JCO Precis Oncol 2022 Apr
Comprehensive Genomic Profiling ofHigh-Risk Pediatric Cancer Patients Has aMeasurable Impact on Clinical Care
Abstract
Purpose
Profiling of pediatric cancers through deep sequencing of large gene panels and whole exomes is rapidly being adopted in many clinical settings. However, the most impactful approach to genomic profiling of pediatric cancers remains to be defined.
Methods
We conducted a prospective precision medicine trial, using whole-exome sequencing of tumor and germline tissue and whole-transcriptome sequencing (RNA Seq) of tumor tissue to characterize the mutational landscape of 127 tumors from 126 unique patients across the spectrum of pediatric brain tumors, hematologic malignancies, and extracranial solid tumors.
Results
We identified somatic tumor alterations in 121/127 (95.3%) tumor samples and identified cancer predisposition syndromes on the basis of known pathogenic or likely pathogenic germline mutations in cancer predisposition genes in 9/126 patients (7.1%). Additionally, we developed a novel scoring system for measuring the impact of tumor and germline sequencing, encompassing therapeutically relevant genomic alterations, cancer-related germline findings, recommendations for treatment, and refinement of risk stratification or prognosis. At least one impactful finding from the genomic results was identified in 108/127 (85%) samples sequenced. A recommendation to consider a targeted agent was provided for 82/126 (65.1%) patients. Twenty patients ultimately received therapy with a molecularly targeted agent, representing 24% of those who received a targeted agent recommendation and 16% of the total cohort.
Conclusion
Paired tumor/normal whole-exome sequencing and tumor RNA Seq of de novo or relapsed/refractory tumors was feasible and clinically impactful in high-risk pediatric cancer patients.
Related Questions
How do you envision genomic scoring systems for pediatric cancers being applied in a real-world setting?
We see our impact in genomic scoring system being used to compare the impact of different and evolving tumor genomic sequencing platforms as the NGS assays (and soon cell free tumor (CT) DNA NGS platforms) are constantly being refined and used for clinical care decisions. Some platforms are more com...
What are the perceived implications of broader genomic sequencing as it pertains to interpreting variants of unknown significance and germline predisposition mutations?
Variants of unknown significance (VUS) are constantly being revised when it comes to identifying “potentially pathogenic mutations.” We work with a molecular pathologist as well as the pathologists at Exact Sciences to understand in real time where VUSs fall in regards to their pathogenicity and act...
What is your current practice around genomic sequencing for pediatric cancers?
As mentioned in our article, we currently offer tumor genomic sequencing to patients who have high risk pediatric cancers at diagnosis who do not routinely undergo molecular characterization as a standard of care diagnostic procedure and for pediatric cancer patients whose tumors are refractory to t...
Do you feel that more frequent genomic sequencing will be cost-effective in the management of high-risk pediatric cancers?
Currently, the increased utilization of tumor genomic sequencing in pediatric cancer (which I assume you mean by “more frequent sequencing”) has resulted in more companies and academic practices implementing NGS platforms and on-site sequencing. This increased clinical use leads to an increased numb...