日本国立癌症中心的儿科精准医学：作为TOP-GEAR项目一部分的儿科癌症患者前瞻性基因组研究。

Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project.

作者信息

Tao Kayoko, Yamazaki Fumito, Kubo Takashi, Sunami Kuniko, Kumamoto Tadashi, Arakawa Ayumu, Sugiyama Masanaka, Watanabe Yuko, Nakajima Miho, Shirakawa Nami, Tanimura Kazuki, Koyama Takafumi, Hirata Makoto, Sudo Kazuki, Tanabe Noriko, Watanabe Tomoko, Yoshida Teruhiko, Kitami Mayuko, Yoshida Akihiko, Yatabe Yasushi, Nakano Yoshiko, Ohira Miki, Kamijo Takehiko, Nakazawa Atsuko, Kato Motohiro, Ichimura Koichi, Kohno Takashi, Yamamoto Noboru, Hishiki Tomoro, Ichikawa Hitoshi, Ogawa Chitose

机构信息

Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.

Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.

出版信息

JCO Precis Oncol. 2023 Jul;7:e2200266. doi: 10.1200/PO.22.00266.

DOI:10.1200/PO.22.00266

PMID:37410973

Abstract

PURPOSE

This single-center, prospective molecular profiling study characterizes genomic alterations and identifies therapeutic targets in advanced pediatric solid tumors.

METHODS

As part of the TOP-GEAR (Trial of Onco-Panel for Gene profiling to Estimate both Adverse events and Response by cancer treatment) project at the National Cancer Center (NCC), Japan, we enrolled pediatric patients with a refractory or recurrent disease during August 2016-December 2021 and performed genomic analysis of matched tumors and blood using originally developed cancer gene panels, NCC Oncopanel (ver. 4.0) and NCC Oncopanel Ped (ver. 1.0).

RESULTS

Of 142 patients (age, 1-28 years) enrolled, 128 (90%) were evaluable for genomic analysis; 76 (59%) patients harbored at least one reportable somatic or germline alteration. The tumor samples were collected during the initial diagnosis in 65 (51%) patients, after treatment initiation in 11 (9%) patients, and upon either disease progression or relapse in 52 (41%) patients. The leading altered gene was , followed by , , and . The commonly affected molecular processes were transcription, cell-cycle regulation, epigenetic modifiers, and RAS/mitogen-activated protein kinase signaling. Twelve (9%) patients carried pathogenic germline variants in cancer-predisposing genes. Potentially actionable findings were identified in 40 (31%) patients; to date, 13 (10%) patients have received the recommended therapy on the basis of their genomic profiles. Although four patients had access to targeted therapy through clinical trials, the agents were used in nine patients in an off-label setting.

CONCLUSION

The implementation of genomic medicine has furthered our understanding of tumor biology and provided new therapeutic strategies. However, the paucity of proposed agents limits the full potential of actionability, emphasizing the significance of facilitating access to targeted cancer therapies.

摘要

目的

本单中心前瞻性分子图谱研究旨在表征晚期儿童实体瘤的基因组改变并确定治疗靶点。

方法

作为日本国立癌症中心（NCC）的TOP-GEAR（用于基因谱分析以评估癌症治疗的不良事件和反应的肿瘤面板试验）项目的一部分，我们纳入了2016年8月至2021年12月期间患有难治性或复发性疾病的儿科患者，并使用最初开发的癌症基因面板NCC Oncopanel（第4.0版）和NCC Oncopanel Ped（第1.0版）对匹配的肿瘤和血液进行基因组分析。

结果

在纳入的142例患者（年龄1至28岁）中，128例（90%）可进行基因组分析；76例（59%）患者至少有一项可报告的体细胞或种系改变。肿瘤样本在65例（51%）患者的初始诊断时采集，11例（9%）患者在开始治疗后采集，52例（41%）患者在疾病进展或复发时采集。最常发生改变的基因是，其次是、和。常见受影响的分子过程是转录、细胞周期调控、表观遗传修饰因子以及RAS/丝裂原活化蛋白激酶信号传导。12例（9%）患者在癌症易感基因中携带致病性种系变异。在40例（31%）患者中发现了潜在可采取行动的结果；迄今为止，13例（10%）患者已根据其基因组图谱接受了推荐治疗。尽管有4例患者通过临床试验获得了靶向治疗，但这些药物在9例患者中属于超适应症使用。