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Abstract：
LUME-Colon 1 (NCT02149108) was a global, placebo-controlled phase III study of nintedanib in advanced colorectal cancer (CRC). Pre-specified biomarker analyses investigated the association of CRC consensus molecular subtypes (CMS) and tumor genomic and circulating biomarkers with clinical outcomes.
Archival tumor tissue, cell-free DNA (cfDNA), and plasma samples were collected for genomic, transcriptomic, and proteomic analyses to investigate potential associations between CRC CMS and other biomarkers with nintedanib response and clinical outcomes.
Of the 765 treated patients, 735, 245, and 192 patient samples were analyzed in the circulating protein, tumor tissue, and cfDNA datasets, respectively. Patients were classified as CMS1 (1.7%), CMS2 (27.7%), CMS3 (0.9%), CMS4 (51.5%), or unclassified (18.2%). Unclassified/mixed CMS was associated with longer overall survival (OS) with nintedanib vs. CMS2 or CMS4 (interaction P-value = .0086); no association was observed for CMS4. Gene expression-based pathway analysis revealed an association between vascular endothelial growth factor-related signaling and OS for nintedanib (P = .0498). The most frequently detected somatic mutations were APC (72.0% [tumor tissue] vs. 56.8% [cfDNA]), TP53 (47.1% vs. 34.9%), KRAS (40.8% vs. 28.6%), and PIK3CA (16.6% vs. 11.5%); concordance rates were > 80%. Median OS differences were observed for APC and TP53 mutations vs. wild-type in cfDNA, indicating a potential prognostic value. Circulating ANG-2, CA-9, CEACAM1, collagen-IV, IGFBP-1, ICAM-1, IL-8, and uPAR were potentially prognostic for both OS and progression-free survival.
We demonstrated the feasibility of large-scale biomarker analyses and CMS classification within a global clinical trial, and identified signals suggesting a potential for greater nintedanib treatment response in the unclassified/mixed CMS subgroup, despite these tumors showing heterogeneous patterns of CMS mixtures. Our results revealed a high degree of concordance in somatic mutations between tumor tissue and cfDNA. Associations with prognosis for cfDNA somatic mutations, as well as several protein-based biomarkers, may warrant further investigation in future trials.
Archival tumor tissue, cell-free DNA (cfDNA), and plasma samples were collected for genomic, transcriptomic, and proteomic analyses to investigate potential associations between CRC CMS and other biomarkers with nintedanib response and clinical outcomes.
Of the 765 treated patients, 735, 245, and 192 patient samples were analyzed in the circulating protein, tumor tissue, and cfDNA datasets, respectively. Patients were classified as CMS1 (1.7%), CMS2 (27.7%), CMS3 (0.9%), CMS4 (51.5%), or unclassified (18.2%). Unclassified/mixed CMS was associated with longer overall survival (OS) with nintedanib vs. CMS2 or CMS4 (interaction P-value = .0086); no association was observed for CMS4. Gene expression-based pathway analysis revealed an association between vascular endothelial growth factor-related signaling and OS for nintedanib (P = .0498). The most frequently detected somatic mutations were APC (72.0% [tumor tissue] vs. 56.8% [cfDNA]), TP53 (47.1% vs. 34.9%), KRAS (40.8% vs. 28.6%), and PIK3CA (16.6% vs. 11.5%); concordance rates were > 80%. Median OS differences were observed for APC and TP53 mutations vs. wild-type in cfDNA, indicating a potential prognostic value. Circulating ANG-2, CA-9, CEACAM1, collagen-IV, IGFBP-1, ICAM-1, IL-8, and uPAR were potentially prognostic for both OS and progression-free survival.
We demonstrated the feasibility of large-scale biomarker analyses and CMS classification within a global clinical trial, and identified signals suggesting a potential for greater nintedanib treatment response in the unclassified/mixed CMS subgroup, despite these tumors showing heterogeneous patterns of CMS mixtures. Our results revealed a high degree of concordance in somatic mutations between tumor tissue and cfDNA. Associations with prognosis for cfDNA somatic mutations, as well as several protein-based biomarkers, may warrant further investigation in future trials.
