Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto, Japan.
JCO Precis Oncol. 2024 Oct;8:e2400284. doi: 10.1200/PO.24.00284. Epub 2024 Oct 24.
Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development.
We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations.
Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in (78%), (37%), (29%), (11%), (10%), (9%), (6%), and (6%). Loss of / was only observed in -mutated GISTs, while alterations in were only detected in wild-type GISTs. Among 119 -mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding and . However, among 25 wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in -mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden-high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for fusion in one with wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with -mutated GIST.
This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.
综合基因组分析（CGP）在精准医疗中的临床应用已经得到证实。虽然已经有一些关于胃肠道间质瘤（GIST）基因组特征的报道，但针对 GIST 的大规模数据仍然有限，尤其是在亚洲。此外，CGP 鉴定的分子靶向药物的适用性也尚未得到广泛研究。我们利用国家癌症基因组学和先进治疗学中心（C-CAT）数据库，调查了日本晚期 GIST 患者的基因组改变状况，以确定新的治疗策略和药物研发方向。
我们回顾性分析了 C-CAT 数据库中登记的晚期 GIST 患者的临床和 CGP 数据，以评估基因组特征和潜在的可操作改变。
共分析了 144 例患者的数据。在 （78%）、 （37%）、 （29%）、 （11%）、 （10%）、 （9%）和 （6%）中经常检测到致癌改变。只有在 （mutated）GIST 中才观察到缺失，而 （alterations）仅在 野生型（ wild-type）GIST 中检测到。在 119 例 （mutated）GIST 中，95 例（80%）有致癌性基因组改变，29 例（24%）有可操作性改变，不包括 （和）。然而，在 25 例 野生型（ wild-type）GIST 中，22 例（88%）有致癌改变，11 例（44%）有可操作性改变。在 （mutated）和野生型 GIST 中，针对基因组匹配治疗的代表性候选药物如下：帕博利珠单抗（ pembrolizumab）用于肿瘤突变负荷高的患者各 1 例；多聚腺苷二磷酸核糖聚合酶抑制剂（poly-adenosine diphosphate ribose polymerase inhibitors）用于同源重组缺陷相关改变的患者各 12 例和 1 例；NTRK 抑制剂（NTRK inhibitor）用于 融合的患者 1 例且为 野生型（ wild-type）GIST；人表皮生长因子受体 2-抗体药物偶联物（human epidermal growth factor receptor 2-antibody-drug conjugate）用于 （mutated）GIST 患者 1 例。
本研究强调了晚期 GIST 的基因组特征以及 CGP 在确定合理的分子靶向治疗选择方面的重要作用。
