Next-generation sequencing offers hope for kids with cancer

2019 04 26 23 40 2961 Doctor Woman Girl Child 400

Whole exome and RNA sequencing are useful tools for analyzing the molecular profiles of cancers in children and adolescents with a poor prognosis and guiding treatment accordingly, according to a prospective Canadian study published in JAMA Network Open on April 26.

Molecular profiling helped identify genetic mutations that could be acted upon in 54 out of 62 children and adolescents whose tissue could be evaluated in the Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood (TRICEPS) study, reported Fida Khater, PhD, and colleagues at the Centre Hospitalier Universitaire Sainte-Justine in Montreal.

"Despite the challenges associated with translating genomic cancer landscape discoveries into a clinical setting, the TRICEPS study has shown its value to therapeutic management, including treatment options and diagnoses that change patient outcomes," the authors wrote. "By generating clinically actionable findings, the TRICEPS study is establishing processes for incorporating [next-generation sequencing] into routine cancer care."

Room to improve in treating pediatric cancers

Researchers conducted the TRICEPS study in a bid to improve the current treatment landscape for childhood and adolescent cancers, a heterogeneous group of rare diseases that are hard to treat.

While the classification of pediatric cancers has been refined and the rate of overall survival is almost 80%, cases of refractory and recurrent cancers are associated with a poor prognosis and death, the researchers noted.

"The hard-to-treat cancers remain the leading cause of disease-related mortality among children and adolescents in Western countries," Khater et al wrote. "Little progress has been made to further improve the outcomes of these patients, highlighting the urgent need for new research avenues to tackle this challenge."

The advent of next-generation sequencing means there are "unprecedented opportunities to fully characterize cancer genomes" and identify genetic mutations and molecular signatures that may be used to guide treatment, the group explained.

The TRICEPS study was funded by a grant from the government in Quebec, and Khater's research was supported by a fellowship at the Cole Foundation, a private, Montreal-based organization that promotes research in pediatric oncology and hematology.

For the study, the researchers enrolled 84 children and adolescents (mean age, 10 years) with hard-to-treat refractory or relapsed childhood and adolescent cancers who were being seen consecutively at four pediatric oncology centers between 2014 and 2018.

Of the total, tissues for 62 trial participants were suitable for molecular profiling. The researchers analyzed the specimens using the SureSelect XT Clinical Research Exome kit (Agilent) and HiSeq 2500 or 4000 sequencing systems (Illumina) at the Integrated Centre for Pediatric Clinical Genomics of the Centre Hospitalier Universitaire Sainte-Justine.

Results were checked against a panel of genes included in the Catalogue of Somatic Mutations in Cancer (COSMIC) database, FoundationOne Heme profiling test (Foundation Medicine), and My Cancer Genome precision medicine tool.

Tumor mutation burden (TMB), a biomarker that helps inform clinicians about prognosis, was also assessed. A higher number of mutations in tumor cells suggests the cancer is more aggressive but also that it may respond to treatment with immunotherapy drugs.

Profiles matched to targeted treatments

The researchers checked the literature to see whether there were novel treatments available for the genetic alterations they had identified. Khater and colleagues found at least one alteration that was actionable in 54 out of 62 (87%) participants; the most common alterations were missense mutations, which accounted for 38%.

"These alterations might either have changed the initial diagnosis (for 12 of 54 patients [22%]) or refined the risk stratification (for 1 of 54 patients [2%])," they wrote.

The study's multidisciplinary tumor board, which included pediatric oncology, genetics, and pathology experts, came up with a recommendation for treatment, which was provided to patients' referring clinicians.

The pediatric patients' overall TMB was lower than what has been reported for adults, ranging from approximately 1 to 8 mutations per megabase (Mb), with a median of 1.09 mutations/Mb, and 10% of participants had a TMB over 5.

Khater and colleagues reported that out of the 62 participants, 13% had one germline pathogenic variant. They also noted at least one gene fusion that could be used to detect and follow minimal residual disease in 23 patients, most of whom had leukemia and sarcomas.

For 47 patients, experts identified a mutation for which there was a drug approved by the U.S. Food and Drug Administration (FDA) or available through participation in a clinical trial, and nine went on to get a targeted therapy. The rest were either on a targeted drug already, had stable disease, or had died by the time the sequencing results were available.

"The alterations in the targeted therapy category were mostly identified by the [whole exome sequencing], whereas the [minimal residual disease]/biomarker and risk stratification categories were identified by RNA sequencing, illustrating the power of a multimodal strategy," the group wrote.

Treatments included MEK, JAK inhibitors

Overall, whole exome and RNA sequencing spurred treatment decisions in 22 participants, including a patient with pilocytic astrocytoma, a type of brain cancer, who received the MEK inhibitor trametinib (Mekinist, Novartis) and responded to treatment. Another participant with an aggressive type of acute lymphoblastic leukemia was given a JAK inhibitor.

The researchers concluded that molecular profiling is feasible and could be achieved in a median of 24 days, a time frame they described as "clinically reasonable" and in line with what has been reported in other trials.

The number of actionable mutations was higher than what has been reported in other trials, perhaps due to differences in how this was defined, the group acknowledged.

Limitations of TRICEPS included the small number of patients studied and lack of long-term follow-up.

It's likely that studies like TRICEPS will become more commonly done, they suggested.

"The development of standardized definitions for clinical categorization of somatic mutations will be critical to conducting comparative analyses between different genomic testing platforms and patient populations," they concluded.

Page 1 of 51
Next Page