Health Economic Evidence and Modeling Challenges for Liquid Biopsy Assays in Cancer Management:A Systematic Literature Review

BACKGROUND: Cancer-derived material circulating in the bloodstream and other bodily fluids, referred to as liquid biopsies (LBs), has become an appealing adjunct or alternative to tissue biopsies, showing vital promise in several clinical applications.PURPOSE: A systematic literature review was conducted to (1) summarize the current health economic evidence for LB assays and (2) identify and analyze the studies addressed or reported on the challenges of health economic modeling in precision medicine.METHODS: Relevant studies were identified in the EMBASE, MEDLINE, Cochrane Library, EconLit, and the University of Melbourne Full Text Journal databases from 1 January 2013 to 16 September 2022. Included papers were selected if they were economic evaluations and/or budget impact analyses.RESULTS: A total of 24 studies were included and analyzed, with the majority being full economic evaluations (n = 19, 79.2%). Four studies (16.7%) were health and budget impact analyses, and one study (4.1%) incorporated both an economic evaluation and a budget impact analysis. Cohort-level modeling techniques were the most common approach (n = 16; 80%). LB technologies were cost-effective in 15 studies (75%) considering different biomarkers, cancer types and stages, and economic analyses. These studies evaluated LBs for screening and early detection (66.7%), treatment selection (26.7%), and monitoring treatment response (6.6%). Budget impact analysis results were varied among included studies, with the majority of studies (n = 4; 80%) reporting either cost savings, minimal, or modest budget impact, while one study (20%) reported LBs as an efficient strategy. The reviewed studies often inadequately reported or addressed modeling challenges, such as patient-level processes, the combination of tests and treatments, preferences, and uncertainty.CONCLUSION: LBs could provide a cost-effective approach for treatment selection in lung cancer and aid in the screening and early detection of other cancers, including colorectal, gastric, breast, and brain cancers. This is in comparison with various alternatives, such as the standard of care (SOC) and no screening scenario. However, it is important to mention that in some comparisons, LBs were used in combination with SOC instead of replacing it. Importantly, few studies have pointed toward LBs' cost-effectiveness for monitoring treatment response. Most health and budget impact analyses, especially those focused on lung cancer, suggest potential cost savings or a minimal-to-moderate budget impact. Nevertheless, additional research is needed to ascertain their effectiveness across various stages of lung and colorectal cancer, as well as to address potential modeling challenges.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022307939.</p

Low-coverage whole-genome sequencing of extracellular vesicle-associated DNA in patients with metastatic cancer

© 2021, The Author(s). Low-coverage whole-genome sequencing (LC-WGS) can provide insight into oncogenic molecular changes. Serum extracellular vesicles (EV) represent a novel liquid biopsy source of tumoral DNA. This study compared copy number alteration (CNA) profiles generated from LC-WGS of formalin-fixed paraffin-embedded (FFPE) tumoral DNA and EV-DNA obtained from cancer patients. Patients with squamous cell carcinoma of the base of tongue (n = 3) and cutaneous squamous cell carcinoma (n = 2) were included. LC-WGS (0.5-1X coverage) was performed on FFPE-DNA and serum EV-DNA. Similarity between CNA profiles was analysed using QDNAseq. FFPE samples had a mean CNA of 31 (range 17–50) over 1.9 × 109 (range 1.0–2.6 × 109) bp in length, and EV samples had a mean CNA value of 17 (range 7–19) over 7.6 × 108 (range 2.9–15 × 108) bp in length. A mean of 8 (range 0–21) CNA over 5.9 × 108 (range 1.6–14 × 108) bp in length was found to overlap between EV and FFPE-derived samples per patient. Although the mean correlation efficient between samples was r = 0.34 (range − .08 to 0.99), this was not statistically significant (p \u3e 0.05). Regions of highest deletion and duplication in FFPE samples were not well reflected in the EV-DNA. Selected CNA regions in EV-associated DNA were reflective of the primary tumor, however appreciation of global CNA and areas of most significant change was lost. The utility of LC-WGS of EV-derived DNA is likely limited to molecular alterations of known interest

Giant microwave–optical Kerr nonlinearity via Rydberg excitons in cuprous oxide

Microwave–optical conversion is key to future networks of quantum devices, such as those based on superconducting technology. Conversion at the single quantum level requires strong nonlinearity, high bandwidth, and compatibility with a millikelvin environment. A large nonlinearity is observed in Rydberg atoms, but combining atomic gases with dilution refrigerators is technically challenging. Here, we demonstrate a strong microwave–optical nonlinearity in a cryogenic, solid-state system by exploiting Rydberg states of excitons in Cu2O. We measure a microwave–optical cross-Kerr coefficient of B0 = 0.022 ± 0.008 m V−2 at 4 K, which is several orders of magnitude larger than other solid-state systems. The results are in quantitative agreement with a nonlinear susceptibility model based on the giant microwave dipole moment between nearby excitonic states. Our results highlight the potential of Rydberg excitons for nonlinear optics and form the basis for a microwave–optical frequency converter based on Cu2O

Genomic analysis of circulating tumor DNA using a melanoma-specific UltraSEEK Oncogene Panel

