Comprehensive genomic profiling with whole-genome sequencing has emerged as a promising approach for pediatric precision medicine. Recently, the Australian Zero Childhood Cancer Precision Medicine Program used this strategy and reported that more than 70% of children with cancer had potentially targetable genomic alterations—and almost a third of patients who received a matched therapy responded.

Research groups worldwide have launched pediatric precision medicine programs to match children with targeted therapies. The Australian Zero Childhood Cancer program uses a comprehensive genomic profiling approach that includes whole-genome sequencing—and they've shown it can be effective: In a recent study, more than 70% of pediatric patients had potentially targetable genomic alterations—and almost a third of those who received matched therapies responded.

About 80% of children with cancer can be cured by standard chemotherapy and radiation. However, the rest either relapse or have few therapeutic options to begin with, pointing to the need for more—and more effective—treatments.

Launched in 2015, Zero Childhood Cancer enrolls children with cancer who have a less than 30% chance of survival at diagnosis or relapse. They undergo germline and tumor whole-genome sequencing and RNA sequencing, as well as methylation profiling for brain tumors. In an analysis of 252 patients, 93.7% had at least one germline or tumor alteration, and 71.4% had an alteration deemed potentially targetable by an existing therapy. Of 38 evaluable patients who received recommended therapies, 11 had objective responses and 14 experienced stable disease. “The fact that we're seeing these responses in such a group was astonishing—we did not expect to see that at all,” says senior author Paul Ekert, PhD, of Murdoch Children's Research Institute in Melbourne, Australia.

“The main thing is that this is feasible, it can be done in real time, have results fed back to patients, and [affect] their treatment and their outcomes,” adds another senior author, David Ziegler, MBBS, PhD, of the Children's Cancer Institute in Sydney, Australia. The researchers now plan to assess whether patients who received targeted therapies lived longer than those who didn't.

Zero Childhood Cancer will expand to include all children with cancer in Australia so that the team can explore whether its approach helps those with intermediate- and low-risk cancers. The researchers are also designing companion trials to improve access to therapies and test combinations. “The ultimate question in the next 4 years is, ‘Does this make difficult-to-survive tumors more survivable?’” Ekert says.

Pratiti Bandopadhayay, PhD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the study, says the program is ambitious, but “they show it can be done.” She praises the use of whole-genome sequencing, which found higher rates of clinically relevant alterations and germline mutations than previous studies. “I think every child with cancer should have their tumor profiled as comprehensively as possible,” she says. However, she notes that such sequencing takes longer to complete than targeted panels, presenting a challenge for widespread adoption.

“This study is not novel in finding that multimodality sequencing provides greater insight than single-modality sequencing, but it's a powerful example of how it can be implemented clinically,” says Charles Mullighan, MD, of St. Jude Children's Research Hospital in Memphis, TN, who was not connected to the work. Although pediatric tumors are often not as genomically complex as adult tumors, he says this study confirms that “the genomic alterations are diverse in nature, and many of those identified have profound implications for treatment.”

At St. Jude, all children diagnosed with cancer undergo comprehensive genomic profiling as part of the Genomes for Kids protocol. “I think there's growing evidence that this approach is here—and it's here to stay—and it's time we did it accurately and well,” Mullighan says.

Stefan Pfister, MD, of the German Cancer Research Center and Hopp Children's Cancer Center in Heidelberg, is an advisor to Zero Childhood Cancer and leads the European INFORM trial, which employs a similar approach. He says the next step in advancing cancer treatment for children is to combine the knowledge and data being gathered by various precision medicine efforts worldwide. “Many of [our] questions can only be answered if we join forces.” –Catherine Caruso

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.