Companion Testing Research Articles

Companion Tests and Personalized Cancer Therapy: Reaching a Glass Ceiling.

The use of companion diagnostics has become a standard in precision oncology in the context of ongoing therapeutic innovation. However, certain limitations make their application imperfect in current practice. This position paper underscores the need to broaden the notion of companion testing, considering the potential of emerging technologies, including computational biology, to overcome these limitations. This wave of progress should impact not only our representation of the analytical tool itself but also the nature of the tumoral sample under analysis (liquid biopsies). The complex inter-relationship between companion test guided-personalized therapy, and health agency policies for new drug agreements will also be discussed.

Effect of real-time data-driven physician engagement on appropriate precision oncology testing.

11168 Background: Precision medicine is a paradigm shift in healthcare: 24% of all FDA approvals are precision medicines, with 67% of new approvals relying on companion or complementary testing or on diagnostics prior to clinical use. Yet a recent publication indicates that approximately 64% of potentially eligible patients could be lost due to various clinical practice gaps along patient journey (Sadik et al JCO 2022). Low prevalence biomarker testing is proven to be one of the critical determinants of missed therapy, potentially due to poor physician awareness. The increasingly advanced machine learning (ML) and natural language processing (NLP)-based ability to label, analyze, and segment data can be utilized to monitor and influence testing behavior in real-time. We hypothesize that a real-time data-driven physician-targeted digital engagement can increase biomarker testing rate and in turn enhance patient identification for precision therapies. Methods: Unstructured real-world, real-time biomarker testing reports were collected from 494 laboratories across the US. These testing reports were first curated, labeled and extracted via ML and NLP-based technologies to allow data analysis and reveal testing behavior. Suboptimal testing behavior was defined as no requisition of the selected novel biomarker as part of the diagnostic workups. Physicians who identified as having suboptimal testing behavior were selected as candidates to receive a personalized digital engagement over a 4-week period. The digital engagement's purpose was to raise clinical awareness towards the novel biomarker testing. The follow-up testing behavior was analyzed again over laboratory reports collected from 26-weeks’ time after the initial engagement. Results: 822 physicians were identified with suboptimal testing behavior and selected to receive 4 weeks' follow-up digital engagement. 271 out of 822 (33%) recipients were successfully engaged shown as open and read the digital communication. 42 (~15%) physicians reacted to the communications and ordered the new test at least once during this period. The initial 4 weeks' engagement was observed to be the most impactful, when 23 out of the 42 (~55%) physicians ordered the novel biomarker test for the first time.71 new therapy-eligible patients were identified via data-driven targeted physician digital engagement during the 26 weeks’ follow-up period. Conclusions: This study illustrates the value of data in influencing or reinforcing testing behaviors and emphasizes the value of data-driven physician-targeted digital engagement in addressing clinical practice gaps which in turn, drive patient identification to match potential eligible precision therapies.

Effect of Covid-19 in Management of Lung Cancer Disease: A Review

COVID-19 outcomes may be more severe in lung cancer patients. As a COVID-19 pandemic spreads, it's critical to identify which people and malignancies are most susceptible. COVID-19 appears to have the worst results in lung cancer patients. Lung damage or reduced lung capacity can be caused by the disease itself or by cancer treatments such as radiation and surgery. The earlier lung cancer is diagnosed, the better the prognosis. As a result, early detection technology for cancer is in high demand. Early diagnosis in large population screens is closely connected to non-invasiveness and cost-effectiveness. As a result, microelectronic-based sensor technology may be used to construct sensitive biomarker detection systems. Various biosensors have recently recognized cancer-related proteins. Researchers are increasingly interested in testing for volatile metabolites found in the breath. Companion testing for innovative anti-cancer drugs and re-biopsy for new therapeutic uses are helping to speed up the development of lung cancer diagnostic tests. This review covers all current lung cancer diagnostic modalities in depth.

Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer.

