Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib An Exploratory Analysis of a Randomized Clinical Trial
Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib An Exploratory Analysis of a Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2016.5751
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发表时间：
2017-05-01
期刊：
影响因子：
28.4
通讯作者：
Reichardt, Peter
中科院分区：
文献类型：
--
作者：
Joensuu, Heikki;Wardelmann, Eva;Reichardt, Peter
伊马替尼辅助治疗的持续时间是否影响KIT原癌基因受体酪氨酸激酶（KIT）和血小板衍生生长因子受体a（PDGFRA）突变的预后意义，目前尚不清楚。本探索性研究基于斯堪的纳维亚肉瘤第VIII组/Arbeitsgemeinschaft Internistische Onkologie（SSGXVIII/AIO）多中心临床试验。在2004年2月4日至2008年9月29日期间，400例因GIST手术且复发风险高的患者随机接受伊马替尼辅助治疗1年或3年。在提供知情同意书的397例患者中，341例（85.9%）具有中心确认的局部GIST，并使用常规测序集中进行KIT和PDGFRA突变分析。在中位随访88个月（2013年12月31日完成）期间，142例患者发生GIST复发。可评价人群的数据分析于2004年2月4日至2013年12月31日。主要结局和指标主要结局为RFS。突变按基因和外显子分组。KIT外显子11突变进一步分为缺失或插入-缺失突变、替换突变、插入或重复突变以及涉及密码子557和/或558的突变。（男175人，女166人;入组研究时的中位年龄，62岁）（1年组）和60岁（3年组），274（80.4%）有KIT突变，43例（12.6%）有PDGFRA突变，24例（7.0%）为野生型。PDGFRA突变和KIT 11号外显子插入或重复突变与有利的RFS相关，而KIT 9号外显子突变与不利的结局相关。与1年组相比，KIT 11号外显子缺失或插入-缺失突变的患者分配到3年组时的RFS更好（5年RFS，71.0% vs 41.3%; P
IMPORTANCE Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA) mutations.OBJECTIVE To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib.DESIGN, SETTING, AND PARTICIPANTS This exploratory study is based on the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) multicenter clinical trial. Between February 4, 2004, and September 29, 2008, 400 patients who had undergone surgery for GISTs with a high risk of recurrence were randomized to receive adjuvant imatinib for 1 or 3 years. Of the 397 patients who provided consent, 341 (85.9%) had centrally confirmed, localized GISTs with mutation analysis for KIT and PDGFRA performed centrally using conventional sequencing. During a median follow-up of 88 months (completed December 31, 2013), 142 patients had GIST recurrence. Data of the evaluable population were analyzed February 4, 2004, through December 31, 2013.MAIN OUTCOMES AND MEASURES The main outcome was RFS. Mutations were grouped by the gene and exon. KIT exon 11 mutations were further grouped as deletion or insertion-deletion mutations, substitution mutations, insertion or duplication mutations, and mutations that involved codons 557 and/or 558.RESULTS Of the 341 patients (175 men and 166women; median age at study entry, 62 years) in the 1-year group and 60 years in the 3-year group), 274 (80.4%) had GISTs with a KIT mutation, 43 (12.6%) had GISTs that harbored a PDGFRA mutation, and 24 (7.0%) had GISTs thatwere wild type for these genes. PDGFRA mutations and KIT exon 11 insertion or duplication mutations were associated with favorable RFS, whereas KIT exon 9 mutations were associated with unfavorable outcome. Patients with KIT exon 11 deletion or insertion-deletion mutation had better RFS when allocated to the 3-year group compared with the 1-year group (5-year RFS, 71.0% vs 41.3%; P