SUMMARY: It is estimated that cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum account for approximately 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US. There are currently no screening tests available for cancers of the gallbladder, bile duct, and pancreatic cancer. Although screening tests do exist for other types of GI malignancies such as colorectal and stomach cancer, many of them are invasive. Further, when GI malignancies are diagnosed, they are frequently at advanced stages and are more difficult to treat.
A noninvasive, liquid biopsy assay based on circulating tumor DNA (ctDNA) has the potential to detect cancer in early stages among asymptomatic individuals. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. ctDNA can detect almost all molecular alterations present in cancer cells and genotyping circulating cell-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape. The proportion of cfDNA that originates from a tumor depends on the anatomic location, tumor burden and cell turnover. cfDNA also allows real-time monitoring for treatment response and resistance.
The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community, and helped advance health and science technologies.
The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, case-control, observational study with longitudinal follow up, and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection based on cell-free DNA (cfDNA). This study completed enrollment of approximately 15,000 participants with and without cancer (56% with more than 20 tumor types and all clinical stages), across 142 sites in the US and Canada. The purpose of this study is to collect biological samples from patients with a new diagnosis of cancer (blood and tumor tissue) and from individuals who do not have a diagnosis of cancer (blood), in order to characterize the population heterogeneity in cancer and non-cancer participants, and to develop models for distinguishing cancer from non-cancer. The principal goal is to develop a noninvasive cancer detection assay and the CCGA was designed to characterize the landscape of genomic cancer signals in the blood and to detect and validate GRAIL, Inc.’s multi-cancer early detection blood test through three pre-planned sub-studies.
GRAIL, Inc., is a healthcare company focused on the early detection of cancer by using the power of Next-Generation Sequencing, population-scale clinical studies, and state-of-the-art computer science and data science to enhance the scientific understanding of cancer biology, and to develop its multi-cancer early detection blood test. GRAIL’s high efficiency methylation technology preferentially targets the most informative regions of the genome, and is designed to use its proprietary database and machine-learning algorithms to both detect the presence of cancer and identify the tumor’s Tissue of Origin. GRAIL’s sequencing database of cancer and non-cancer methylation signatures is believed to be the largest of its kind, and covers approximately 30 million methylation sites across the genome, with more than 20 cancer types across stages represented within the database.
Previously reported data from the first sub-study of CCGA showed GRAIL’s prototype technology could detect the presence of multiple deadly cancer types with a low rate of false positive results (high specificity). In this analysis blood samples from 166 participants who had a cancer diagnosis at the time of enrollment were evaluated, and cancer was detected using the methylation technology. Results showed that GRAIL’s prototype technology correctly identified the tumor’s Tissue of Origin in 87% of the blood samples evaluated (N=144/166), including 96% of breast cancer cases (N=22/23), 88% of lung cancer cases (N=29/33), 90% of liver cancer cases (N=9/10) and 100% of pancreatic cancer cases (N=17/17).
GRAIL has since selected methylation as its preferred approach and evaluated its refined methylation blood test in the second pre-planned sub-study of CCGA. It was determined that whole-genome bisulfite sequencing for DNA methylation was the most effective approach for early cancer detection. DNA methylation is a natural epigenetic mechanism used by cells to regulate gene expression with some regions of hypermethylation and some regions of hypomethylation, and is a chemical modification to DNA, that can change how a gene’s function is carried out by the body without changing the order of the DNA bases. In cancer, abnormal methylation patterns and the resulting changes in gene expression can contribute to tumor growth (hypermethylation can cause tumor-suppressor genes to be inactivated). Methylation patterns or signatures, are unique to the tumor DNA, enabling tumor detection and localization, but are not of value when it comes to precision therapies. This is unlike mutations and copy number changes, which can be detected in white blood cells in individuals without cancer as well, leading to false-positives.
The researches in this second substudy reported the performance of methylation-based cfDNA early multi-cancer detection test, for GastroIntestinal (GI) tract cancers, and also provided data from individuals without known cancer (non-cancer controls). To test the current assay, the second substudy included approximately 4,500 individuals, both with and without cancer, who were split into a training cohort and a validation cohort. Of the 2,185 patients with newly-diagnosed cancer in the second substudy, 447 patients were diagnosed with GI malignancies. Plasma cfDNA was subjected to targeted methylation analysis to develop an algorithm that could identify the presence or absence of cancer, as well as the Tissue of Origin of the cancer. The GI malignancies included Esophagus/Stomach (N=67), Pancreas/Gallbladder/Extrahepatic bile duct (N=95), Liver/Intrahepatic bile duct (N=29), and Colon/Rectum (N=121). To minimize the likelihood of false-positives, the targeted methylation assay was pre-set to yield greater than 99% specificity.
The test showed a sensitivity level of approximately 82% for detecting GI cancers of all stages in the independent validation set. The predicted Tissue of Origin accuracy across all GI cancers was 92%.
It was concluded that this assay performed using a single noninvasive blood sample, has the potential to diagnose a variety of gastrointestinal cancers earlier, when they are more treatable, with good sensitivity and with a low rate of false positives. Performance of a blood-based test for the detection of multiple cancer types. Wolpin BM, Richards DA, Cohn AL, et al. J Clin Oncol. 2020;38(suppl 4; abstr 283).
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