Whole-Genome Sequencing Emerging for Routine Cancer Care

M. Alexander Otto, PA, MMS

March 11, 2021

Almost 20 years after the human genome was first mapped, whole-genome sequencing might finally be ready to enter routine cancer care.

Researchers at Washington University in St. Louis, St. Louis, Missouri, are commercializing an automated sequencing method they developed to improve risk stratification of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The method, which is called ChromoSeq, may be expanded for use in other types of cancer, including solid tumors.

In a proof-of-concept study published online March 11 in The New England Journal of Medicine, the researchers used ChromoSeq to genetically profile 263 patients with AML or MDS treated at the university and then compared the results with results from conventional piecemeal genetic testing.

Whole-genome sequencing identified all 40 recurrent translocations and 91 copy number alterations picked up by cytogenetic testing. It identified additional relevant genetic variations in 40 of 235 patients (17%).

Sequencing of the 117 prospective patients in the study provided new genetic data on 29 patients (25%), more than half of whom would have been assigned to a different ― generally lower ― genetic risk category on the basis of standard screening.

ChromoSeq is "a reliable and practical approach for detecting all of the changes that are important for assessing the risk of relapse for AML and MDS patients, using a single test. This approach can be performed when conventional testing methods are unsuccessful and also could be applied to other cancers, including solid tumors," senior author David Spencer, MD, PhD, assistant professor of medicine and medical director of Washington University's clinical sequencing facility, commented in a statement.

A One-Stop Shop

If it pans out, "a combined whole-genome sequencing process that yields all of these results together with one test within about 5 days would be absolutely practice changing," said Thomas LeBlanc, MD, a leukemia specialist and associate professor of medicine at Duke University, Durham, North Caroline, when asked for comment.

"What's most impressive is that they actually beat the traditional way of doing AML risk stratification, and they did so in less time than it usually takes now," LeBlanc said.

Genetic signatures are key to risk stratification of myeloid cancers and to selecting optimal treatment, but current testing is piecemeal, spread across several platforms, each with its own limitations. Karyotyping, for instance, requires cancer cell culture, but the cells don't always grow. Fluorescence in situ hybridization and next-generation sequencing assess prespecified targets and can miss others.

Treatment decisions need to be made quickly, but test results can take a few weeks. "It's a problem when many of them just take too long to come back," LeBlanc said.

The ChromoSeq study "demonstrates, first, that this technology can be implemented in real-world clinical practice, and second, that we can make more accurate choices of treatments for patients with blood cancers," commented Peter Campbell, MD, PhD, leader of cancer genome sequencing research at the Wellcome Sanger Institute in Cambridge, United Kingdom. He was not involved in the study and was commenting in the University of Washington press release.

"Our task is now to take this blueprint for blood cancers and apply it to all cancers....

"We stand on the threshold of an era in which we can identify every relevant genetic change in a given patient's cancer in real time," he added.

Commercial Launch Soon

Spencer and his colleagues have been working for years to solve the piecemeal testing problem with whole-genome sequencing. The cost and complexity have come down enough in recent years, making it clinically feasible for routine practice, they say.

Turnaround time in the study was a median of 5.1 days and was as short as 3 days. The technical cost of ChromoSeq was about $1900 per patient, similar to the $1000 to $2000 price tag for conventional testing, but Spencer told Medscape Medical News that he anticipates that the commercial cost will be higher.

The Washington University team is working with insurance companies to establish coverage indications and reimbursement rates. They anticipate that ChromoSeq will launch this spring in the St. Louis–area Barnes Jewish Hospital system. The idea is to roll the test out locally and "then more broadly once we have everything in place. We would like to offer this to patients from elsewhere," Spencer said.

As for other cancer types, the team notes that whole-genome sequencing can be performed on DNA from solid-tumor biopsy specimens, which are often insufficient for molecular assays and are difficult to culture for cytogenetics. The team hopes to extend ChromoSeq to other cancers soon.

The work was funded by Alvin J. Siteman Cancer Research Fund, the National Cancer Institute, and the National Center for Advancing Translational Sciences. Reagents were provided by Illumina. one of the investigators is a consultant for Illumina. Spencer and several coauthors have various ties to pharmaceutical companies. LeBlanc has disclosed no relevant financial relationships.

N Engl J Med. Published online March 11, 2021. Abstract

M. Alexander Otto is a physician assistant with a master's degree in medical science and a Newhouse journalism degree from Syracuse University. He is an award-winning medical journalist who worked for McClatchy and Bloomberg before joining Medscape, and also a MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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