Next-generation personalised medicine for high-risk paediatric cancer patients – The INFORM pilot study. (September 2016)

• Record Type: Journal Article
• Authors: Worst, Barbara C.; van Tilburg, Cornelis M.; Balasubramanian, Gnana Prakash; Fiesel, Petra; Witt, Ruth; Freitag, Angelika; Boudalil, Miream; Previti, Christopher; Wolf, Stephan; Schmidt, Sabine; Chotewutmontri, Sasithorn; Bewerunge-Hudler, Melanie; Schick, Matthias; Schlesner, Matthias; Hutter, Barbara; Taylor, Lenka; Borst, Tobias; Sutter, Christian; Bartram, Claus R.; Milde, Till; Pfaff, Elke; Kulozik, Andreas E.; von Stackelberg, Arend; Meisel, Roland; Borkhardt, Arndt; Reinhardt, Dirk; Klusmann, Jan-Henning; Fleischhack, Gudrun; Tippelt, Stephan; Dirksen, Uta; Jürgens, Heribert; Kramm, Christof M.; von Bueren, Andre O.; Westermann, Frank; Fischer, Matthias; Burkhardt, Birgit; Wößmann, Wilhelm; Nathrath, Michaela; Bielack, Stefan S.; Frühwald, Michael C.; Fulda, Simone; Klingebiel, Thomas; Koscielniak, Ewa; Schwab, Matthias; Tremmel, Roman; Driever, Pablo Hernáiz; Schulte, Johannes H.; Brors, Benedikt; von Deimling, Andreas; Lichter, Peter; Eggert, Angelika; Capper, David; Pfister, Stefan M.; Jones, David T.W.; Witt, Olaf;
• Is Part Of: European journal of cancer. Volume 65(2016)
• Page Start: 91
• Page End: 101
• Publication Date: 2016-09
• Subjects: Personalised medicine -- Oncology -- Paediatrics -- Precision medicine -- Molecular targeted therapy -- Deep sequencing -- Cancer -- Sarcoma -- Brain; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2016.06.009
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: 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. Highlights: Germany-wide personalised medicine study for high-risk paediatric cancer patients. Comprehensive sequencing and analysis is feasible in clinically relevant time frame. Half of patients across entities harbored a reasonable confidence druggable target. Cases of clinical response to targeted agents demonstrate proof of principle. This model can expand paediatric access to molecular profiling and targeted therapies.