Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial.
Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial.
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DOI：
10.1158/1078-0432.ccr-17-2994
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发表时间：
2018-03-15
期刊：
影响因子：
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通讯作者：
Knox JJ
中科院分区：
文献类型：
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作者：
Aung KL;Fischer SE;Denroche RE;Jang GH;Dodd A;Creighton S;Southwood B;Liang SB;Chadwick D;Zhang A;O'Kane GM;Albaba H;Moura S;Grant RC;Miller JK;Mbabaali F;Pasternack D;Lungu IM;Bartlett JMS;Ghai S;Lemire M;Holter S;Connor AA;Moffitt RA;Yeh JJ;Timms L;Krzyzanowski PM;Dhani N;Hedley D;Notta F;Wilson JM;Moore MJ;Gallinger S;Knox JJ
目的：对晚期胰腺导管腺癌(PDAC)进行实时全基因组测序(WGS)和RNA测序(RNAseq)，以确定预测突变和转录特征，以便更好地选择治疗方案。在一线联合化疗之前，前瞻性地招募晚期PDAC患者。图像引导下经皮核心活检获取新鲜肿瘤组织，进行WGS和RNAseq检查。所有病例均行激光捕获显微解剖。主要终点是在8周后第一次疾病评估CT扫描之前报告WGS结果的可行性。主要的次要终点是发现具有预测性突变和转录特征的患者亚群。2015年12月至2017年6月期间，63名患者接受了肿瘤活检。WGS成功62例(98%)，RNAseq成功60例(95%)。基因组结果报告的中位数为35天(范围为19-52天)，达到了主要的可行性终点。目的经典型PDAC RNA亚型患者对一线化疗的疗效明显好于基底细胞样亚型患者(P=0.004)。经m-FOLFIRINOX治疗的经典型亚型患者的无进展生存率最高。用RNA原位杂交检测肿瘤组织中GATA6的表达，发现GATA6是区分经典和基底样型PDAC亚型的可靠替代生物标志物。在30%的患者中发现了潜在的可操作的基因改变。晚期PDAC的前瞻性基因组图谱是可行的，我们的早期数据表明，不同基因组/转录亚型患者的化疗反应不同。
To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture micro-dissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19–52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.