Simple SummarySeveral methods targeting the programmed death protein-1 (PD-1) axis have been developed and evaluated for the detection of immune checkpoint levels that are strongly involved in immunotherapy for patients with metastatic breast cancer. Variations in different assays used in diverse studies have affected their result interpretation and clinical utility. When applying these assays to the laboratory, a comprehensive understanding of the characteristics of them should be recognized. We reviewed applied laboratory techniques for detecting PD-1, PD-ligand (L)1, PD-L2, and soluble PD-L1, which are important for selecting metastatic cancer patients for immunotherapy. Advances in methodologies according to the epoch are also investigated to gain insight into immunologic techniques and to facilitate appropriate laboratory settings for evaluating the PD-1 axis status, which are useful for estimating outcomes and planning patient-tailored immunotherapy strategies.Approximately 20% of breast cancer (BC) patients suffer from distant metastasis. The incidence and prevalence rates of metastatic BC have increased annually. Immune checkpoint inhibitors are an emerging area of treatment, especially for metastatic patients with poor outcomes. Several antibody drugs have been developed and approved for companion testing of the programmed death protine-1 (PD-1) axis. We reviewed currently used laboratory methodologies for assays determining PD-1 axis to provide a comprehensive understanding of principles, advantages, and drawbacks involved in their implementation. The most commonly used method is immunohistochemistry (92.9%) for PD-L1 expression using tissue samples (96.4%). The commonly used anti-PD-L1 antibody clone were commercially available 22C3 (30.8%), SP142 (19.2%), SP263 (15.4%), and E1L3N (11.5%). Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay that target soluble PD-ligand (L)1 were developed and popularized in 2019–2021, in contrast to 2016–2018. Easy accessibility and non-invasiveness due to the use of blood samples, quantitative outputs, and relatively rapid turnaround times make them more preferable. Regarding scoring methods, a combination of tumor and immune cells (45.5% in 2016–2018 to 57.1% in 2019–2021) rather than each cell alone became more popular. Information about antibody clones, platforms, scoring methods, and related companion drugs is recommended for reporting PD-L1 expression.

In Situ Measurement of Concrete Static Modulus of Elasticity: Proof of Concept Implementation

ABSTRACT This paper reports a laboratory implementation of a prototype sensor for the measurement of in situ concrete static modulus of elasticity. Sensor measurements for a trial concrete mixture were generated, post-processed, and calibrated to best match companion ASTM C469 modulus of elasticity testing performed on the same mixture for concrete ages up to 28 days. The sensor prototype measurements demonstrated close agreement with ASTM C469 testing with approximately 90% of calibrated sensor prototype measurements within ±5% of companion testing. The initial sensor prototype implementation reported in this study affirms the feasibility of in situ concrete modulus of elasticity measurement and justifies further sensor development and implementation efforts.

Hürthle cell hurdles: Why do tumors derived from this cell type refuse to reveal their secrets and weaknesses?

Hürthle cell lesions are difficult to classify by cytology alone. Molecular companion testing has added some insight, but has not resolved these diagnostic challenges.

Analysis of real-world PD-L1 IHC 28-8 and 22C3 pharmDx assay utilisation, turnaround times and analytical concordance across multiple tumour types

AimsProgrammed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitor therapy is accompanied by companion or complementary PD-L1 testing in some tumour types. We investigated utilisation of the Dako PD-L1 IHC 28-8 and...

