May 20, 2019
2 min read

Precision medicine ‘can now be a reality’ for hard-to-treat pediatric cancers

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Comprehensive molecular profiling feasibly identified potentially actionable mutations among children and adolescents with hard-to-treat cancers, according to results of a prospective study published in JAMA Network Open.

“The importance of genomic profiling in the diagnosis and treatment of pediatric cancers is reflected in the World Health Organization’s recent decision to classify these tumors by the genetic alterations within them, rather than by broad tumor type,” Daniel Sinnett, PhD, scientific director of the TRICEPS Program and professor in the department of pediatrics at Université de Montréal, said in a press release. “Targeted therapies are likely to become more effective when combined with specific abnormalities in tumor cells. Our results show that precision medicine for pediatric tumors can now be a reality.”

The analysis included 84 patients (mean age, 10.1 years; range, 1-21; 54% male) with hard-to-treat cancers enrolled in TRICEPS, a prospective genome sequencing study conducted in Quebec that sought to identify personalized targeted therapies for children and adolescents with relapsed or refractory cancer.

Of the 84 patients, 62 had tissues suitable for multimodal molecular profiling, including whole-exome sequencing and RNA sequencing. These patients included 37 with solid tumors, 20 with hematologic malignancies and five with brain tumors.

Researchers considered the other 22 patients as screening failures due to benign or necrotic biopsies (n = 7), low tumor content (n = 14) or insufficient material (n = 1).

The mutations observed in the 62 patients included drug-targetable alterations (76%), alterations that modify diagnosis or risk stratification (21%), and alterations with a potential for disease monitoring (37%).

Median time from DNA/RNA isolation to genomic sequencing and data analysis was 24 days (range, 4-41).

Of the 62 patients, 54 (87%) had at least one potentially actionable alteration detected by comprehensive genomic analysis. These alterations might have changed the initial diagnosis (22%) or refined risk stratification (2%). Twenty-three patients (43%) had gene fusions that could be used to detect minimal residual disease (MRD), and 47 (87%) had a mutation that could be targeted by an FDA-approved drug or a drug in a clinical trial.

Of the 191 alterations detected, most (73%) were missense mutations, and most of the remaining (8%) were mutations that resided in indels.

These findings let to action in 22 (41%) of the patients. Another 18 were either on second- or third-line treatment, in remission or had stable disease, so no action was taken.


Disease-specific alterations appeared to be useful in assigning targeted therapies. In one patient with pilocytic astrocytoma, molecular analysis revealed a NF1 mutation. That patient received a MEK inhibitor, and radiologic evaluation after 8 months of treatment showed reductions in primary mass size and enhancing. The patient remains clinically stable.

Researchers also used alterations to monitor MRD. They identified at least one fusion gene expressed in 12 patients with leukemia. A reverse transcriptase PCR-based assay for four of the fusion genes was developed to allow for MRD follow-up.

Researchers identified a fusion in conjunction with a cryptic that was missed by conventional cytogenetics in two patients, which would have changed their stratification and led to treatment on a higher-risk arm.

The small number of patients, as well as their heterogeneous nature, served as study limitations.

“Because of major improvements in caring for children and adolescents with hard-to-treat cancer, studies such as the TRICEPS study will likely become more frequent,” researchers colleagues wrote. “Thus, exploring the ethical issues associated with these studies is important. More than 90% of parents reported that taking part in the TRICEPS study was advantageous for several reasons, but mainly it gave their children ‘all their chances’ and an opportunity to give back (ie, improve care for future patients).” – by John DeRosier

Disclosures: Sinnett reports grants from Ministry of Development, Economy and Innovation in Quebec and Sainte Justine Hospital Foundation and funding as the Francois-Karl-Viau research chair in pediatric oncogenomics. Please see the study for all other authors’ relevant financial disclosures.