Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer

Abstract

Background: 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). Patients and methods:We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N ¼ 1656) and treated (N ¼ 980), stage II (N ¼ 1799) and III (N ¼ 837) CRCs. We defined CMS scores and estimated CD8þ 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: CytoLymþCAF]).Results: 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 [HR¼0.71 (0.6-0.9); P ¼ 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P ¼ 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P ¼ 0.04). Conclusions: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.

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer

“…Nevertheless, recent data support that tumour microenvironment markers could better reflect the risk of recurrence in localised CC than transcriptomic markers. 7 Subtyping based on genes expressed by stromal cells other than epithelial tumour cells may provide a more accurate molecular characterisation of CC. 24 Intratumoural heterogeneity leads to underestimation of the molecular landscape from single tumour-biopsy samples, 25 leading to inaccuracy in molecular portrayal.…”

“…As the TGF-β stromal programme has a role in metastasis initiation, the tumour microenvironment potentially influences prognosis in localised colon cancerCC. 7 Moreover, plasma circulating tumour DNA (ctDNA) has recently been shown to detect minimal residual disease (MRD) after curative treatment and can help identify a subset of patients at higher risk of recurrence. [8][9][10] Our study aims at integrating novel biological factors into a multimodal approach to improve on our ability to pinpoint the risk of relapse.…”

Characteristics of Subtypes Within Microsatellite Instability-high Gastric Cancer Based on a Gene Signature Related to Immune Microenvironment Components

“…The effect of the MSI-H status on prognosis depends on the type of tumor. It is considered to lead to more aggressive malignancy in endometrial cancer [31], whereas it is associated with better clinical prognosis in colorectal and gastric cancers [32][33][34][35]. Recently, studies have discussed more about chemotherapy resistance in MSI-H tumors; the negative prognostic effects of adjuvant chemotherapy in MSI-H colorectal cancer have been con rmed [32,36].…”

Downregulation of PLK4 Expression Induces Cellular Dormancy in Colorectal Cancer via Mesenchymal-to-epithelial Transition

“…Remarkably, up to 65% of patients with stage IV CRC have relapsed disease after treatment with curative intent, while on 30% of patients with stage I-III CRC experience relapse after similar treatment [3]. Although modern curative treatments have already greatly improved the overall survival (OS) and disease-free survival (DFS) of patients with CRC in recent years, the success of these treatment strategies is generally based on early detection of primary and recurrent CRC [4,5]. Therefore, further exploration of the molecular mechanism underlying CRC recurrence and metastasis and identi cation of candidate biomarkers of these processes are urgently needed and important for improving the CRC survival rate.…”