Clinical impact of the personalized medicine for neuroblastoma patients: Six years of experience of the PREME program

Background: PREME (PeRsonalizEdMEdicine) program is an Italian, multicentric, prospective study focused on research of possible molecular therapeutic targets for early and relapsed/refractory neuroblastoma (NB). Methods: From 2019 to 2024, 86 patients were enrolled out of 106 eligible. Molecular alterations (MA) were detected by whole-exome-sequencing (WES) and by Cancer Gene Panel (CGP) sequencing. Somatic Point Mutations (SPM) were classified as either Very-High-Priority (VHP) or High-Priority (HP). Results: MA, including somatic, germline or copy-number-variations (CNVs): 9 were detected at first diagnosis and 43 at relapse. Specifically, SPM were detected in 94% of patients (n=49), 9 at disease-onset and 40 at relapse. Around 35% (n=17) had VHP alterations, 43% (n=21) HP and 22% (n=11) both. Samples from 11 patients were analyzed at different times during the course of disease: first diagnosis and relapse (n=3), primary and further relapses (n=8); in 9 of those, assessment of molecular tumor changes were detected. An actionable target emerged in 75.5% of patients with SPM (n= 37). A molecular target-therapy was proposed by the study-expert-board, which was implemented in 21 patients. ALK was the most frequent mutated gene (43%), but other potentially actionable alterations were detected, both in tumor at first diagnosis and at relapse. Among tumor samples at relapse, from WES analysis emerged alterations in gene encoding for mitogen-activated protein kinase ( MAPK ; 12% of cases), ATM mutation (4%), in gene encoding for proteasome subunit member proteins ( PSMC/B ; 6%) and other less common SPMs, such as CULA4 , TP53 , TNKS , PIK3R1 , mTOR , and ATR mutations in 6 corresponding patients. Targeted-therapy was implemented in 11 patients with ALK mutations, in 2 patients with MAPK alterations, in one patient with PSMC/B mutation, in one patient with ATM mutation and in those 6 patients harboring the less common SPMs. Generally, among all patients treated, a complete remission was obtained in 3 patients, a partial response in 13, and stable disease as best response in 2 cases. A progression disease and subsequent death occurred in 3 patients. Somatic CNVs were detected in 31 patients (59.61%); among them, 3 patients showed no SPM and a targeted-therapy potentially actionable somatic CNVs was proposed for one of those harboring TSC2 -deletion. Germline alterations were found in 19.2% of patients (n=10). Conclusions: PREME program is a useful tool to improve the prognosis of refractory/relapsing NB.