ASCO 2017: New High-Intensity Genomic Sequencing Approach Detects Circulating Tumor DNA at a High Rate
In a study of 124 patients with advanced breast, lung, and prostate cancers, a new high-intensity genomic sequencing approach detected circulating tumor DNA at a high rate. In 89% of patients, at least one genetic change detected in the tumor was also detected in the blood. Overall, 627 (73%) genetic changes found in tumor samples were also found in blood samples with this approach. The study was presented today by Razavi et al at the 2017 ASCO Annual Meeting (Abstract LBA11516).
This innovative approach—using high-intensity sequencing to detect cancer from circulating tumor DNA in the bloodstream—heralds the development of future tests for early cancer detection.
The high-intensity sequencing approach used in this study has a unique combination of breadth and depth. It scans a broad area of the genome (508 genes and more than 2 million base pairs or letters of the genome [ie, A, T, C, and G]) with high accuracy (each region of the genome is sequenced or “read” 60,000 times), yielding about 100 times more data than other sequencing approaches. This enormous amount of data will be instrumental in developing a blood test to detect cancer early.
This approach, however, differs from liquid biopsies, including commercial tests, which only profile a relatively small portion of the genome in patients already diagnosed with cancer for the purpose of helping to monitor the disease or detect actionable alterations that can be matched to available drugs or clinical trials.
“Our findings show that high-intensity circulating tumor DNA sequencing is possible and may provide invaluable information for clinical decision-making, potentially without any need for tumor tissue samples,” said lead study author Pedram Razavi, MD, PhD, a medical oncologist and instructor in medicine at Memorial Sloan Kettering Cancer Center. “This study is also an important step in the process of developing blood tests for early detection of cancer.”
About the Study
The researchers prospectively collected blood and tissue samples from 161 patients with metastatic breast cancer, non–small cell lung cancer (NSCLC), or castration-resistant prostate cancer. A total of 37 patients were excluded due to unavailability of the results of the genetic analysis of the tumor or cell-free DNA samples. For 124 evaluable patients for concordance analysis, researchers compared genetic changes in the tumors to those in circulating tumor DNA from the blood samples. Tumor tissues were analyzed using MSK-IMPACT, a 410-gene diagnostic test that provides detailed genetic information about a patient’s cancer. In each blood sample, the researchers separated plasma from the blood cells. The cell-free DNA extracted from the plasma and, separately, the genome of white blood cells, was then sequenced using the high-intensity, 508-gene sequencing assay.
“Finding tumor DNA in the blood is like looking for a needle in a haystack. For every 100 DNA fragments, only 1 may come from the tumor, and the rest may come from normal cells, mainly bone marrow cells,” said Dr. Razavi. “Our combined analysis of cell-free DNA and white blood cell DNA allows for identification of tumor DNA with much higher sensitivity, and deep sequencing also helps us find those rare tumor DNA fragments.”
Patients’ tumors may have various genetic changes; there can be different changes in different parts of the same tumor, as well as in different sites where the tumor spreads in the body. For these reasons, sequencing over broad regions of the genome is critically important to identify the multitude and diversity of genetic changes in the tumor.
Key Findings
In 89% of patients, at least one genetic change detected in the tumor was also detected in the blood (97% in metastatic breast cancer patients, 85% in those with NSCLC, and 84% in those with metastatic prostate cancer). Overall, including all genomic variations present in most, if not all, tumor cells (clonal), as well as those present only in subsets of the cancer cells (subclonal) from tumor tissue, the researchers detected a total of 864 genetic changes in tissue samples across the 3 tumor types, and 627 (73%) of those were also found in the blood. It is important to note that without any prior knowledge of the analysis of tumor tissue, 76% of actionable mutations detected in tissue were also detected in blood.
“Prior research in the field has primarily focused on using knowledge from tumor tissue sequencing to identify specific changes to look for in circulating tumor DNA. This approach allows us to detect, with high confidence, changes in circulating tumor DNA across a large part of the genome without information from tumor tissue,” said Dr. Razavi. Although circulating tumor DNA tests targeting a smaller set of cancer genes are already available for use in routine practice to guide care, by covering a much larger number of cancer genes, this high-intensity sequencing approach may enable development of future tests for early detection of cancer.
Commentary
“We continue to see promising reports about possible uses of circulating tumor DNA analysis. While this approach has a [way] to go before it becomes a proven technology for early cancer detection, this research is an important step in that direction”, said ASCO expert John Heymach, MD, PhD.
This study was funded in part by GRAIL, Inc.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
