Genomic profiling tumors from pediatric patients whose cancer has returned can help a significant proportion receive an appropriately matched therapy, an international European study suggests.
The researchers identified 432 patients with potentially actionable alterations, 30% of whom received treatment with a matched targeted therapy.
“The main purpose [of the study] was to genetically profile the patients’ tumors and use that to suggest a treatment,” Birgit Geoerger, MD, PhD, Gustave Roussy Cancer Campus, University Paris-Saclay, Villejuif, France, said in a statement.
Overall, the trial “underlies the feasibility of molecular profiling at the time of pediatric cancer recurrence on a multicenter international level,” the authors conclude.
The study was published online March 16 in Cancer Discovery.
MAPPYACTS, which stands for Molecular Profiling for Pediatric and Young Adult Cancer Treatment Stratification, is a prospective, precision medicine trial that aims to define tumor molecular profiles in pediatric patients with recurrent or refractory malignancies and determine the most appropriate salvage treatment.
A total of 774 patients from France, Spain, Ireland, and Italy underwent a biopsy, surgical tumor resection, or blood or bone marrow sampling to collect cancer tissue. The median age at study enrollment was 11.6 years and the median time since initial cancer diagnosis at first relapse or progression was 1.8 years. Over one third of the tumors sequenced (37%) were sarcomas followed by central nervous system tumors, other solid tumors, leukemia, and lymphomas.
Molecular profiling was performed on 84% of samples from 88% of patients (n = 679), with successful sequencing on the majority of samples using whole exome (WES), RNA, or panel sequencing. The authors defined a genetic somatic or a germline alteration as “ready for routine use” if there was significant clinical evidence that a drug could treat tumors harboring that mutation. A “potentially actionable” mutation was one that would be theoretically targetable by an approved or investigational agent.
Overall, 436 (69%) of those who underwent successful sequencing had at least one genetic alteration that could be paired with a targeted treatment.
Of those patients, 356 had a minimum follow-up of 12 months, and 30% received recommendations for 122 matched targeted therapies. Only 11% of these therapies (14) were considered “ready for routine use,” while 80% (97) were considered investigational and 9% (11) hypothetical.
Patients received a median of two treatment recommendations for targeted therapies that were given either as a single agent or in combination.
Of 109 patients with evaluable or measurable disease response and evaluation, 17% showed an objective response rate (ORR) to therapy and 25% demonstrated stable disease, for an overall disease control rate of 41%. ORR was more likely among patients with “ready for routine use” alterations (38%) compared with those with “investigational” alterations (14%) and “hypothetical” alterations (10%).
Investigators also explored the role liquid biopsies might play in detecting tumor-specific molecular alterations in advanced pediatric disease. Plasma samples were taken at the time of tissue collection.
Among 190 patients in whom tumor WES analysis was successful, circulating cell free DNA (cfDNA) WES was considered effectively sequenced in two thirds of samples (n = 128). Success was more frequent in patients with metastases than those with localized disease.
Although the researchers did not make treatment decisions based on these results, they did find 94 potentially actionable mutations among 128 patients. Interestingly, among 14 patients, 35 variants in potentially actionable genes were observed by cfDNA WES but not tumor WES.
The hope with liquid biopsy, according to Geoerger, is to spare some children from invasive procedures and allow profiling of tumors that are difficult to biopsy or resect.
Overall, the trial demonstrates the potential usefulness of molecular profiling in pediatric patients whose cancer has recurred, the authors conclude. Based on the results, “our recommendation would be to have a sequencing panel for the ‘ready for routine use’ mutations and fusions,” Geoerger said.
The work was supported by grants from the Institut National du Cancer among others. The authors have disclosed no relevant financial relationships.
Cancer Discovery. Published online March 16, 2022. Abstract
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