Koschmann Carl, Wu Yi-Mi, Kumar-Sinha Chandan, Lonigro Robert, Vats Pankaj, Kasaian Katayoon, Cieslik Marcin, Cao Xuhong, Anderson Bailey, Frank Kevin, Zhao Lili, Prensner John R, Zureick Andrew H, Everett Jessica, Mullan Brendan, Marini Bernard, Camelo-Piragua Sandra, Venneti Sriram, McKeever Paul, McFadden Kathryn, Lieberman Andrew P, Leonard Marcia, Maher Cormac O, Garton Hugh, Muraszko Karin, Robertson Patricia, Robinson Dan, Chinnaiyan Arul M, Mody Rajen
University of Michigan School of Medicine, Ann Arbor, MI.
Boston Children's Hospital, Boston, MA.
JCO Precis Oncol. 2018;2. doi: 10.1200/po.17.00133. Epub 2018 May 4.
Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors.
Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference.
Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months.
Selection of personalized agents for children and young adults with highrisk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors.
脑肿瘤已成为年轻患者癌症相关死亡的主要原因。迫切需要基于每种肿瘤独特生物学特性的新型有效疗法。本研究的目的是评估综合临床测序和遗传咨询在高危脑肿瘤儿童和年轻成人中的可行性、实用性及临床影响。
52例被治疗神经肿瘤学家认定为高危（治疗失败几率>25%；平均年龄10.2岁；范围0至39岁）的脑肿瘤儿童和年轻成人纳入一项前瞻性、观察性、连续病例系列研究，参与者接受综合临床外显子组（肿瘤和种系DNA）及转录组（肿瘤RNA）测序和遗传咨询。结果在多机构脑肿瘤精准医学电话会议上进行了讨论。
测序显示，在40例有足够组织的肿瘤中，25例（63%）存在潜在可采取行动的种系或肿瘤改变，其中21例（53%）对治疗或诊断改变有影响。在20例（45%）胶质肿瘤中的9例中发现血小板衍生生长因子受体或成纤维细胞生长因子受体途径改变。8例（20%）测序肿瘤在RNA测序中发现致癌融合。20例胶质肿瘤患者中有17例（85%）有潜在可采取行动的结果，其中14例（70%）患者治疗发生改变。接受靶向治疗的复发性脑肿瘤患者的无进展生存期（从开始治疗起）中位数为4个月。
基于综合临床测序为高危脑肿瘤儿童和年轻成人选择个性化药物是可行的，并且导致超过三分之二的高危胶质肿瘤儿童和年轻成人治疗发生改变。
