Genomic Profiling of Children May Lead to New Treatments

Pediatric patients whose cancer had relapsed were successfully matched to new gene-targeted therapies in large European trial, according to a study in the AACR journal Cancer Discovery

Dr. Birgit Geoerger

Genomic sequencing can help doctors identify new and emerging treatments for children with cancers that have relapsed after initial therapy, according to results from a European clinical trial published in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). 

The study examined the genetic makeup of the tumors in the children and considered whether they could be given new treatments aimed at specific genetic alternations that are either already in use or being tested in clinical trials. 

“The main purpose was to genetically profile the patients’ tumors and use that to suggest a treatment,” said Birgit Geoerger, MD, PhD, a professor of pediatric clinical research at Gustave Roussy Cancer Center in France. “Are there molecular alterations that we can target with these newer drugs?” 

Pediatric cancers, such as various types of leukemia, lymphoma, glioblastoma, and neuroblastoma, can be successfully treated, with 85 percent of patients surviving five years or longer after diagnosis. However, they also have a high rate of remission, and if the cancer returns, treatment options are limited.  

New cancer treatments have been developed that target mutations in specific genes, such as ALK, BRAF, and NTRK. If these mutated genes can be counteracted, in some cases the growth of the cancer can be slowed or stopped.  

Dr. Geoerger and colleagues initiated the MAPPYACTS clinical trial to recruit pediatric patients with relapsed cancers and perform comprehensive whole exome sequencing (WES) and/or RNA sequencing in order to recommend a therapy tailored to each patient. They collected tissue samples from 774 patients, 632 of which were successfully sequenced. A clinical molecular tumor board then reviewed the sequencing data from each patient. 

Mutations were considered “ready for routine use” if there was significant clinical evidence that a drug could effectively treat tumors harboring the mutation. Mutations were considered “potentially actionable” if any evidence existed that an approved or investigational drug—a drug being tested in clinical trials—could target the mutated protein or another member of the affected signaling pathway.  

The clinical molecular tumor board identified 432 patients with potentially actionable alterations, 107 of whom were then treated with a matched targeted therapy, either alone (57 percent), in combination with chemotherapy (37 percent) or in combination with another targeted therapy (11 percent). Notably, 42 percent of the “ready for routine use” alterations found in this study were previously unknown or had not been identified by previous diagnostics. The majority of cancers with “ready for routine use” were tumors of the central nervous system, such as gliomas and medulloblastomas, or anaplastic large cell lymphomas

Dr. Geoerger said this lack of detection was not because tests for these alterations do not exist, but because they are not always used.  

“It didn’t mean an alteration couldn’t be found, rather that nobody looked for it,” she said. 

The overall response rate of patients who received a matched therapy was 17 percent. In about 25 percent of patients, the disease remained stable, for an overall disease control rate of 41 percent.  

The researchers also investigated the possibility of using circulating tumor DNA (ctDNA)—fragments of tumor cell DNA that circulate in the blood—to identify targetable mutations. Though the researchers did not make treatment decisions based on this arm of the study, they successfully performed WES on ctDNA from 128 patients with matched tumor WES and found 94 potentially actionable mutations, 35 of which had not been detected by tumor WES. Sequencing of ctDNA also successfully identified 76 percent of potentially actionable alterations that were found in tumor tissue.  

Dr. Geoerger hopes that ctDNA sequencing can spare some children from invasive procedures and allow also for the profiling of tumors that are difficult to biopsy or resect, such as those found in the central nervous system. 

“Our recommendation would be to have a sequencing panel for the ‘ready for routine use’ mutations and fusions,” Dr. Geoerger said. “Nearly everybody should have that as part of their diagnostic setup.”