Abstract B021: Imaging immunotherapy in the tumor microenvironment in 3D

Abstract The range of experimental and approved cancer immunotherapies is growing exponentially, creating a pressing need for assays to match patients to agents and evaluate efficacy. Immunohistochemistry (IHC) remains the gold standard for companion, predictive and on-treatment testing to evaluate immunotherapy. By detecting only one or two antigens in each two-dimensional (2D) tissue section, IHC leaves room for diagnostic and therapeutic uncertainty. IHC is satisfactory for analysis of PD-L1 immunoreactivity but fares particularly poorly as a tool to examine tumor-infiltrating lymphocytes (TILs), a complex biomarker predicting therapeutic responses to immunotherapies. IHC is also poorly suited to following recruitment of tumor-specific, activated cytotoxic T-cells, which mediate tumor regression. The ideal test would not only permit detection of checkpoint markers such as PD-L1 but also identify and enumerate TILs and report on their distribution and activity. Recently, chemical treatment of tissue to enhance transparency, combined with new methods for three dimensional fluorescent imaging, has been established as a key tool for establishing connectivity in the central nervous system. Multiple methods to render brain tissue transparent and label multiple targets with fluorescently labeled antibody probes have been reported. Similar optical clearing, staining, and imaging are beginning to be applied to cancer, but practical methods for multiplexed 3D immunolocalization in tumors have remained lacking. Toward answering the challenge of 3D imaging cytometry of the tumor immune microenvironment, we recently developed Transparent Tissue Tomography (T3), a fast and simple protocol based on lightly fixing tissue, staining with cocktails of fluorescent antibodies and then clarifying with fructose before confocal imaging. T3 is particularly well-suited to examining immune infiltrates, suggesting potential as a diagnostic tool. We have validated T3 imaging cytometry not only in mouse tumor models but also human cancer biopsies. To evaluate feasibility as a diagnostic tool, surgical biopsies from head and neck cancer patients were sampled with a core needle biopsy device, immunostained for EGFR (cancer cells), CD3 (T-cells), CD8 (cytotoxic T-cells), CD31 (tumor blood vessels) and PD-L1, rendered transparent with 80% D-fructose, mounted and then scanned by confocal microscopy to obtain 3D images. It was straightforward to distinguish samples based on differential expression of PD-L1 and evaluate whether the expression was on tumor cells and/or stroma. Further, the levels of CTL infiltration into the tumor and/or stroma was readily determined. We could also observe a unique advantage of T3 in allowing evaluation of blood vessel density, morphology and penetration into the tumor cells, which further distinguished "hot" from "cold" tumors. Using mouse models, we have examined other potential applications for T3, including mapping the distribution of both innate and adaptive immune cell infiltrates, defining the perfused and hypoxic volumes in tumors, evaluating the dynamic antitumor immune response using markers of CTL activitation in response to therapy, and as a tool for pharmacokinetics and pharmacodynamics of checkpoint blockade antibody drugs. In particular, we have applied T3 to examine the effects of radiation on the tumor cells, immune infiltrate and microvasculature and the resulting impacts on checkpoint antibody delivery and distribution. Thereby, we have better defined the conditions to enhance synergy of radiation and checkpoint blockade. Given the simple methods and rapid sample-to-answer time, we propose T3 as a practical new tool to predict and track response to checkpoint blockade from small biopsy samples. Citation Format: Stephen J. Kron, Steve Seung-Young Lee, David Scholten, Vytautas Seung-Young Bindokas, Jacqueline Brinkman. Imaging immunotherapy in the tumor microenvironment in 3D [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B021.

Coregionalization analysis with a drift (CRAD): a methodological review with companion testing procedures, software and applications

The method of ‘coregionalization analysis with a drift’ (CRAD) developed by Pelletier et al. (Environ Ecol Stat 16:439–466, 2009a; Environ Ecol Stat 16:467–494, 2009b) was designed to assess the multi-scale variability of and relationships between ecological variables from a multivariate spatial (continuous quantitative) dataset, parsimoniously regarding model parameterization. In two phases, drifts are estimated for one variable at a time, and a ‘linear model of coregionalization’ (LMC) where spatial autocorrelation is nonlinearly parameterized through the range is fitted to all the experimental, direct and cross variograms of residuals. The original focus of statistical inference was estimation (i.e., estimated generalized least squares) instead of testing. Ten years after the two CRAD manuscripts went to press, the first two authors report on their refined understanding of the differences with approaches and methods with tangential objectives, the experience they gathered from applying the CRAD method, and the availability of testing procedures and software for future applications. For example, inferential differences and similarities with linear mixed models, and by extension generalized linear models, are emphasized, and the LMC is a suitable modeling compromise in the estimation of the numbers of effective degrees of freedom for a new modified F-test at the end of CRAD first phase. In conclusion, the CRAD toolbox ( http://environmetricslab.mcgill.ca/Programs.html ) now contains more devices than at the beginnings, and it is expected that users will benefit from the updates and upgrades, and apply the method at greater potential.

