The individualized THERapies for children with cancer or iTHER is the Dutch prospective national precision oncology program aiming to define the molecular profiles of very high-risk, primary, relapsed or refractory tumors in children and adolescents. iTHER demonstrated its feasibility by running next generation sequencing techniques, and as of 2022 became the Maxima Precision Program (MaxPM). Next-generaton sequencing is nowadays run as a standard-of-care for diagnostics, with approximately 600 patents with primary tumors and 150 relapse cases per year in The Netherlands. Approximately 70 patents per year are registered in MaxPM and for these patents an additional analysis by disease-specific experts is performed to prioritize targets for precision medicines.

Within iTHER, next generation sequencing techniques like whole exome (WES), RNA sequencing as DNA methylation profiling (solid and brain tumors) are performed in all pediatric patients of different ages, and with different tumor types and stages (Langenberg et al., 2022). Between April 2017 and April 2021, samples of 253 patients were included and WES, RNA-seq, and DNA methylation successfully were performed in 226 samples, providing highly valuable information on diagnosis, prognosis, and targetable alterations. Since the start of MaxPM until December 2023, 116 patents were analyzed, including 15 brain tumors, 16 soft tissue sarcomas, 52 other solid tumors, 33 hematological malignancies. For two-thirds of these patients MaxPM analysis was done on a relapse sample and for one-third the patient was included because of primary high-risk or refractory disease.

Through iTHER/MaxPM, we expect to improve diagnosis, prognosis, risk stratification, the

identification of targetable lesions as well as reportable germline variants. Furthermore, we expect to accurately match these lesions with the most optimal treatment according to the disease unique characteristics. The program will provide improved access to innovative treatments within biology-driven combination trials and pathway-targeting agents that is required to ultimately improve survival.

Bas Tops, Diagnostic Lab

Patrick Kemmeren, Big Data Core

Jan Molenaar and Max v. Noesel, Solid Tumors Group

Judith Boer, Hematological malignancies group

Jarno Drost , Soft Tissues group

Ester Hulleman, Brain tumors group

In iTHER, high-throughput, sequencing-based, predictive biomarker detection in tumor material is implemented through WES, RNAseq and methylation profiling.

Langenberg, K. P., Meister, M. T., Bakhuizen, J. J., Boer, J. M., van Eijkelenburg, N. K., Hulleman, E., & Molenaar, J. J. (2022). Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’. European Journal of Cancer, 175, 311-325.