TEST:

Epi proColon®

Hypermethylated DNA biomarkers BCAT1, IKZF1 and SEPT9 were largely stable across different stages of disease and were highly selective for gastrointestinal adenocarcinomas relative to other cancer types. Existing CRC methylated ctDNA blood tests for BCAT1/IKZF1 and SEPT9 might be usefully repurposed for use in other gastrointestinal adenocarcinomas and warrant further prospective ctDNA studies.

However, compared with currently recommended annual FIT screening and 10-yearly colonoscopy screening, blood-based screening would result in lower effect and higher costs. Even with higher screening uptake, triennial blood-based screening with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with FIT screening and colonoscopy screening.

The Kappa test value for this experiment was 0.76, indicating a high degree of consistency between ColonUSK and pathological diagnosis. Our results suggest that ColonUSK holds potential as a non-invasive screening tool for colorectal cancer.

The study's insights into the differential expression patterns of these biomarkers can inform targeted screening strategies. Further research is needed to assess their potential to enhance early tumor detection in Hispanics.

"Epigenomics AG...closed...the agreement entered into on July 24, 2023 with New Day Diagnostics LLC ('New Day Diagnostics'), a U.S.-based diagnostics and contract research company, for the sale of its major assets. As a result, almost all of the Company’s assets have been transferred to New Day Diagnostics...The sale also offers the realistic possibility that Epigenomics’ intensive upfront work will benefit patients through the further development of the blood-based colorectal cancer screening test."

P=N/A; N=646; Completed; Sponsor:University of Miami

"Epigenomics AG...and New Day Diagnostics LLC...entered into an agreement for the sale of substantially all of the Company’s assets...The sale of the assets to New Day Diagnostics is expected to enable the commercialization of Epi proColon 'Next-Gen' and secure future cash flows for Epigenomics AG. In addition, the likelihood of reimbursement by CMS increases due to the option to combine the biomarkers of Epigenomics AG and New Day Diagnostic LLC, allowing the 'Next-Gen'-Test to make an important contribution to reducing the burden of colorectal cancer disease and deaths."

Semi-quantification of the single ctDNA marker, mSEPT9, a prevalent biomarker of CRC, was an independent predictor of PFS whereas CEA was not. High levels of both CEA and mSEPT9 ctDNA were independent predictors of OS, showing that mSEPT9 ctDNA added value to CEA in evaluation of OS. The mSEPT9 ctDNA test is rapid turn-around and easy to perform in molecular diagnostic pathology laboratories, thus may serve as a valuable adjunct to CEA for frequent testing in the setting of metastatic CRC.

The plasma SEPT9 DNA methylation level and Serum CCSA-2 could be used as promising non-invasive methods for observing the CRC patients postsurgical response to predict the occurrence of complete remission or relapses.

"Epigenomics AG...has decided to restructure the Company and to significantly reduce the Company’s operations...The Restructuring is carried out to minimize the Company’s costs. In addition, this is intended to extend the time period available to the Company to secure financing for the further development of the 'Next-Gen'-test for detecting colorectal cancer (CRC)...The Company will stop the sale of Epi proColon and recall the product."

The stool SDC2 methylation test had a better performance in detecting nonmetastatic CRC and adenoma than evaluations of mSEPT9, CEA, CA19-9 and CA724 in blood. Our findings could be used to modify approaches for CRC prevention and early detection.

We are the first to demonstrate the feasibility of associating central carbon metabolites with ctDNA and KRAS mutation status. As ctDNA positivity and KRAS MT status have evolving prognostic potential in CRC, associated metabolic signatures may identify metabolic pathways for novel biomarker development. Our findings also show that KRAS MT CRC appears to be enriched in intermediates of glycolytic, methyl donor, and O-GlcNAcylation pathways.

We demonstrate how an adequate thermal model of the specific LoC system can help us to identify a suitable thermal profile, even for complex HeavyMethyl qPCRs, with reduced experimental effort. Using a simulation-based approach, we demonstrate a proof-of-principle for the successful LoC transfer of colorectal SEPT9/ACTB-qPCR from Epi Procolon® colorectal carcinoma test, by avoidance of oligonucleotide interactions.

Our results show the beneficial use of mSeptin9 as a potent follow-up parameter of colorectal cancer especially for R+ status patients. A prospective comparison of the R+ patients with PET-CT-results is planned.

mSEPT9 is a sensitive and specific biomarker for EOCRC detection. These results suggest that mSEPT9 may be useful in the detection of EOCRC, providing a minimally invasive method for screening in this growing population of CRC patients.