The analysis of circulating tumor DNA provides a minimally invasive molecular interrogation that has the potential to guide treatment selection and disease monitoring. Here, the authors evaluated a custom UltraSEEK melanoma panel for the MassARRAY system, probing for 61 mutations over 13 genes. The analytical sensitivity and clinical accuracy of the UltraSEEK melanoma panel was compared with droplet digital PCR. The blinded analysis of 68 mutations detected in 48 plasma samples from stage IV melanoma patients revealed a concordance of 88% between the two platforms. Further comparison of both methods for the detection of BRAF V600E mutations in 77 plasma samples demonstrated a Cohen\u27s κ of 0.826 (bias-corrected and accelerated 95% CI, 0.669-0.946). These results indicate that the UltraSEEK melanoma panel is as sensitive as droplet digital PCR for the detection of circulating tumor DNA in this cohort of patients but highlight the need for detected variants to be confirmed orthogonally to mitigate any false-positive results. The MassARRAY system enables rapid and sensitive genotyping for the detection of multiple melanoma-associated mutations in plasma

Metal-Insulator Transitions in Degenerate Hubbard Models and Ax_xC60_{60}

Mott-Hubbard metal-insulator transitions in $N$-fold degenerate Hubbard models are studied within the Gutzwiller approximation. For any rational filling with $x$ (integer) electrons per site it is found that metal-insulator transition occurs at a critical correlation energy $U_c(N,x)=U_c(N,2N-x)=\gamma(N,x)|\bar{\epsilon}(N,x)|$, where $\bar{\epsilon}$ is the band energy per particle for the uncorrelated Fermi-liquid state and $\gamma(N,x)$ is a geometric factor which increases linearly with $x$. We propose that the alkali metal doped fullerides $A_xC_{60}$ can be described by a 3-fold degenerate Hubbard model. Using the current estimate of band width and correlation energy this implies that most of ${\rm A_xC_{60}}$, at integer $x$, are Mott-Hubbard insulators and ${\rm A_3C_{60}}$ is a strongly correlated metal.Comment: 10 pages, Revte

Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10-8 and 6.4 × 10-4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories

A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes

Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing because of the significant costs involved

A Time-Series Method for Automated Measurement of Changes in Mitotic and Interphase Duration from Time-Lapse Movies

Automated time-lapse microscopy can visualize proliferation of large numbers of individual cells, enabling accurate measurement of the frequency of cell division and the duration of interphase and mitosis. However, extraction of quantitative information by manual inspection of time-lapse movies is too time-consuming to be useful for analysis of large experiments.Here we present an automated time-series approach that can measure changes in the duration of mitosis and interphase in individual cells expressing fluorescent histone 2B. The approach requires analysis of only 2 features, nuclear area and average intensity. Compared to supervised learning approaches, this method reduces processing time and does not require generation of training data sets. We demonstrate that this method is as sensitive as manual analysis in identifying small changes in interphase or mitotic duration induced by drug or siRNA treatment.This approach should facilitate automated analysis of high-throughput time-lapse data sets to identify small molecules or gene products that influence timing of cell division

Theory and Validation of Magnetic Resonance Fluid Motion Estimation Using Intensity Flow Data

15 p.Background Motion tracking based on spatial-temporal radio-frequency signals from the pixel representation of magnetic resonance (MR) imaging of a non-stationary fluid is able to provide two dimensional vector field maps. This supports the underlying fundamentals of magnetic resonance fluid motion estimation and generates a new methodology for flow measurement that is based on registration of nuclear signals from moving hydrogen nuclei in fluid. However, there is a need to validate the computational aspect of the approach by using velocity flow field data that we will assume as the true reference information or ground truth. Methodology/Principal Findings In this study, we create flow vectors based on an ideal analytical vortex, and generate artificial signal-motion image data to verify our computational approach. The analytical and computed flow fields are compared to provide an error estimate of our methodology. The comparison shows that the fluid motion estimation approach using simulated MR data is accurate and robust enough for flow field mapping. To verify our methodology, we have tested the computational configuration on magnetic resonance images of cardiac blood and proved that the theory of magnetic resonance fluid motion estimation can be applicable practically. Conclusions/Significance The results of this work will allow us to progress further in the investigation of fluid motion prediction based on imaging modalities that do not require velocity encoding. This article describes a novel theory of motion estimation based on magnetic resonating blood, which may be directly applied to cardiac flow imaging.Kelvin Kian Loong Wong, Richard Malcolm Kelso, Stephen Grant Worthley, Prashanthan Sanders, Jagannath Mazumdar, Derek Abbot

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer.

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.Cancer Research UK Clinician Scientist Fellowship C53779/A20097 (M.L.B), Leukaemia Foundation Australia Senior Fellowship and Howard Hughes Medical Institute International Research Scholarship 55008729 (M.A.D), Peter and Julie Alston Centenary fellowship (K.D.S.), Wellcome Trust Principal Research Fellowship 101835/Z/13/Z (P.J.L), Peter MacCallum Postgraduate Scholarship (C.E.S), NHMRC Postgraduate Scholarship (K.L.C.), Maddie Riewoldt's Vision 064728 (Y-C.C), Victorian Cancer Agency (E.Y.N.L), CSL Centenary fellowship (S-J.D), National Breast Cancer Foundation Fellowship ECF-17-005 (P.A.B.), Addenbrooke’s Charitable Trust and NIHR Cambridge BRC (M.L.B., P.J.L), NHMRC grant 1085015, 1106444 (M.A.D) and 1128984 (M.A.D, S-J.D)