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UK Study Shows Benefits of Whole-Genome Sequencing for Children With Cancer


NEW YORK – A study published Tuesday in Nature Medicine demonstrated the usefulness of routine whole-genome sequencing (WGS) in diagnosing and clinically managing children suspected of having cancer within the UK's National Health Service.

Previous studies have suggested that WGS has utility in diagnosing pediatric cancers, which can often be driven by gene alterations that are therapeutically targetable. To date, however, WGS has mostly been implemented within academic facilities and large, regional healthcare systems for children with high-risk tumors and relapsed disease. But some countries have launched WGS-focused initiatives, including the Genomic Medicine Service within the NHS. One of the goals of the service, which was introduced in 2018 and built out of the NHS 100,000 Genomes Project, is to deliver WGS to every child in England with a suspected cancer.

Despite increasing interest in using WGS to diagnose childhood cancers, according to the authors of the Nature Medicine paper, no studies thus far have compared the benefits of incorporating WGS into routine clinical practice against using standard-of-care molecular tests for all children with suspected cancer. Researchers with the Wellcome Sanger Institute, Cambridge University Hospitals NHS Trust, Great Ormond Street Hospital, and the University of Cambridge explored this in the new study by analyzing the use of routine WGS at Cambridge University and Great Ormond Street hospitals.

The researchers offered WGS to all children suspected of having cancer at the two study sites, including tumor and germline testing, and 289 out of 291 families accepted. The analysis included sequencing data on 282 tumors from 281 children, of whom 19 had relapsed disease. The median turnaround time for return of WGS results was 18 days for solid tumors and 19 days for hematological malignancies.

The researchers reported that WGS provided a clinical benefit to patients in 24 percent of cases in terms of faster results, aiding diagnosis, or offering additional diagnostic information compared to standard-of-care molecular tests. WGS also enabled the use of targeted drugs in pediatric patients with specific, clinically actionable genetic variants. Testing also directly changed clinical management of 20 children, or about 7 percent of cases.

In one case of a child with thoracic neuroblastoma, WGS identified a germline pathogenic variant in the PALB2 gene associated with a higher risk of breast cancer. That allowed her doctors to change the radiotherapy field to avoid exposing her breast buds to radiation. That PALB2 variant was not identified by previous, less comprehensive molecular testing the child received.

In another example, investigators discovered an IGH-DUX4 gene fusion in a child with B-cell acute lymphoblastic leukemia via WGS that is rarely detected by standard molecular tests. That child would normally have received intensive therapy, but because that genetic alteration is associated with a good, but slow response, doctors were confident in not escalating therapy.

The study authors noted that WGS was particularly helpful for children with non-neoplastic bone marrow failure, who are typically tested on as many as four different targeted gene sequencing panels, and it can take months to return results. In contrast, in this study, WGS results came back to families in a median 17 days, allowing patients to move quickly to therapy.

Sam Behjati, a senior study author and a professor of pediatric oncology at the University of Cambridge, said his team was expecting to see benefits from WGS in terms of identifying actionable mutations that allow pediatric patients to receive targeted therapies. However, they were surprised to find that much of the clinical benefit seen in the study was less direct, such as the patient for whom they altered radiotherapy field. "[Whole-genomic sequencing] was helpful in all sorts of other very roundabout but tangible ways that enabled us to better deliver treatment," Behjati said.

Jack Bartram, another senior study author and a pediatric hematologist at Great Ormond Street Hospital, noted that in addition to showing the benefit of WGS in patient care, the study also tested the robustness of the Genomic Medicine Service. The service is organized into seven hubs that process tests for the whole country. In conducting the study, the researchers streamlined the logistics around routine WGS testing and those process improvements will now impact future WGS tests performed for children with suspected cancer. "We now have true equity of access so every patient can access this test wherever you are in the country," Bartram said.

According to Bartram, turnaround time was the biggest challenge the researchers faced because each patient sample had to be sent to a genomic laboratory hub where the DNA was extracted and sequenced. Centralized testing ensured there were enough samples to allow a sequencer to run continuously — 24 hours a day, seven days a week — taking advantage of economies of scale. Once the sequencing was completed and results released, a molecular tumor board discussed the findings and shared a report with the physician. Because of the many steps involved, Bartram said it was "challenging at the beginning" to get results quickly, "but now we have shown that it can be done as quickly as 10 days, if you really pull out all the stops."

Behjati placed particular emphasis on the comparison his team did of the utility of WGS testing and individual molecular tests or sequencing panels. "Whole-genome sequencing faithfully reproduces every single test result and a whole lot more," Behjati said. "You could think of a future where everybody uses whole-genome sequencing as their initial molecular test to get all the information they need to treat children with cancer accurately."

The researchers have already begun a study in Sweden and France to reproduce their results in a large, international patient cohort, which they hope will show that WGS is equivalent to standard-of-care molecular testing across different health systems and treatment protocols. That study will include 1,000 children to 2,000 children.

Behjati said his team will also continue to expand the current study by enrolling more children from the NHS, estimating that in two years they may enroll an additional 1,500 children.

In addition to more validation data, before WGS can be routinely implemented in the NHS for all children suspected of having cancer, the researchers must assess the true cost of WGS per patient, and such a cost-effectiveness study is already in the works. "We've proved it can replace all those standard-of-care molecular diagnostics, but financially, is it viable?" Bartram said.