Improved methods validate the use of blood samples for studying patients’ cancer genomes.

Researchers at the Broad Institute of MIT and Harvard, Koch Institute at MIT, Dana-Farber Cancer Institute, and Massachusetts General Hospital Cancer Center have developed an accurate, scalable approach for monitoring cancer DNA from blood samples.

The team demonstrated 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—a number likely to increase as sequencing becomes cheaper. This less-invasive tumor sampling, as a window into the cancer’s genome, has a range of potential applications.

“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.”

This ability to detect and analyze cancer DNA from a patient’s blood sample is emerging as a promising alternative to invasive surgical biopsies, which can be difficult, painful, and costly—especially when tumors have appeared in locations that are challenging to access.

Blood biopsies are poised to overcome many of these issues. They have the potential to allow doctors to track the progress of disease and treatment in real-time and to help researchers understand how tumors resist treatment with far greater resolution.

Cells in the body, including tumor cells, regularly expel fragments of DNA into the bloodstream when they die. With blood biopsies, clinicians collect this “cell-free” DNA from a blood draw and then detect and comprehensively profile the fragments originating from cancer cells. Tracking this data could make it possible to monitor cancer recurrence, a patient’s response to treatment, and other clinically important features, all from blood samples.

The research and development arena for blood biopsies is frequented by both academic and industry players, but with scalable whole-exome sequencing, a team led by Adalsteinsson and colleagues Gavin Ha, Sam Freeman, Matthew Meyerson, J. Christopher Love, and Gad Getz is taking the field in a new and innovative direction.

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. Because of this variation, the team first desired an unbiased approach for detecting and measuring levels of cancer DNA before attempting whole-exome sequencing.

Across the field, many blood biopsy methods detect tumor DNA by screening for mutations in known cancer-related genes, but this targeted sequencing misses cancers without those mutations.

Co-first author Ha, a postdoctoral scholar at the Broad Institute and Dana-Farber Cancer Institute (DFCI), led the development of a tool called 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. Ha focused on detecting stretches of DNA that have either fewer or greater copies in cancer cells, in contrast to healthy cells.

The research team tested and refined ichorCNA on 1,439 blood samples collected prospectively from 520 metastatic breast or prostate cancer patients at DFCI (a significant effort championed by medical oncologists Atish Choudhury, Daniel Stover, Heather Parsons, Nikhil Wagle, and colleagues).

Using this approach, the researchers found that in 33% to 49% of the metastatic breast and prostate cancer patients, depending upon whe