Molecular profiling of 888 pediatric tumors informs future precision trials and data-sharing initiatives in pediatric cancer

Abstract

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children's Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Fig. 1. CONSORT diagram of analytic cohort.

Flow chart illustrating derivation of the final study cohort.

Fig. 2. Longtail of patient diagnoses classified by ICD-O-3.2.

The number of tumors sequenced with each pathologic diagnosis are shown. Diagnoses are color coded by disease sub-group. Diagnoses marked with * and in bold were not included in two prior pediatric pan-cancer sequencing studies^,.

Fig. 3. The distribution of pediatric extracranial solid tumor diagnoses represented in this study cohort compared to the NCCR Registries 2014-2018.

The percentage of patients with each extracranial solid tumor diagnosis or diagnosis group is shown.

Fig. 4. Patients with oncogenic tumor variants matching to a treatment arm of the NCI-COG Pediatric MATCH Trial, NCI-MATCH Trial, or ASCO TAPUR Study.

Gene altered and corresponding matching targeted therapy type are shown. The size of each dot represents the number of patients with a matching variant in that gene, and the color of the dot represents the type of variant. Matched patients’ diagnosis grouping is shown by gene and type of targeted treatment.

Fig. 5. Patients who received molecularly targeted therapy to identified aMOIs.

The number and proportion of patients who received matched therapy is shown by inhibitor type. The black color indicates receipt of matched therapy via single patient protocol or off-label, and the red color indicates receipt of matched therapy on a clinical trial.

Fig. 6. OncoPrint showing most common oncogenic alterations in the histologies not included in two prior pediatric pan-cancer sequencing studies.

Alterations with > 1% frequency within the shown patients are displayed along with clinical features of each case for a Extracranial solid tumors (n = 235) and b CNS tumors (n = 75).