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LAM’s Liquid Biopsy Test of cfDNA Methylation Panel Enables Highly Sensitive and Specific Detection of the Most Common Liver Cancer (Hepatocellular Carcinoma)

Today we discuss the dissemination of DNA-methylation-based tests for non-invasive detection of cancer. BioQuick News recently sat down with Dhruvajyoti Roy (photo), PhD, who is the Director of Technology at the Laboratory for Advanced Medicine Inc. (LAM), an AI-driven healthcare company focused on commercializing early cancer detection tests from a simple blood draw, to learn about the company’s technology and recent advances in the field of DNA methylation analysis. LAM developed a blood-based Liver Cancer Test, which can be used for early detection of liver cancer, as well as for monitoring disease recurrence. Dr. Roy had presented data from a validation study conducted by LAM on the ability of the assay to detect hepatocellular carcinoma (HCC), the most common form of liver cancer (more than 75% of all liver cancers, at The Liver Meeting® 2019 hosted by the American Association for the Study of Liver Diseases (AASLD), which was held in Boston from November 8-12, 2019. AASLD selected LAM's data for its poster presentation as a "Poster of Distinction." Posters of Distinction are classified as being in the top 10% of scored poster abstracts. (Dr. Roy was interviewed by BioQuick News editor Michael D. O'Neill and the text of the interview is provided below). QUESTION: Why did your group decide to focus on methylation status of cfDNA for your test? DR. ROY: Both genetic and epigenetic changes are known to be associated with the development of tumors. Over the last decade, analysis of cell-free DNA (cfDNA) from liquid biopsy samples, has emerged as a promising and potentially transformative, non-invasive diagnostic approach in oncology. cfDNA is composed of fragmented DNA released by cells into the circulation, typically as a result of cell death. In cancer patients, some portion of the overall cfDNA is composed of DNA released by tumor cells, often termed circulating tumor DNA (ctDNA). Most tests that are on the market or are in development to date utilizing cfDNA for cancer detection have focused on the detection of mutations in cancer-related genes. However, this approach for early cancer detection poses several key challenges. While this approach can be invaluable for monitoring tumor cells with actionable mutations, the diagnostic sensitivity of mutation-based approaches may be low among patients with early-stage cancer due to a limited number of recurrent mutations. A further limitation of this approach is that the sensitivity of detecting specific somatic mutation in cfDNA is lowered by the clonality and heterogeneity of the tumor tissue. This can significantly dilute the signal that is detectable in circulation. These limitations are in sharp contrast to what applies in the use of DNA methylation to detect and classify early-stage cancers. Epigenetic alterations, such as aberrant DNA methylation, occur very early in tumorigenesis and can be tissue- and cancer-type specific. DNA methylation patterns are also consistent across a genomic region and this enables the use of multiple DNA methylation sites for clinical detection. In addition, recent studies have explored the potential of DNA methylation and have identified many diagnostic and therapeutic targets for various cancer types. The integrated analysis of multiple data sets in conjunction with clinical information has facilitated identification of those diagnostic markers that may influence clinical management of cancer diagnostics. Therefore, considering the clinical utility of DNA methylation analysis for early detection, our group decided to focus on a DNA methylation-based approach. You will also notice that a shift of the cancer diagnostic paradigm is underway as a result of growing research and commercialization of liquid biopsies based on DNA methylation analysis.

Q: Can you describe LAM’s blood-based DNA-methylation test, how it works, and its potential use in the clinic?

DR. ROY: LAM’s blood-based DNA methylation test platform measures the methylation status of cfDNA extracted from blood samples at target sites. These target sites have been demonstrated to be hypermethylated when liver cancers are present. The blood samples are collected by using specialized cfDNA stabilization tubes and the samples are then shipped to a clinical laboratory. After receiving the collection tubes, the whole blood samples are first processed to plasma and then total cfDNA is isolated from the plasma fraction. Then, the extracted cfDNA is processed and the methylation status of specific target sites is determined. Finally, the DNA methylation data are analyzed by using specialized algorithms to produce the final result.

Analyzing the methylation status of cfDNA has the potential to be used for cancer detection, monitoring tumor burden, and even determining what type of cancer is present. Several studies, including our present studies, clearly demonstrate that DNA methylation analysis can facilitate the molecular diagnosis of high-risk asymptomatic populations and highlight the potential value of epigenomic testing in the routine clinical assessment to guide treatment decisions, and ultimately improve patient outcomes.

