Objective:The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations inKIT,PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA,SDHB,SDHC, andSDHDgenes). A small fraction of GISTs lack alterations inKIT,PDGFRA, andSDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs.Methods:We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients.Results:Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with aBRAFV600E mutation and two withNF1loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two withTP53LOF mutations, one withNTRK3fusion (ETV6-NTRK3), one withPTENdeletion, one withFGFR1gain-of-function (GOF) mutation (K654E), one withCHEK2LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one withFANCAdeletion. Patients had better responses with molecularly targeted therapies than with imatinib.Conclusions:Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared toKIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.
目的：绝大多数胃肠道间质瘤（GIST）由KIT、PDGFRA或琥珀酸脱氢酶（SDH）复合体组分（SDHA、SDHB、SDHC和SDHD基因）的激活突变驱动。一小部分GIST缺乏KIT、PDGFRA和SDH的基因改变。本研究旨在进一步明确这类所谓“三阴性”GIST的临床和基因组特征。 方法：我们从MD安德森癌症中心诊断为GIST且拥有临床新一代测序数据的患者中提取临床和基因组数据，以识别“三阴性”患者。 结果：在确定的20例患者中，11例（55.0%）原发部位在胃，8例（40.0%）在小肠，1例（5.0%）在直肠。总计18例患者（90.0%）最终出现复发或转移性疾病，其中8例为新发转移性疾病。在13例可评估伊马替尼疗效的患者中（例如新辅助治疗或针对复发/转移性疾病），伊马替尼治疗的中位无进展生存期（PFS）为4.4个月（范围0.5–191.8个月）。患者结局差异很大，部分患者疾病迅速进展，而另一些患者疾病则更为惰性。关于潜在的基因组驱动因素，发现4例患者存在RAS/RAF/MAPK通路改变：2例为BRAF V600E突变，2例为NF1功能缺失（LOF）突变（1例缺失，1例剪接位点突变）。此外，我们发现2例患者存在TP53 LOF突变，1例存在NTRK3融合（ETV6-NTRK3），1例存在PTEN缺失，1例存在FGFR1功能获得（GOF）突变（K654E），1例存在CHEK2 LOF突变（T367fs*），1例存在极光激酶A融合（AURKA-CSTF1），以及1例存在FANCA缺失。与伊马替尼相比，患者对分子靶向治疗的反应更好。 结论：三阴性GIST是一个包含不同驱动突变的异质性群体。与KIT/PDGFRA突变型GIST相比，伊马替尼在三阴性GIST中观察到的获益有限。深入的分子谱分析有助于识别驱动突变并指导治疗。
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