Genomic profiling of pediatric tumors after relapse may widen treatment options
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Genomic sequencing of tumors enabled 107 patients with pediatric cancer who experienced relapse to receive an appropriate matched therapy that is not standard of care, according to study results reported in Cancer Discovery.
The international MAPPYACTS precision medicine clinical trial sought to use results of genetic profiling of tumors to suggest treatments targeted to molecular alterations.
“Most new agents are targeted, and genetic events are often relevant for activity of new such agents,” Birgit Geoerger, MD, PhD, head of the pediatric new drug development program and CLIP2 and group head of pediatric precision medicine and experimental therapeutics at Gustave Roussy Cancer Center in France, told Healio. “We don’t cure 20% of all pediatric cancers — some even to a higher percentage. Cancer remains the leading cause of death in childhood.”
Methodology
Geoerger and colleagues prospectively recruited children and young adults with relapsed cancers and performed comprehensive whole exome sequencing and/or RNA sequencing with the aim of recommending a therapy tailored to each patient.
“Only 4% of cancers have a key driver where a single agent exhibits relevant activity,” Geoerger told Healio. “However, 95% of patients have complexed constellations, which represents the challenge today — how do we address this cancer complexity?”
The analysis included 432 patients from France, Italy, Ireland and Spain with potentially actionable alterations, including 107 treated with a matched targeted therapy, either alone (57%) or in combination with chemotherapy (37%), or in combination with another targeted therapy (11%).
Researchers defined mutations as “ready for routine use” if significant clinical evidence existed that a drug could effectively treat tumors harboring the mutation. They defined mutations as “potentially actionable” if any evidence existed that an approved or investigational drug could target the mutated protein or another member of the affected signaling pathway.
Key findings
Results showed that 42% of the “ready for routine use” alterations discovered by Geoerger and colleagues went undiscovered in previous diagnostics. Additionally, most cancers with “ready for routine use” mutations were tumors of the central nervous system, including gliomas, medulloblastomas or anaplastic large cell lymphomas.
“It didn’t mean an alteration couldn’t be found, rather that nobody looked for it,” Geoerger said in a press release.
Researchers reported an overall response rate of 17% among patients who received a matched therapy, with a 41% disease control rate. Additionally, they reported an objective response rate of 38% among patients with “ready for routine use” alterations who received treatments as monotherapy and a 14% overall response rate among patients with “potentially actionable” mutations.
“Our recommendation would be to have a sequencing panel for the ‘ready for routine use’ mutations and fusions. Nearly everybody should have that as part of their diagnostic setup,” Geoerger said in the release.
Implications
Researchers noted study limitations, including changes in treatment recommendations that occurred after the clinical molecular tumor board issued decisions in 2016, as well as the fact that treatment regimens have not been extensively tested in children. The latter can complicate decisions on dosing and duration, they said.
Geoerger and colleagues concluded, however, that the study results provide evidence for widespread genetic sequencing of pediatric cancers and the matching of patients’ tumor genetic profiles with targeted therapies and their combinations.
“We will have to go beyond the genetic level and address targeting cancer complexity with innovative trial designs, which we will pursue in the MAPPYACTS 2 trial,” Geoerger told Healio.
References:
Berlanga P, et al. Cancer Discov. 2022:doi:10.1158/2159-8290.CD-21-1136.
Genomic profiling of pediatric cancer may expand treatment options for patients experiencing a relapse (press release). https://www.aacr.org/about-the-aacr/newsroom/news-releases/genomic-profiling-of-pediatric-cancer-may-expand-treatment-options-for-patients-experiencing-a-relapse/. Published March 16, 2022. Accessed April 18, 2022.
For more information:
Birgit Geoerger, MD, PhD, can be reached at Gustave Roussy Cancer Campus, Department of Pediatric and Adolescent Oncology, Université Paris-Saclay, 114 Rue Eduard Vaillant, 94805 Villejuif, France; email: birgit.geoerger@gustaveroussy.fr.
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