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

Worst BC1, van Tilburg CM2, Balasubramanian GP3, Fiesel P4, Witt R5, Freitag A6, Boudalil M7, Previti C8, Wolf S9, Schmidt S10, Chotewutmontri S11,Bewerunge-Hudler M12, Schick M13, Schlesner M14, Hutter B15, Taylor L16, Borst T17, Sutter C18, Bartram CR19, Milde T20, Pfaff E21, Kulozik AE22, von Stackelberg A23, Meisel R24, Borkhardt A25, Reinhardt D26, Klusmann JH27, Fleischhack G28, Tippelt S29, Dirksen U30, Jürgens H31, Kramm CM32, von Bueren AO33, Westermann F34, Fischer M35, Burkhardt B36, Wößmann W37, Nathrath M38, Bielack SS39, Frühwald MC40, Fulda S41, Klingebiel T42,Koscielniak E43, Schwab M44, Tremmel R45, Driever PH46, Schulte JH47, Brors B48, von Deimling A49, Lichter P50, Eggert A51, Capper D52, Pfister SM53,Jones DT54, Witt O55.

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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.