Genomic sequencing of tumors from pediatric cancer patients who had relapsed enabled 107 patients to receive appropriate, matched therapy that is not the standard of care, according to data from the international clinical trial MAPPYACTS, published in Cancer Discovery, a journal of the American Association for Cancer Research.
Pediatric cancers have a high rate of remission, with 85 percent of patients surviving five years or more after diagnosis. However, if the cancer returns, treatment options are limited.
“The main goal was to genetically profile the patients’ tumors and use that to suggest treatment,” said Birgit Geoerger, MD, PhD, a professor of pediatric clinical research at the Gustave Roussy Cancer Center in France. . “Are there molecular changes we can target with these newer drugs?”
In many cases, pediatric cancers are subjected to gene panel sequencing, which involves sequencing the common cancer driver genes to look for mutations. While this information can provide valuable insights into how the tumor works, it is not commonly used to guide treatment decisions. “There aren’t many studies testing targeted therapies in children,” Geoerger said.
Geoerger and colleagues initiated the MAPPYACTS clinical trial to prospectively recruit pediatric patients with recurrent cancers and perform comprehensive complete exome sequencing (WES) and/or RNA sequencing to recommend a therapy tailored to each patient. They collected tissue samples from 774 patients, 632 of which were successfully sequenced. A clinical tumor molecular board then reviewed each patient’s sequence data.
Mutations were considered “ready for routine use” if there was significant clinical evidence that a drug could effectively treat tumors with the mutation. Mutations were considered “possibly actionable” if there was any evidence that an approved or investigational drug — one 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 useful changes, of whom 107 were treated with matched targeted therapy, either alone (57%), in combination with chemotherapy (37%), or in combination with another targeted therapy (11% ). Notably, 42 percent of the “routine-ready” changes found in this study were previously unknown or had not been identified by prior diagnostics. Most cancers with mutations ready for routine use were tumors of the central nervous system, such as gliomas and medulloblastomas, or anaplastic large cell lymphomas.
Geoerger said this lack of detection was not because tests for these changes don’t exist, but because they aren’t always used. “It didn’t mean that no change could be found, but that no one was looking for it,” she said.
The overall response rate of patients receiving matched therapy was 17%, with a disease control rate of 41%. Of the patients with ready-to-routine adaptations, who all received their treatments as monotherapy, the objective response rate was 38%. Patients with potentially useful mutations who were not ready for routine use had an overall response rate of 14%.
The researchers also explored the possibility of using circulating tumor DNA (ctDNA) — fragments of tumor cell DNA that circulate in the blood — to identify targeted mutations. Although 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 useful mutations, 35 of which had not been detected by tumor WES. Sequencing of ctDNA also successfully identified 76 percent of the potentially useful changes found in tumor tissue.
In addition to explaining tumor heterogeneity that traditional biopsies may lack, Geoerger hopes that liquid biopsies could save some children from invasive procedures and also enable the profiling of tumors that are difficult to biopsy or remove, such as those found in the central nervous system.
Overall, Geoerger believes that this study provides evidence for widespread childhood cancer genetic sequencing and matching the genetic profiles of tumors with targeted therapies and their combinations, research she and her colleagues are continuing in the concurrent AcSé-ESMART study. study and the upcoming MAPPYACTS 2 trial.
“Our recommendation would be to have a sequential panel for the ‘ready for routine use’ mutations and fusions,” Geoerger said. “Almost everyone should have that as part of their diagnostic setup.”
Limitations of this study include the fact that changes in treatment recommendations have evolved since the Clinical Molecular Tumor Board made its decisions in 2016. Furthermore, many of these treatment regimens have not been extensively tested in children, which can complicate dosage and duration decisions. †
This study was funded by the Institut National du Cancer, the Fondation ARC, the Association Imagine for Margo, the Fédération Enfants et Santé, the French Society for the Fight against Childhood and Adolescent Cancer and Leukemia, Dell, the Annenberg Foundation, Association Hubert Gouin —Enfance et Cancer, Meghanora, Fundación FERO, Fundación Rotary and Gustave Roussy Cancer Center. The authors declare no conflicts of interest.
This press release was originally published by the American Association of Cancer Research on March 16, 2022.
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