Two newer screening tests, not yet included in guidelines, are Epi proColon (methylated septin DNA) assay (which detects methylation of the SEPT9 gene associated with CRC) and capsule colonography. All patients also should be informed about lifestyle and diet-related interventions that can decrease CRC risk.

P=N/A; Trial completion date: Feb 2022 --> Feb 2023 | Trial primary completion date: Feb 2021 --> Feb 2023

He has been awarded 10 patents related to DNA methylation technology by the United States Patent and Trademark Office, one of which is the basis for the first US FDA-approved blood-based DNA methylation assay for cancer (Epi proColon). His research findings include the report of a close link between DNA methylation and BRAF mutation in colorectal cancer (Nature Genetics, 2006) [2], the discovery that embryonic stem cell polycomb repressor targets are predisposed to abnormal DNA methylation in cancer (Nature Genetics, 2007) [3], the identification of a novel epigenetic subtype of glioma (G-CIMP), tightly associated with IDH1 mutation (Cancer Cell, 2010) [4], and the connection between nuclear architecture, late replication, and domains of epigenetic instability (Nature Genetics, 2011) [5], later showing a link with mitotic cell division, thus providing a mechanistic explanation for the loss of DNA methylation in aging and cancer first described four decades ago (Nature Genetics, 2018) [6].

P=N/A; Trial completion date: Jan 2022 --> Jan 2024 | Trial primary completion date: Aug 2021 --> Aug 2023

P=N/A; Active, not recruiting --> Completed

The mSEPT9 offers potential diagnostic and prognostic biomarker for HCC. After adjusting for age, mSEPT9 remained associated with liver function, liver fibrosis and inflammatory surrogate markers.

In a retrospective series of EOCRC and healthy controls, mSEPT9 demonstrated high sensitivity and specificity for the detection of EOCRC and was comparable to that observed among individuals aged 50 and older. These results suggest that the initial mSEPT9 detection may be suitable to triage younger individuals to follow-up endoscopy for identification of CRC. This study provides preliminary evidence for the potential efficacy of mSEPT9 for the detection of EOCRC, however the establishment of a prospective, early-onset cohort could better address its utility.

Our microsimulation study identified characteristics of highly efficient theoretical screening tests and confirmed effectiveness and cost-effectiveness of colonoscopy and available urine-, blood- and stool-based tests. Better patient adherence results in superior effectiveness for CRC prevention in the whole population.

P=N/A; Active, not recruiting --> Completed

"First evidence is provided for CRC detection in urine by SEPT9 methylation analysis, which combined with SDC2 allows for an optimal differentiation between CRC patients and controls. Urine therefore provides a promising liquid biopsy for non-invasive CRC detection."

"With subsequent longitudinal monitoring, 14 patients (70%) had detectable ctDNA before recurrence, with a median lead time of 8.0 mo earlier than seen with radiologic imaging. The mqMSP assay is cost-effective and easily implementable for routine clinical monitoring of CRC recurrence, which can lead to better patient management after surgery."

mSEPT9 has potential as HCC detection marker. The use in surveillance of liver cirrhosis could also be of potential. Results here are not applicable to the general population and would require large validatory longitudinal studies.

In addition to the approved tests, faecal-/blood-based microRNA and CRC-related gut microbiome screening markers are under development, with work ongoing to find the best combination of molecular biomarkers which maximise the screening sensitivity and specificity. Maximising the detection accuracy with a cost-effective approach for non-invasive CRC screening is urgently needed to further reduce the incidence of CRC and associated mortality rates.

"Microsimulation modeling supports annual Epi proColon testing, as for FIT. Although the Epi proColon test specificity is lower than that of a FIT, the Epi proColon test may be useful for improving participation and compliance in CRC screening, as evidenced in a small randomized controlled clinical trial which showed that uptake of an offer of an Epi proColon blood test was significantly higher than that for a FIT in subjects who were overdue for CRC screening."

P=N/A; Recruiting --> Completed | N=46 --> 24 | Trial completion date: Aug 2021 --> Aug 2019 | Trial primary completion date: Aug 2020 --> Aug 2019

P=N/A; Trial completion date: Aug 2020 --> Aug 2021

P=N/A; Not yet recruiting --> Recruiting | Initiation date: Nov 2017 --> Feb 2018 | Trial primary completion date: Nov 2019 --> Feb 2021 | Trial completion date: Nov 2020 --> Feb 2022

P=N/A; Trial primary completion date: Aug 2019 --> Aug 2020 | Trial completion date: Aug 2019 --> Aug 2020

P=N/A; N=440; Not yet recruiting; Sponsor:Central Hospital, Nancy, France

P=N/A; Trial primary completion date: Aug 2017 --> Aug 2019