PO.CL07.01 · 临床研究
个体化医疗对神经母细胞瘤患者的临床影响：PREME项目六年经验
Clinical impact of the personalized medicine for neuroblastoma patients: Six years of experience of the PREME program
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PREME（个体化医疗，PeRsonalizEd MEdicine）项目是一项意大利的、多中心、前瞻性研究，聚焦于为早期及复发/难治性神经母细胞瘤（NB）研究可能的分子治疗靶点。
方法：从2019年至2024年，在106例符合条件的患者中入组了86例。通过全外显子组测序（WES）和癌症基因panel（CGP）测序检测分子改变（MA）。体细胞点突变（SPM）被分类为极高优先级（VHP）或高优先级（HP）。
结果：MA，包括体细胞、种系或拷贝数变异（CNVs）：9例在初次诊断时检测到，43例在复发时检测到。具体而言，94%的患者（n=49）检测到SPM，其中9例在疾病发病时，40例在复发时。约35%（n=17）有VHP改变，43%（n=21）有HP改变，22%（n=11）两者兼有。11例患者的样本在疾病病程中的不同时间点进行了分析：初次诊断和复发（n=3），原发和后续复发（n=8）；其中9例检测到肿瘤的分子改变评估结果。在有SPM的患者中，75.5%（n=37）出现了可操作靶点。研究专家委员会提出了分子靶向治疗方案，并在21例患者中实施。ALK是最常见的突变基因（43%），但也检测到其他潜在可操作的改变，无论是在初次诊断时还是在复发时的肿瘤中。在复发时的肿瘤样本中，WES分析发现了编码丝裂原活化蛋白激酶（MAPK；12%的病例）的基因改变、ATM突变（4%）、编码蛋白酶体亚基成员蛋白（PSMC/B；6%）的基因改变，以及其他不太常见的SPM，如6例相应患者中的CULA4、TP53、TNKS、PIK3R1、mTOR和ATR突变。靶向治疗在11例ALK突变患者、2例MAPK改变患者、1例PSMC/B突变患者、1例ATM突变患者以及那6例携带不太常见SPM的患者中实施。总体而言，在所有接受治疗的患者中，3例获得完全缓解，13例部分缓解，2例最佳反应为疾病稳定。3例患者出现疾病进展并随后死亡。31例患者（59.61%）检测到体细胞CNVs；其中，3例患者无SPM，并为其中一例携带TSC2缺失的患者提出了潜在可操作体细胞CNVs的靶向治疗方案。19.2%的患者（n=10）发现了种系改变。
结论：PREME项目是改善难治性/复发性NB预后的有用工具。
查看英文原文 English abstract
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.
利益披露 Disclosure
F. Parisi, None..
E. Ciampi, None..
V. Bensa, None..
F. Serafino, None..
M. Tirelli, None..
L. De Rosa, None..
V. A. Lasorsa, None..
M. Capasso, None..
C. Brignole, None..
L. Amoroso, None..
M. Conte, None..
M. Ponzoni, None..
F. Pastorino, None.