Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Computational Oncology Group, Sage Bionetworks, Seattle, USA.
Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Ann Oncol. 2019 Oct 1;30(10):1622-1629. doi: 10.1093/annonc/mdz287.
It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC).
We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]).
In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04).
Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.
目前尚不清楚共识分子亚型（CMS）分组和免疫-基质浸润模式在多大程度上能够提高我们预测早期结直肠癌（CRC）患者肿瘤-淋巴结-转移（TNM）分期和微卫星不稳定性（MSI）状态以外的预后的能力。
我们对辅助化疗未治疗（n=1656）和治疗（n=980）、Ⅱ期（n=1799）和Ⅲ期（n=837）CRC 患者的预后标志物进行了全面的回顾性生物标志物分析。我们从肿瘤组织转录组中定义 CMS 评分，并估计 CD8+细胞毒性淋巴细胞（CytoLym）和癌症相关成纤维细胞（CAF）浸润评分（CMSclassifier 和 MCPcounter R 包）；构建用于无病生存（DFS）的分层多变量 Cox 模型；并计算每个标志物（临床病理[ClinPath]、基因组学[Gen：MSI、BRAF 和 KRAS 突变]、CMS 评分[CMS]和微环境细胞[MicroCells：CytoLym+CAF]）解释的变异比例。
在多变量模型中，只有 ClinPath 和 MicroCells 仍然是显著的预后因素，CytoLym 和 CAF 浸润评分都提高了对其他标志物的生存预测。在Ⅱ期，ClinPath、MicroCells、Gen 标志物和 CMS4 评分的 DFS 模型的解释变异分别为 77%、14%、5.3%和 3.7%；在Ⅲ期，分别为 55.9%、35.1%、4.1%和 0.9%。与其他亚组相比，肿瘤 CytoLym 高/CAF 低的患者 DFS 更好[HR=0.71（0.6-0.9）；P=0.004]。微卫星稳定的肿瘤具有 CytoLym 高评分时生存改善的最强信号（交互 P=0.04），而高 CAF 评分与预后不良仅限于Ⅲ期疾病（交互 P=0.04）。
我们的结果证实，肿瘤微环境浸润模式是早期 CRC 远处播散风险的有力决定因素。多变量模型表明，MSI 和 CMS 分组的预后价值在很大程度上可以用 CytoLym 和 CAF 浸润模式来解释。
Zotero 插件