An accurate, scalable approach for monitoring cell-free DNA (cfDNA) from blood samples has been developed.
Reporting in Nature Communications, today, researchers at the Broad Institute of MIT and Harvard, Koch Institute at MIT, Dana-Farber Cancer Institute (DFCI), and Massachusetts General Hospital showed that nearly 90% of a tumor's genetic features can be detected in blood samples using whole-exome sequencing, and that the method can be effectively applied in up to 49% of patients with advanced cancer.
"Our ultimate hope is to use blood biopsies to exhaustively search for and characterize even the smallest remnants of tumors," explained Viktor Adalsteinsson, co-first author on the paper and group leader at the Broad Institute, where he leads the Blood Biopsy Team. "And, as tumors evolve in more advanced stages of cancer, developing resistance or becoming metastatic, we might access timepoints that could be pivotal in deciding which therapies are right for that patient."
Compiling a whole exome from DNA fragments currently requires at least 10% tumor DNA in a blood sample, but the fraction of tumor DNA in the blood can vary wildly from patient to patient.
To address this problem, Gavin Ha, a postdoctoral scholar at the Broad Institute and DFCI, led the development of ichorCNA that can analyze DNA fragments for mutation patterns nearly universal in cancer genomes, and as a result capture cancers with both known and unknown mutations. The research team tested and refined ichorCNA on 1,439 blood samples collected prospectively from 520 metastatic breast or prostate cancer patients.
Using this approach, the researchers found that in 33 to 49% of the metastatic breast and prostate cancer patients, depending upon whether one or multiple blood samples were examined, tumor DNA made up greater than 10% of the cell-free DNA in their blood, enough to make whole-exome sequencing of cell-free DNA feasible.
Then, to determine whether this sequencing of cell-free tumor DNA could offer the same level of insight into cancer genetics as a tissue biopsy could, the team compared surgically obtained tumor biopsies to data collected from whole-exome sequencing of cell-free DNA from a group of 41 patients. The researchers found that genetic data from blood whole-exome sequencing and tissue biopsies matched significantly across a number of genetic features, such as clonal somatic mutations (88% match) and copy number alterations (80% match).
These results support cell-free DNA whole-exome sequencing, from blood samples, as a potential substitute for metastatic tumor biopsy sequencing for many patients.
"Our study has demonstrated that we can get a cancer whole exome reliably, from blood; that it reflects the matched tumor biopsy; and that it can be done for a significant fraction of patients with metastatic cancer," said Adalsteinsson. "This validation suggests that we can use blood biopsies for large-scale genomic characterization of disease in patients with metastatic cancer."
Image: Blood cells. Image courtesy of Dreamstime.