The evolution of high complexity companion testing for targeted and immuno-oncology.

The evolution of high complexity companion testing for targeted and immuno-oncology.

Companion testing using next-generation sequencing as compared with FDA-cleared kits.

e23146Background: Companion diagnostic tests are currently recommended for the prescription of multiple therapeutic agents in oncology. Most of these companion tests are FDA-cleared kits. We compar...

Australian health technology assessment of companion testing for cancer drugs.

e17500 Background: Patients in Australia access oncology therapies and diagnostic tests through two universal tax funded schemes: the Pharmaceutical Benefits Scheme (PBS) and the Medical Benefits Scheme. Since 1993 health technology assessment (HTA) has been a mandatory requirement for listing new drugs on the PBS. In 2010 HTA of biomarker diagnostic tests have been performed in parallel with the dependant drug. Several cancer drugs have gone through this process since 2010. This study aims to review the process and outcome for these cancer drugs. Methods: The HTA companion testing process in Australia was sourced from Government websites. Public summary documents for all HTAs related to cancer drugs with a companion test were reviewed from 2010. Time from HTA initiation to approval was calculated and compared. Results: Eleven drugs have gone through the parallel diagnostic/drug HTA process since 2010 in five different tumor types (breast, colorectal, gastric, melanoma, NSCLC). Time to reimbursement approval for each of the drugs and companion tests are summarized in the Table. Conclusions: While targeted therapies should assist decision making and improve time to patient access, experience in Australia demonstrates that HTA of companion testing adds another layer of complexity to the overall cost-effectiveness assessment, with potential consequences being delay to patient access. Pharmaceutical companies need to take this into account when they plan late phase clinical trials as well as regulatory and reimbursement submissions. Drug Indication Biomarker Proportion with biomarker Reimbursement Panitumumab Colorectal KRAS 40% Initiated 22Jul12 Approved 5Apr13 Gefitinib NSCLC EGFR 10-20% Initiated 6Apr11 Deferred 1Aug13 Dabrafenib Melanoma BRAF 45.8% Initiated 22Sep11 Approved 1Aug13 Trastuzumab Gastric HER2 14-23% Initiated 21Apr11 Deferred 30Nov12 Vemurafenib Melanoma BRAF 45.8% Initiated 28Jun11 Deferred 2Aug12 Erlotinib NSCLC EGFR 10-20% Initiated 28Jun11 Deferred 1Aug13 Trastuzumab Breast HER2 15% Initiated N/A Approved 2Aug13 Afatinib NSCLC EGFR 10-20% Initiated May12 Deferred 1Aug13 Crizotinib NSCLC ALK 5% Initiated 28Nov11 Not assessed yet Cetuximab Colorectal KRAS 40% Initiated 7Jun13 Not assessed yet

Stress rate sensitivity of Paskapoo sandstone under flexure

This paper evaluates the dynamic flexural response of sandstone from the Paskapoo formation in Alberta. Sandstone prisms were subjected to quasi-static flexure as per ASTM while a drop-weight impact tester was employed to generate stress rates up to 108 kPa/s. Companion testing under quasi-static compression on sandstone cylinders helped establish baseline properties including the compressive strength, elastic modulus, and Poisson’s ratio. It was found that the flexural strength and fracture toughness of Paskapoo sandstone obey stress rate sensitive models developed originally for concrete. However, the fracture toughness was more stress rate sensitive than its flexural strength.

