polygenic score, with 4 (5.8%) having no variants. Conclusions: Our data indicate that in addition to variants in LDLR, APOB, PCSK9, APOE, LDLRAP1, and STAP1, variants in ABCG5/8, CYP27A1, LIPA, LIPC, and LIPG may be associated with hypercholesterolemia and such information should be used to optimize therapy. Fil: Corral, Pablo. Universidad Fasta; Argentina Fil: Geller, Andrew S.. Boston Heart Diagnostics; Estados Unidos Fil: Polisecki, Eliana Y.. Boston Heart Diagnostics; Estados Unidos Fil: Lopez, Graciela Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Bañares, Virginia Gabriela. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina Fil: Cacciagiu, Leonardo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Berg, Gabriela Alicia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Hegele, Robert A.. University Western Ontario; Canadá Fil: Schaefer, Ernst J.. Boston Heart Diagnostics; Estados Unidos Fil: Schreier, Laura Ester. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina more...

Sitosterolemia is associated with increases in intestinal sterol absorption, low-density lipoprotein cholesterol (LDL-C), and cardiovascular disease risk.We examined the relationship between hypercholesterolemia and sitosterolemia in a large population and report a new sitosterolemia case.Plasma sterol concentrations were measured by gas chromatography/mass spectrometry, and LDL-C by direct assay.Of 207,926 subjects tested, 4.3% had LDL-C ≥190 mg/dL. Plasma β-sitosterol concentrations ≥8.0 mg/L (99th percentile) were found in 4.3% of these subjects vs 0.72% with LDL-C130 mg/dL. Among all subjects, 0.050% had β-sitosterol levels ≥15.0 mg/L, consistent with sitosterolemia, while among those with LDL-C ≥190 mg/dL, 0.334% had this rare disorder. A 13-year-old boy with the highest LDL-C (679 mg/dL) of all subjects had planar xanthomas and a β-sitosterol level of 53.5 mg/L (normal3.3 mg/L). He was a compound heterozygote for 2 ABCG8 mutations (p.N409D and an intron 11+2TA splice site mutation). On a low-cholesterol and plant-sterol diet, his LDL-C decreased to 485 mg/dL (-29%) and β-sitosterol to 44.6 mg/L (-27%). On atorvastatin 20 mg/d, his LDL-C decreased to 299 mg/dL (-38%). With added ezetimibe 10 mg/d, his LDL-C normalized to 60 mg/dL (-80% further decrease); and his β-sitosterol decreased to 14.1 mg/L (-68% further decrease).Our data indicate that about 4% of subjects with LDL-C concentrations ≥190 mg/dL have plasma β-sitosterol concentrations above the 99th percentile and about 0.3% have concentrations consistent with sitosterolemia. Therefore, this diagnosis should be considered in such patients. more...

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