Tumors In Kids Change Quickly, Making Target Treatment Tricky

New studies hoped to find recurring genome mutations to target treatment, but relatively few were found.

An extensive study of the childhood cancer neuroblastoma has reinforced the challenges in treating the most aggressive forms of this childhood cancer. The disease, which begins as a cancerous tumor generally in the chest or abdomen and can spread to the bones and other areas of the body, accounts for 10 to 15 percent of all childhood cancer-related deaths. It occurs mostly in children under the age of 5.

In hopes of finding recurrent gene mutations that would suggest new targets for neuroblastoma treatments, scientists studied the DNA of children with the disease. However, contrary to expectations and hopes, the scientists found relatively few recurrent gene mutations. Now, researchers say, they have focused their research on how the tumor forms and develops, rather than genetic markers that would allow for more accurate treatments. Treatment decisions, therefore, will continue to be made on where the caner is and how it is spreading. Researchers had hoped that genetic markers would highlight specific target areas for treatment.

“This research underscores the fact that tumor cells often change rapidly over time, so more effective treatments for this aggressive cancer will need to account for the dynamic nature of neuroblastoma,” said study leader John M. Maris, M.D., director of the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia (CHOP).

Neuroblastoma strikes the peripheral nervous system, and notoriously complex, with a broad number of genes changes that can give rise to the disease.

Maris headed the multicenter research collaborative, the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) initiative, which is the largest genomic study of a childhood cancer to date. The finding were released January 20 in Nature Genetics. The study analyzed DNA from 240 children with high-risk neuroblastomas. Using a combination of whole-exome, whole-genome and transcriptome sequencing, the study compared DNA from tumors with DNA in normal cells from the same patients.

Researchers at CHOP and other centers previously discovered neuroblastoma-causing mutations, such as those in the ALK gene. When this occurs, oncologists can provide effective treatment tailored specifically to one child’s genetic profile. Researchers were hoping this study would expand on those earlier findings.

“A few years ago, we thought we would be able to sequence the genomes of individual patients with neuroblastoma, detect their specific cancer-causing mutations, and then select from a menu of treatments,” said Maris.

However, while the researchers confirmed that roughly 10 percent of the study’s neuroblastoma patients had ALK mutations, and found that a handful of other gene mutations each accounted for percentages in the single digits, there were relatively few recurrent mutations in somatic (non-germline) cells. “The relative paucity of recurrent mutations challenges the concept that druggable targets can be defined in each patient by DNA sequencing alone,” wrote the researchers.

“Personalized medicine is more complex than we had hoped,” Maris summarizes. “While there are successes such as those in treating patients whose tumors harbor ALK mutations, this study implies that we must think very differently about how we’ll use genomics to define treatment.”

Researchers are now back to understanding the disease, and basing treatments on how the cancer spreads and which parts of the body are effected. While the overall cancer death rate is slowly declining, neuroblastoma is still the deadliest form of childhood cancer.