NEW YORK – New data has demonstrated that sequencing the tumors of relapsing pediatric cancer patients can uncover alterations linked to existing and emerging targeted therapies, potentially offering improved outcomes over standard chemotherapy.
Researchers from France's Gustave Roussy Cancer Center and elsewhere published their findings this Wednesday in Cancer Discovery. Investigators said the results, from a prospective trial called MAPPYACTS (Molecular Profiling for Pediatric and Young Adult Cancer Treatment Stratification), support the use of tumor sequencing for the most well-established genes as a part of the diagnostic workup for all childhood cancer patients.
Birgit Geoerger, professor of pediatric clinical research at Gustave Roussy, said in a statement that while pediatric tumors are increasingly being sequenced, there are relatively few trials that have analyzed the impact of genomically guided targeted therapy.
To a certain extent, this is because childhood cancers have a high rate of remission, even with standard therapies, with 85 percent of patients surviving five years or longer after diagnosis. However, when a pediatric cancer returns, treatment options are much more limited.
In their study, Geoerger and her colleagues prospectively recruited pediatric patients with relapsed cancers, performing comprehensive whole-exome sequencing and/or RNA sequencing in order to identify potential personalized treatment strategies.
Overall, the group collected tissue samples from 787 patients in France, Italy, Ireland, and Spain from 2016 to 2020, with a subset of 624 individuals successfully sequenced.
A clinical molecular tumor board then reviewed the data for each participant, and classified the findings into two groups, either "ready for routine use," which comprised gene alterations with significant clinical evidence supporting targeted drug efficacy, or "potentially actionable," which meant cases where there was at least some evidence that an approved or investigational drug could target the mutated protein or another member of the affected signaling pathway.
Among the 624 sequenced patients, the Gustave Roussy molecular tumor board marked 436 as having potentially actionable alterations, with about 10 percent of those "ready for routine use." Oncologists went on to treat 107 of these individuals with a matched targeted therapy, either alone, in combination with chemotherapy, or with another targeted drug.
About half the patients were treated in the context of a clinical trial, mainly AcSé-ESMART, a basket trial employing drugs that are "currently not adequately employed for pediatric patients in Europe."
According to the authors, almost half of the "ready for routine use" alterations they found in the study were previously unknown, either because patients hadn't been previously sequenced, or because other diagnostics had missed them. Most of these were in patients with tumors of the central nervous system, such as gliomas and medulloblastomas, or anaplastic large cell lymphomas.
For patients who received a matched therapy, the average overall response rate was 17 percent, with a 41 percent disease control rate. For the subset with "ready for routine use" alterations the objective response rate was 38 percent.
In parallel with the study's tumor tissue sequencing, collaborating author and Institut Curie researcher Gudrun Schleiermacher also led an effort to investigate the utility of noninvasive circulating tumor DNA testing.
Though physicians did not make treatment decisions based on this arm of the study, the group was successful in sequencing whole exomes in ctDNA from 128 patients, identifying 94 potentially actionable mutations — about 76 percent of those found in tumor tissue. Liquid biopsy also identified 35 targets that had not been detected by the matched tumor WES.
Overall, Geoerger and colleagues concluded that the results support widespread genomic sequencing of pediatric cancers. The team is continuing its work to assess the resulting impact on patient outcomes in additional studies including the AcSé-ESMART trial and the upcoming MAPPYACTS 2 trial.
"Our recommendation would be to have a sequencing panel for the 'ready for routine use' mutations and fusions," Geoerger said in a statement. "Nearly everybody should have that as part of their diagnostic setup."
The authors wrote that the relatively low proportion of alterations with high-level evidence in the study cohort underlines the current limitations of precision oncology.
They cautioned, though, that during the time period of the study, precision oncology strategies continuously evolved and will hopefully continue to do so.
"Limited understanding of the function of gene variants of unknown significance and lack of insight about post-translational and immunological contexts are major limits of current precision medicine programs [and] our study now further highlights these observations," the group wrote.
"Innovative clinical trials, the development of new technologies that allow cancer characterization beyond the genetic level, the development of combination strategies, and analysis of the personal immune response of each patient are needed to overcome the current limitations," they added.