Harris Marian H, DuBois Steven G, Glade Bender Julia L, Kim AeRang, Crompton Brian D, Parker Erin, Dumont Ian P, Hong Andrew L, Guo Dongjing, Church Alanna, Stegmaier Kimberly, Roberts Charles W M, Shusterman Suzanne, London Wendy B, MacConaill Laura E, Lindeman Neal I, Diller Lisa, Rodriguez-Galindo Carlos, Janeway Katherine A
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
Division of Pediatric Hematology Oncology, University of California-San Francisco Benioff Children's Hospital.
JAMA Oncol. 2016 May 1;2(5):608-615. doi: 10.1001/jamaoncol.2015.5689.
Pediatric cancers represent a unique case with respect to cancer genomics and precision medicine, as the mutation frequency is low, and targeted therapies are less available. Consequently, it is unknown whether clinical sequencing can be of benefit.
To assess the feasibility of identifying actionable alterations and making individualized cancer therapy (iCat) recommendations in pediatric patients with extracranial solid tumors.
DESIGN, SETTING, AND PARTICIPANTS: Clinical sequencing study at 4 academic medical centers enrolling patients between September 5, 2012, and November 19, 2013, with 1 year of clinical follow-up. Participants were 30 years or younger with high-risk, recurrent, or refractory extracranial solid tumors. The data analysis was performed October 28, 2014.
Tumor profiling performed on archived clinically acquired specimens consisted of mutation detection by a Sequenom assay or targeted next-generation sequencing and copy number assessment by array comparative genomic hybridization. Results were reviewed by a multidisciplinary expert panel, and iCat recommendations were made if an actionable alteration was present, and an appropriate drug was available.
Feasibility was assessed using a 2-stage design based on the proportion of patients with recommendations.
Of 100 participants (60 male; median [range] age, 13.4 [0.8-29.8] years), profiling was technically successful in 89 (89% [95% CI, 83%-95%]). Median (range) follow-up was 6.8 (2.0-23.6) months. Overall, 31 (31% [95% CI, 23%-41%]) patients received an iCat recommendation and 3 received matched therapy. The most common actionable alterations leading to an iCat recommendation were cancer-associated signaling pathway gene mutations (n = 10) and copy number alterations in MYC/MYCN (n = 6) and cell cycle genes (n = 11). Additional alterations with implications for clinical care but not resulting in iCat recommendations were identified, including mutations indicating the possible presence of a cancer predisposition syndrome and translocations suggesting a change in diagnosis. In total, 43 (43% [95% CI, 33%-53%]) participants had results with potential clinical significance.
A multi-institution clinical genomics study in pediatric oncology is feasible and a substantial proportion of relapsed or refractory pediatric solid tumors have actionable alterations.
clinicaltrials.gov Identifier: NCT01853345.
儿童癌症在癌症基因组学和精准医学方面是一个独特的案例，因为其突变频率低，且靶向治疗药物较少。因此，临床测序是否有益尚不清楚。
评估在患有颅外实体瘤的儿科患者中识别可操作的改变并做出个体化癌症治疗（iCat）建议的可行性。
设计、设置和参与者：在4个学术医疗中心进行的临床测序研究，于2012年9月5日至2013年11月19日招募患者，并进行1年的临床随访。参与者年龄在30岁及以下，患有高危、复发性或难治性颅外实体瘤。数据分析于2014年10月28日进行。
对存档的临床采集标本进行肿瘤分析，包括通过Sequenom检测或靶向二代测序进行突变检测，以及通过阵列比较基因组杂交进行拷贝数评估。结果由多学科专家小组进行审查，如果存在可操作的改变且有合适的药物可用，则做出iCat建议。
基于有建议的患者比例，采用两阶段设计评估可行性。
100名参与者（60名男性；中位[范围]年龄，13.4[0.8 - 29.8]岁）中，89名（89%[95%CI，83% - 95%]）的分析在技术上取得成功。中位（范围）随访时间为6.8（2.0 - 23.6）个月。总体而言，31名（31%[95%CI，23% - 41%]）患者收到了iCat建议，3名接受了匹配治疗。导致iCat建议的最常见可操作改变是癌症相关信号通路基因突变（n = 10）以及MYC/MYCN（n = 6）和细胞周期基因（n = 11）的拷贝数改变。还发现了对临床护理有影响但未导致iCat建议的其他改变，包括表明可能存在癌症易感综合征的突变和提示诊断改变的易位。共有43名（43%[95%CI，33% - 53%]）参与者的结果具有潜在临床意义。
儿科肿瘤学的多机构临床基因组学研究是可行的，并且相当一部分复发或难治性儿科实体瘤具有可操作的改变。
clinicaltrials.gov标识符：NCT01853345。