Senior Lifestyles and Injury Prevention

The purpose of this multicenter, before-and-after observational study was to determine whether a short educational intervention was associated with improvement in self-reported safety behavior in older adults. We developed 4 original injury prevention presentations with companion testing materials: Motor Vehicle Safety, Fall Prevention, Pedestrian Safety, and Home Safety. Participants also completed pre-post Short Form Health Survey Instrument (SF-12) quality-of-life surveys. Of 414 participants, 226 completed follow-up testing and SF-12 surveys, for a 54.6% response rate. Those who completed either Pedestrian or Home Safety program showed no significant changes (P > .05) in either test scores or SF-12, and they comprised 61.9% of the final sample. Participants in the Motor Vehicle Safety and Fall Prevention programs accounted for 38.1% of the final sample and did show significant improvements between pre-post test scores. Only Fall Prevention participants showed significant differences in pre-post SF-12 scores. In the Fall Prevention group, numerous SF-12 subscores from the initial survey were significantly inversely correlated with pretest scores, and improvements in some SF-12 subscores correlated with improvements in test scores. Findings from the Fall Prevention group suggest that seniors with quality-of-life limitations may be aware of their increased risk and more willing to make changes to enhance safety. Further study is needed because many questions regarding optimal approaches to injury prevention in the aging demographic remain unanswered.

Stabilizing Wellbores in Unconsolidated Formations for Fracture Stimulation

Summary A wellbore stabilization system incorporating fracture stimulation has been developed and modeled in the laboratory for unconsolidated and dilatant formations. The profile of resin leakoff and penetration depth into the formation is relatively dependent on the pattern of perforations. Use of soluble particulates as a fluid-loss control agent proved to be effective in diverting resin, resulting in a uniform distribution of resin over the highly varying permeability interval. A significant drop in permeability of the near-wellbore area occurred after the resin treatment, but high productivity was re-established by connecting the wellbore with the untreated formation through highly conductive fractures. During companion testing of the resin-consolidation technique, the unconsolidated sandpack became a competent formation with compressive strength in excess of 2,000 psi. This competent material will be affected less by high drawdown pressures and stress cycling during production/shut-in cycles. The injection pressure required to fracture the consolidated wellbore showed an increase when compared to that of the untreated wellbore. Stress levels existing in the formation were shown to control the number and direction of generated fractures by passing the consolidated zone.

Bayesian and threshold probabilities in therapeutic drug monitoring: When can serum drug concentrations alter clinical decisions?

The use of Bayesian and threshold probabilities is examined with respect to the range of probabilities of toxicity for which obtaining a patient's serum drug concentration leads to information that is potentially useful in altering a clinical decision. For the situation of potential drug-induced toxicity, three threshold probabilities are needed to characterize the decision process: the decision threshold for deciding between continuing and discontinuing the drug regimen, the testing threshold that separates the decision to continue the regimen without testing the serum drug concentration from the decision to test before deciding, and the companion testing threshold that separates the decision to discontinue the regimen without testing from the decision to test before deciding. For digoxin, theophylline, aminoglycosides, vancomycin, and phenytoin, three prototypical decision threshold probabilities, 0.33, 0.2, and 0.1, are used, along with published true-positive and false-positive rates, to calculate serum concentration testing thresholds for each drug. Practitioners can be more effective in their use of serum drug concentration data when a Bayesian approach to probability assessment is used in conjunction with testing thresholds.

Fatigue crack growth study of SCS6/Ti-15-3 composite

A study was performed to determine the fatigue crack growth (FCG) behaviour and the associated fatigue damage processes in a [0] 8- and [90] 8-oriented SCS6/Ti-15-3 composite. Companion testing was also done on identically processed Ti-15-3 unreinforced material. The active fatigue crack growth failure processes were very similar for both composite orientations tested. For both orientations, fatigue crack growth was along the fibre direction. It was found that the composite constituent most susceptible to fatigue damage was the interface region and in particular the carbon coating surrounding the fibre. The failure of the interface region led to crack initiation and also strongly influenced the FCG behaviour in this composite. The failure of the interface region was apparently driven by normal stresses perpendicular to the fibre direction. The FCG rates were considerably higher for the [90] 8-oriented CT specimens in comparison to the unreinforced material. This is consistent with the scenario in which the interface has a lower fatigue resistance than the matrix, causing lower composite fatigue resistance. The FCG rates of the [0] 8 composite could not be directly compared to the [90] 8 composite but were shown to increase with an increase in the crack length.