ASCO2013：regorafenib治疗TKI抵抗性GIST效果不受KIT基因突变状态的影响

背景：III 期GRID研究显示REG治疗至少经伊马替尼(IM)和舒尼替尼治疗失败的晚期胃肠道间质瘤(GIST) 相较于安慰剂可显著性改善患者无进展生存期(PFS) (SU; HR 0.27, p<0.0001)。由于肿瘤生长的异质性，明确TKI难治性GIST基因型是一项具有挑战性的任务，而且患者对连续接受一系列的活检也表现出抵触。为克服上述难题，研究者以血浆游离DNA为样本分析肿瘤DNA，并对其突变状态与临床结局之间的关联进行了研究探讨。
方法：研究者分别应用Sanger测序法和BEAMing法对存档组织样本DNA (n=102)和血浆DNA(n=163)进行突变分析。
结果：肿瘤组织样本相关基因的突变频道为：KIT, 66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%。血浆样本的突变频率为：KIT, 58%; PDGFRA, 1%; KRAS, 50%, BRAF, 0%。主要KIT突变在组织和血浆样本中检出的一致率为84%；次要KIT突变在血浆中的检出率(47%)高于组织样本(12%)。对于成像研究的中心和局部回顾的全部亚组中，基于突变位点的亚组分析显示，与安慰剂组相比，REG治疗组可改善PFS。在安慰剂治疗组，血浆检出的次要KIT突变与PFS减少相关(HR 1.82, p=0.05)。KIT外显子9突变的人群中，接受短期伊马替尼治疗和接受长期舒尼替尼治疗的患者与其他GIST基因型相关。PDGFRA突变患者显示出多样化的临床答应局面，1/1 KRAS突变的GIST患者对伊马替尼、舒尼替尼或REG反应均不佳。
结论：KIT基因突变状态与伊马替尼和舒尼替尼治疗时间相关。与既往组织样本研究报道结果相一致，本研究验证了基于血浆游离DNA分析目标癌基因方法的有效性。次要KIT突变似对GIST产生阴性的预后影响，REG治疗与安慰剂相较其临床获益不受KIT基因突变状态的影响。临床试验信息：NCT01271712。
Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes.
Abstract
Background: The phase III GRID study showed that REG provides a significant improvement in progression-free survival (PFS) compared with PL in pts with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27, p<0.0001). Determining GIST genotype in TKI-refractory disease has proven challenging due to inter-tumoral heterogeneity and pt preference to avoid serial biopsies. To overcome this, we analysed circulating DNA in plasma as a source of tumor DNA and studied the correlation between mutational status and clinical outcome. Methods: DNA was isolated from both archival tumor tissue (n=102) and plasma at baseline (n=163) and analyzed for mutations via Sanger sequencing (tissue) or BEAMing (plasma). Results: Mutational frequencies for tumor tissue samples were: KIT, 66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%. For plasma, frequencies were: KIT, 58%; PDGFRA, 1%; KRAS, 1 out of 2 samples, BRAF, 0%. Detection of primary KIT mutations showed 84% concordance between tissue and plasma. Secondary KIT mutations were more commonly detected in plasma (47%) than in tissue (12%). Subgroup analysis based on mutational status showed an improved PFS in REG-treated pts vs PL in all subgroups by both central and local review of imaging studies. The presence of a secondary KIT mutation in plasma was associated with shorter PFS in pts receiving PL (HR 1.82, p=0.05). Pts with a KIT-exon 9 mutation received IM for a shorter period of time, and SU for a longer period of time, relative to other GIST genotypes. Pts with a PDGFRA mutation showed variable clinical responses, while 1/1 KRAS-mutant GIST did not respond well to IM, SU, or REG. Conclusions: KIT mutational status correlated to IM and SU treatment duration. While consistent with prior reports using tissue sampling, this validates the utility of plasma-based circulating DNA analysis of target oncogenes. Secondary KIT mutations appear to have a negative prognostic impact in GIST, while the clinical benefit of REG vs PL was not influenced by KIT mutational status. Clinical trial information: NCT01271712.