ASCO 2016:原发性肿瘤位置与结直肠癌分子分型的关系

2016-06-08 佚名 医脉通

2016年6月3-7日,一年一度的美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)年会在芝加哥举办。6月5日上午的消化系统(结直肠)肿瘤口头报告专场上,一项摘要号为3506的研究,对原发性(1°)位置与转移性结直肠癌(mCRC)抗表皮生长因子受体治疗(αEGFR)后无进展生存期(PFS)和总生存期(OS)分子特征的关系进行描述,整理如下:

2016年6月3-7日,一年一度的美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)年会在芝加哥举办。6月5日上午的消化系统(结直肠)肿瘤口头报告专场上,一项摘要号为3506的研究,对原发性(1°)位置与转移性结直肠癌(mCRC)抗表皮生长因子受体治疗(αEGFR)后无进展生存期(PFS)和总生存期(OS)分子特征的关系进行描述,整理如下:


源于右半结肠(RC)的CRCs特征区别于与那些直肠/左半结肠的CRCs,包括较为频繁的CpG岛甲基化表型(CIMP-高)和BRAF基因突变(MT)。预后和治疗响应,包括αEGFR方案,根据CRC原发性位置有显著不同,但是病理学解释仍不明确。


198例KRAS野生型(WT)mCRC肿瘤通过亚硫酸氢钠测序和PCR扩增对CIMP状态进行检测。同时对BRAF和NRAS测序。首次接受αEGFR方案的PFS在167例患者中回顾性确定。单变量和多变量Cox回归分析联合多重插补法被开展。来自179例独立的CRC患者肿瘤对启动子甲基化(Illumina HumanMethylation450)和基因表达进行检测。


接受αEGFR治疗的较差PFS与RC CRC(HR=1.56,CI 1.01-2.41),CIMP-高(HR=2.38,1.47-3.85),BRAF MT(HR=2.15,1.26-3.65)和NRAS MT(HR=2.11,1.23-3.65)有关。多变量分析显示,CIMP状态(P=0.041),BRAF状态(P=0.038),NRAS MT(P=0.012)仍然存在显著性,但是原发性位置不存在(P=0.27)。较差的OS与RC CRC(HR=1.45,1.04-2.01),CIMP-高(HR=1.53,1.08-2.16),BRAF MT(HR=2.46,1.61-3.75)和NRAS MT(HR=1.70,1.03-2.81)有关。RC原发性位置也与CIMP-高(OR=2.35,1.22-4.54)和BRAF MT(OR=5.45,2.47-12.03)有关。来自MDACC和TCGA的独立数据显示,RC原发性位置和CIMP-高均强烈地与启动子超甲基化和EGFR配体EREG和AREG表达抑制有关。原发性位置也与共识分子亚型(CMS)1和3强烈相关(P<0.001,P=0.03),这在之前的研究中显示,相比于“典型”CMS2亚型,这些mCRC患者的预后较差。


综上所述,在αEGFR治疗后CRC原发性位置与OS和PFS有关。分子分析显示,BRAF MT,NRAS MT,分子亚型,和肿瘤甲基化可能是出现这个效果的原因,同时为与解剖位置的相关性提供了一种生物学解释。



原文摘要:


Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy.(Abstract3506)


Authors:Michael Sangmin Lee, Shailesh M Advani,et al


Session Type:Oral Abstract Session


Background: CRCs originating in the right colon (RC) have features distinct from those in the rectum/left colon, including more frequent CpG island methylator phenotype (CIMP-High) and BRAF mutation (MT). Prognosis and response to therapies, including αEGFR regimens, differ dramatically by 1° site in mCRC, but pathobiologic explanations remain unclear. 


Methods: 198 KRAS wild-type (WT) mCRC tumors were tested for CIMP status via bisulfite pyrosequencing and PCR amplification. BRAF and NRAS were sequenced. PFS on first αEGFR regimen was retrospectively determined in 167 patients. Univariate and multivariate Cox regression analyses with multiple imputations were performed. Tumors from 179 independent CRC patients were tested for promoter methylation (Illumina HumanMethylation450) and gene expression. 


Results: Inferior PFS with αEGFR therapy was associated with RC CRC (HR = 1.56, CI 1.01-2.41), CIMP-High (HR = 2.38, 1.47-3.85), BRAF MT (HR = 2.15, 1.26-3.65), and NRAS MT (HR = 2.11, 1.23-3.65). On multivariate analysis, CIMP status (p = 0.041), BRAF MT (p = 0.038), and NRAS MT (p = 0.012) remained significant, but 1° site did not (p = 0.27). Inferior OS was associated with RC CRC (HR = 1.45, 1.04-2.01), CIMP-High (HR = 1.53, 1.08-2.16), BRAF MT (HR = 2.46, 1.61-3.75), and NRAS MT (HR = 1.70, 1.03-2.81). RC 1° site was also associated with CIMP-High (OR = 2.35, 1.22-4.54) and BRAF MT (OR = 5.45, 2.47-12.03). Independent data from MDACC and TCGA showed RC 1° site and CIMP-High were both strongly associated with hypermethylation of promoters and suppression of expression of the EGFR ligands EREG and AREG. 1° site was also strongly associated with consensus molecular subtypes (CMS) 1 and 3 (p < 0.001, p = 0.03), which were previously shown in mCRC patients to have worse outcomes than the ‘classic' CMS2 subtype. 


Conclusions: CRC 1° site is associated with OS and PFS after αEGFR therapy. Molecular analyses suggest that BRAF MT, NRAS MT, molecular subtypes, and tumor methylation account for the effect and may provide a biologic explanation for the association with anatomic location.



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