Foresight Diagnostics’ PhasED-Seq Circulating Tumor DNA Platform Demonstrates Highly Sensitive Minimal Residual Disease (MRD) Detection in B-Cell Lymphomas
- Extensive clinical validation in 678 samples from 213 patients with B-cell malignancies
- Up to 100-fold improved analytical sensitivity for MRD detection compared to existing approaches
- PhasED-Seq identifies twice as many patients who ultimately experience recurrence
AURORA, COLORADO, July 22, 2021 (GLOBE NEWSWIRE) -- Foresight Diagnostics today announced publication of studies demonstrating unprecedented analytical and clinical sensitivity of the Company’s proprietary circulating tumor DNA (ctDNA) detection platform for minimal residual disease (MRD) detection in B-cell lymphomas. The data showed that Phased variant Enrichment and Detection Sequencing (PhasED-Seq) nearly doubled the identification of aggressive lymphoma patients not cured with standard therapy and thus in need of new treatment strategies. The research was published in the July 22, 2021, issue of Nature Biotechnology and can be found at https://foresight-dx.com/news.
“While many patients with diffuse large B-cell lymphoma (DLBCL) are cured using standard therapies, there remains a great need to accurately and rapidly identify those who are not cured so that alternative treatment regimens can be initiated in a timely way to increase the likelihood of treatment success,” said David Kurtz, M.D., Ph.D., scientific advisor and co-founder of Foresight Diagnostics and lead author of the paper. “The un-matched sensitivity and accuracy of PhasED-Seq for ctDNA-based MRD detection during and after treatment demonstrated in this paper shows that Foresight’s PhasED-Seq platform is poised to become the new standard of care for clinicians to better manage their B-cell lymphoma patients.”
Physicians have recently begun using circulating tumor DNA (ctDNA) as a minimally invasive “liquid biopsy” approach to characterize cancers, particularly in the metastatic setting. In the curative setting, however, where ctDNA levels are low, conventional approaches (e.g., those based on single nucleotide variants (SNVs)) have limited utility and inadequate sensitivity due to inherent limitations posed by the error profile of SNVs. PhasED-Seq overcomes this limitation by targeting a unique class of somatic alteration called a ‘phased variant’, defined as two or more SNVs localized on the same DNA molecule, which enhances sensitivity by up to 100-fold compared to existing MRD assays.
“The results described in our Nature Biotechnology paper demonstrate the utility of PhasED-Seq as a powerful diagnostic tool for monitoring disease status during periods of low and previously undetectable tumor burden,” said Jake Chabon, Ph.D., co-founder and Chief Executive Officer of Foresight Diagnostics. “This also has important implications in drug development where PhasED-Seq could be employed as a companion diagnostic to guide treatment decisions during or after curative intent therapies. We are excited to have an off-the-shelf MRD test for B-cell lymphomas that could impact patient lives in meaningful ways.”
MRD detection in B-Cell lymphomas
B-cell malignancies are unique because phased variants occur in common genomic regions across patients. This enables the use of an ‘off-the-shelf’ approach for MRD detection that does not require customization for a given patient. The results published in Nature Biotechnology validate the clinical utility of the PhasED-Seq approach in longitudinal clinical cohorts consisting of 678 specimens from 213 patients with B-cell lymphomas. Highlights are provided below.
- Detection of ctDNA at levels below one part-per-million: In both clinical and technical samples, PhasED-Seq detected and quantified ctDNA at levels below one part-per million, a limit of detection 40-to-100-fold more sensitive than competing ctDNA detection approaches. Importantly, this higher sensitivity was obtained without molecular barcodes and without sacrificing specificity.
- Superior MRD detection during treatment: PhasED-Seq was compared to SNV-based ctDNA detection in 88 DLBCL patients after 2 cycles of immuno-chemotherapy. SNV-based approaches identified only 11/24 (46%) patients who experienced recurrence, missing more than half of patients in need of additional therapy. In the same samples, PhasED-Seq detected ctDNA in nearly twice as many patients (21/24, or 88%), with many of these additional detected patients harboring ctDNA levels below the analytical limit of detection of SNV-based approaches.
- Superior MRD detection post-treatment: Standard-of-care therapy fails to cure 30-40% of patients with DLBCL. Accurate and rapid detection of residual disease at the completion of therapy presents a meaningful opportunity to intervene and improve outcomes. PhasED-Seq was compared to SNV-based ctDNA detection in 19 DLBCL patients following completion of therapy. Of the five patients who ultimately experienced recurrence, only 40% (2/5) had ctDNA detected by SNVs while 100% (5/5) were detected by PhasED-Seq. Importantly, the remaining 14 patients without ctDNA detected by PhasED-Seq remain disease free after more than two years of follow up.
Preliminary data on PhasED-Seq detection in solid tumors
The potential of PhasED-Seq to detect MRD in solid tumors was evaluated in a pilot cohort of 36 samples from six patients (5 lung cancer, 1 breast cancer). PhasED-Seq detected ctDNA at levels of sensitivity similar to that observed in B-cell lymphoma samples. The lowest measurable tumor fraction using PhasED-Seq was 0.000094%, or less than one part-per-million, in a pre-treatment plasma sample from a stage IB NSCLC patient. These results demonstrate that the PhasED-Seq technology is broadly applicable to cancers other than B-cell lymphomas and these findings are being validated in larger clinical cohorts at Foresight.
About Foresight Diagnostics
Foresight Diagnostics is a privately held cancer diagnostics company and CLIA-registered laboratory. The company has developed a novel liquid biopsy testing platform for the measurement of minimal residual disease (MRD) that is significantly more sensitive (with a detection limit below 0.0001%, or one part-per-million) than existing tests. The improved sensitivity of the Foresight lymphoma MRD assay can provide actionable information to physicians and biopharmaceutical companies to enable more personalized treatment approaches for patients with B-cell malignancies. Foresight is developing an MRD assay for other tumor types based on the same technology. For more information, please visit www.foresight-dx.com and follow us on Twitter and LinkedIn.
The Foresight MRD platform is based on the Phased variant Enrichment and Detection by Sequencing (PhasED-Seq) technology. Similar to duplex sequencing, PhasED-Seq lowers the error profile of mutation detection in sequencing data by requiring the concordant detection of two separate non-reference events in an individual DNA molecule. However, unlike duplex sequencing, both events occur on the same sequencing read pair, thereby increasing the efficiency of genome recovery. By detecting more than one mutation, PhasED-Seq can more accurately distinguish tumor-derived cell free DNA (i.e., ctDNA) from healthy cell free DNA – enabling detection of ctDNA at levels below one part-per-million (<0.0001%). PhasED-Seq has been extensively validated in hundreds of patients with B-cell lymphomas.
Name: Mukul Agarwal
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