摘要：
LUME-Colon1（NCT02149108）是一个全球性的，尼达尼布治疗晚期结直肠癌（CRC）的安慰剂对照III期研究。预先指定的生物标志物分析研究了CRC共有分子亚型(CMS)和肿瘤基因组和循环生物标志物与临床结果的关联。
存档肿瘤组织，无细胞DNA（cfDNA），并收集血浆样本用于基因组，转录组，和蛋白质组学分析，以调查CRCCMS和其他生物标志物与尼达尼布反应和临床结果之间的潜在关联。
在765名接受治疗的患者中,对735、245和192例患者样本进行了循环蛋白分析，肿瘤组织，和cfDNA数据集，分别。患者被分类为CMS1（1.7％），CMS2（27.7%），CMS3（0.9%），CMS4（51.5%），或未分类（18.2%）。未分类/混合CMS与尼达尼布的总生存期（OS）更长CMS2或CMS4(相互作用P值=.0086);对于CMS4未观察到关联。基于基因表达的通路分析显示血管内皮生长因子相关信号与nintedanib的OS之间存在关联(P=.0498)。最常见的体细胞突变是APC(72.0%[肿瘤组织]vs.56.8%[cfDNA])，TP53（47.1%与34.9%），KRAS（40.8%与28.6%），和PIK3CA（16.6%与11.5%)；一致率>80%。观察到APC和TP53突变的中位OS差异与cfDNA中的野生型，表明潜在的预后价值。循环ANG-2，CA-9，CEACAM1，胶原IV，IGFBP-1、ICAM-1、IL-8和uPAR是OS和无进展生存期的潜在预后因素。
我们证明了在全球临床试验中进行大规模生物标志物分析和CMS分类的可行性，和确定的信号表明，在未分类/混合CMS亚组中，尼达尼布治疗反应的可能性更大，尽管这些肿瘤显示CMS混合物的异质性模式。我们的结果表明，肿瘤组织和cfDNA之间的体细胞突变具有高度的一致性。与cfDNA体细胞突变的预后相关，以及几种基于蛋白质的生物标志物，可能需要在未来的试验中进一步调查。
存档肿瘤组织，无细胞DNA（cfDNA），并收集血浆样本用于基因组，转录组，和蛋白质组学分析，以调查CRCCMS和其他生物标志物与尼达尼布反应和临床结果之间的潜在关联。
在765名接受治疗的患者中,对735、245和192例患者样本进行了循环蛋白分析，肿瘤组织，和cfDNA数据集，分别。患者被分类为CMS1（1.7％），CMS2（27.7%），CMS3（0.9%），CMS4（51.5%），或未分类（18.2%）。未分类/混合CMS与尼达尼布的总生存期（OS）更长CMS2或CMS4(相互作用P值=.0086);对于CMS4未观察到关联。基于基因表达的通路分析显示血管内皮生长因子相关信号与nintedanib的OS之间存在关联(P=.0498)。最常见的体细胞突变是APC(72.0%[肿瘤组织]vs.56.8%[cfDNA])，TP53（47.1%与34.9%），KRAS（40.8%与28.6%），和PIK3CA（16.6%与11.5%)；一致率>80%。观察到APC和TP53突变的中位OS差异与cfDNA中的野生型，表明潜在的预后价值。循环ANG-2，CA-9，CEACAM1，胶原IV，IGFBP-1、ICAM-1、IL-8和uPAR是OS和无进展生存期的潜在预后因素。
我们证明了在全球临床试验中进行大规模生物标志物分析和CMS分类的可行性，和确定的信号表明，在未分类/混合CMS亚组中，尼达尼布治疗反应的可能性更大，尽管这些肿瘤显示CMS混合物的异质性模式。我们的结果表明，肿瘤组织和cfDNA之间的体细胞突变具有高度的一致性。与cfDNA体细胞突变的预后相关，以及几种基于蛋白质的生物标志物，可能需要在未来的试验中进一步调查。
