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Next-generation personalised medicine for high-risk paediatric cancer patients – The INFORM pilot study

2016; Elsevier BV; Volume: 65; Linguagem: Inglês

10.1016/j.ejca.2016.06.009

1879-0852

Barbara C. Worst, Cornelis M. van Tilburg, Gnana Prakash Balasubramanian, Petra Fiesel, Ruth Witt, Angelika Freitag, Miream Boudalil, Christopher Previti, Stephan Wolf, Sabine Schmidt, Sasithorn Chotewutmontri, Melanie Bewerunge‐Hudler, Matthias Schick, Matthias Schlesner, Barbara Hutter, Lenka A. Taylor, Tobias Borst, Christian Sutter, Claus R. Bartram, Till Milde, Elke Pfaff, Andreas E. Kulozik, Arend von Stackelberg, Roland Meisel, Arndt Borkhardt, Dirk Reinhardt, Jan‐Henning Klusmann, Gudrun Fleischhack, Stephan Tippelt, Uta Dirksen, Heribert Jürgens, Christof M. Kramm, André O. von Bueren, Frank Westermann, Matthias Fischer, Birgit Burkhardt, Wilhelm Wößmann, Michaela Nathrath, Stefan Bielack, Michael C. Frühwald, Simone Fulda, Thomas Klingebiel, Ewa Kościelniak, Matthias Schwab, Roman Tremmel, Pablo Hernáiz Driever, Johannes H. Schulte, Benedikt Brors, Andreas von Deimling, Peter Lichter, Angelika Eggert, David Capper, Stefan M. Pfister, David Jones, Olaf Witt,

Lung Cancer Treatments and Mutations

The ‘Individualized Therapy for Relapsed Malignancies in Childhood’ (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of ‘intermediate’ or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase–mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine.