Nearly half of childhood tumors treated with common chemotherapies carry detectable DNA changes, researchers at The Hospital for Sick Children. The discovery could eventually help clinicians spot treatment resistance earlier, opening the door to a more precise use of chemotherapy.
While childhood cancer outcomes have vastly improved over the past 50 years, chemotherapy can still damage healthy cells and cause lifelong health consequences, including the risk of heart damage or another cancer years later. Such “late effects” are uniquely impactful for children.
“For a young patient with their whole life ahead of them, developing a secondary cancer or cardiac issue a decade later means confronting a new, life-altering crisis in their teens or twenties,” says first author Mehdi Layeghifard, Senior Research Associate at The Hospital for Sick Children.
Genomic signatures
For the study, published in Nature, scientists analyzed more than 600 tumor samples from 544 patients across Canada, Australia and the United States. By pairing whole genome sequencing with detailed treatment histories and computational tools developed in-house, the team identified distinct genomic “signatures” that specific chemotherapy drugs leave behind in surviving cancer cells. Some of these patterns showed up in as little as 91 days after treatment began.
The most notable results centered on platinum-based chemotherapy, a drug class given to roughly half of all pediatric cancer patients. According to the study results, 48 percent of tumors carried a detectable platinum-related signature within a year and a half of treatment.
“We spent years analyzing the data and developing new computational methods to pinpoint these subtle patterns and connect them to specific therapies,” said lead author Adam Shlien, senior scientist and a lab director at Sick Kids.
The research was made possible because researchers had access to detailed chemotherapy exposure information, such as therapy type, dose and timing from so many families, the majority of whom engaged in the SickKids Kids Cancer Sequencing (KiCS) program.
Early warning system
The finding challenges long-held assumptions about pediatric tumors. Shlien noted that childhood cancers have generally been considered stable, making it striking to see how much mutation in relapsed or metastatic tumors traced back to the very chemotherapy used to treat the original cancer.
Researchers say the genomic signatures identified in the study could act as biomarkers to create a potential early warning system for children undergoing cancer treatment.
“Ultimately the goal is for clinicians to use these to identify those patients where they could de-escalate chemotherapy and intervene as early as three months if they see concerning genomic signatures,” said Layeghifard.
In the future, that could mean a blood test for patients of any age who face the need for chemotherapy.
Importantly, the research team validated their findings in independent datasets, which included adult patients.
“We ultimately believe these findings will have tremendous clinical value for adult cancers treated with similar drugs,” said Shlien.