Discovery of actionable genetic alterations with targeted panel sequencing in children with relapsed or refractory solid tumors

Advances in genomic technologies and the development of targeted therapeutics are making the use of precision medicine increasingly possible. In this study, we explored whether precision medicine can be applied for the management of refractory/relapsed pediatric solid tumors by discovering actionable alterations using targeted panel sequencing. Samples of refractory/relapsed pediatric solid tumors were tested using a targeted sequencing panel covering the exonic DNA sequences of 381 cancer genes and introns across 22 genes to detect clinically significant genomic aberrations in tumors. The molecular targets were tiered from 1 to 5 based on the presence of actionable genetic alterations, strength of supporting evidence, and drug availability in the Republic of Korea. From January 2016 to October 2018, 55 patients were enrolled. The median time from tissue acquisition to drug selection was 29 d (range 14–39), and tumor profiling was successful in 53 (96.4%) patients. A total of 27 actionable alterations in tiers 1–4 were detected in 20 patients (36.4%), and the majority of actionable alterations were copy number variations. The tiers of molecular alterations were tier 1 (clinical evidence) in 4 variants, tier 2 (preclinical evidence) in 8 variants, tier 3 (consensus opinion) in 2 variants, and tier 4 (actionable variants with a drug that is available in other countries but not in the Republic of Korea) in 9 variants. In one patient with relapsed neuroblastoma with ALK F1174L mutation and ALK amplification, lorlatinib was used in a compassionate use program, and it showed some efficacy. In conclusion, using a targeted sequencing panel to discover actionable alterations in relapsed/refractory pediatric solid tumors was practical and feasible.基因组技术的进步与靶向治疗药物的研发，正让精准医学（precision medicine）的应用愈发具备可行性。本研究旨在通过靶向测序面板（targeted panel sequencing）检测可操作基因组变异（actionable alterations），探究精准医学能否用于难治/复发儿童实体瘤的诊疗。本研究采用覆盖381个癌症基因外显子DNA序列以及22个基因内含子区域的靶向测序面板，对难治/复发儿童实体瘤样本进行检测，以识别肿瘤中具有临床意义的基因组畸变。研究团队根据可操作遗传变异的存在情况、支持证据的强度以及大韩民国境内的药物可及性，将分子靶标分为1至5级。2016年1月至2018年10月期间，本研究共纳入55例患者。从组织获取到药物遴选的中位时间为29天（范围14~39天），53例（96.4%）患者成功完成肿瘤基因组分型。共计在20例患者（占比36.4%）中检出27个1~4级可操作基因组变异，其中绝大多数为拷贝数变异（copy number variations）。分子变异的分级情况为：4个变异属于1级（具备临床证据），8个属于2级（具备临床前证据），2个属于3级（具备专家共识意见），另有9个属于4级（对应的药物已在其他国家获批，但大韩民国境内尚未上市）。1例复发神经母细胞瘤患者同时携带ALK F1174L突变与ALK基因扩增，研究团队通过同情性用药计划为其使用洛拉替尼（lorlatinib），该药物展现出一定疗效。综上，采用靶向测序面板检测复发/难治儿童实体瘤的可操作基因组变异，具备实用性与可行性。