Q. Can you tell us about the study that you presented at this recent meeting? What were the results?

DR. ROY: At a recent conference dedicated to liver diseases, we presented the performance characteristics of our DNA methylation panel for hepatocellular carcinoma (HCC) in a large, retrospective patient cohort. The two existing surveillance methods (ultrasound and alpha-fetoprotein) for HCC have a poor sensitivity for early disease, when cancer is most vulnerable to therapies. So, there is a great need for the development of biomarkers that are both sensitive and specific indicators of HCC at early stages. In this study, blood samples were analyzed from 450 subjects, including: 249 subjects diagnosed with HCC (Stage I to IV), 83 healthy subjects, and 118 subjects diagnosed with benign diseases that may influence cfDNA methylation analysis, such as cysts and benign nodules of the liver and other organs. Cell-free DNA was extracted from the blood samples, bisulfite converted, and DNA methylation was then quantified at target sites.

A total of 218 of the 249 samples drawn from subjects with HCC were correctly identified for an overall sensitivity of 88% (range 81% to 94%). Additionally, 96% of healthy donor samples and 98% of samples drawn from subjects with benign disease were correctly identified as negative for HCC for a combined specificity of 97%.

Q. What are your future plans for this technology? Are there upcoming trials with this assay that are in the works to validate it further?

DR. ROY: LAM’s goal is to develop accurate and cost-effective clinical tests that can detect cancer early. Through collaborations with leading scientists, physicians, and research institutions worldwide, we aim to validate our products and provide the most effective diagnostic technologies to patients and doctors.

LAM is currently conducting extensive clinical study programs in both the United States and China.

In the United States, LAM is conducting a large, prospective clinical trial called CLiMB. In this CLiMB study, subjects with a diagnosis of liver cirrhosis and who are currently recommended for hepatocellular carcinoma (HCC) surveillance every six months by ultrasound are being enrolled during a routine HCC surveillance visit. The study is enrolling approximately 1,600 participants. This study is expected to be completed in 2020.

In China, a large trial is also underway to evaluate the performance of our liver cancer test against the current standards of care.

Q. How long does your test take to complete—from blood draw to final result?

DR. ROY: After receiving the blood sample, the results of the test are often completed within five business days.

Q. How long would you estimate before your HCC test is available for use in the clinic?

DR. ROY: We expect to achieve large-scale clinical application of our liver test once we receive FDA approval.

Q. How does progress on your test compare with progress by other groups on methylation-based tests for other cancers?

DR. ROY: There are several other groups pursuing cfDNA methylation tests for cancer diagnostics. Over the past 10 years, the team of scientists at LAM has used Artificial Intelligence and Machine Learning to identify unique DNA methylation patterns that predict the presence of cancer as early as Stage I. Through this work, LAM has identified several lead targets that are being further evaluated and validated for use on our DNA methylation platform for the detection of multiple deadly cancer types.

As LAM continues to systematically identify further DNA methylation targets for the most common cancers, we hope to gain and subsequently maintain an advantage in this rapidly evolving market.

Q. Are you working on similar cfDNA methylation panel tests for other cancers? Would such tests depend on developing different methylation panels or would the same panel be useful?

DR. ROY: Yes, we continue to evaluate additional DNA methylation biomarkers to both improve our existing tests and to develop novel clinical tests for diagnostic, predictive, or prognostic indications such as minimal residual disease (MRD) monitoring. We have validated panels for colorectal cancer and breast cancer detection tests. We are performing some additional validations. Brain, ovarian, and pancreatic cancers are some of the additional cancers for which we wish to discover accurate detection tests.

It is anticipated that a separate, targeting DNA methylation panel will be needed for every application. However, LAM’s DNA methylation platform may be used for each application.

MIKE O'NEILL: Thank you very much, Dr. Roy, and good luck with your company’s very exciting work.

[Laboratory for Advanced Medicine (LAM)] [CLiMB trial] [2019 American Association for the Study of Liver Diseases (AASLD) Annual Meeting]

Dr. Dhruvajyoti Roy speaks at AASLD 2019.