Abstract
Advanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC with a low immunoscore is associated with shorter survival times. Non-metastatic CRC with microsatellite instability (MSI) is associated with a lower risk of recurrence. We evaluated outcome (lymph node metastases [LNM] or cancer recurrence) in these tumor subtypes in patients with surgically-removed non-pedunculated T1 CRC by performing a multicenter case-cohort study. We included all patients in 13 hospitals in the Netherlands from 2000–2014 (n = 651). We randomly selected a subgroup of patients (n = 223) and all patients with LNM or recurrence (n = 63), and median follow-up of 44 months. We centrally reviewed tumor-slides, and constructed and immunostained tissue microarrays determining MSI, CMS (MSI/CMS1, CMS2/3, or CMS4), and immunoscore (I-low/I-high). We used weighted Cox proportional hazard models to evaluate the association of MSI, CMS, and immunoscore with LNM or recurrence, adjusting for conventional histologic risk factors. In the randomly selected subgroup of patients, 7.1% of tumors were MSI/CMS1, 91.0% CMS2/3, 1.8% CMS4, and 25% I-low. In the case-cohort, patients with CMS4 tumors had an increased risk for LNM or recurrence compared with patients with tumors of other CMSs (adjusted hazard ratio [HR], 3.97; 95% CI, 1.12–14.06; P = 0.03). Albeit not significant, tumors with MSI had a lower risk for LNM or recurrence than other tumor subtypes (adjusted HR, 0.52; 95% CI, 0.12–2.30; P = 0.39), whereas tumors with a low immunoscore had an increased risk for LNM or recurrence (adjusted HR, 1.30; 95% CI, 0.68–2.48; P = 0.43). In conclusion, in a case-cohort study of patients with non-pedunculated T1 CRC, MSI, and immunoscore were not significantly associated with adverse outcome after surgery. CMS4 substantially increased the risk of adverse outcome. However, CMS4 is rare in T1 CRCs, limiting its value for determining the risk in patients.
Highlights
The prognosis and therapeutic decision making in patients with colorectal cancer (CRC) rely on the TNM classification, concerning tumor invasion and metastasis [1]
We identified 651 patients with non-pedunculated T1 CRC treated with surgery within the participating hospitals, with a median follow-up time of 44 months (Interquartile range (IQR) 17–78)
consensus molecular subtype 4 (CMS4) is uncommon in T1 CRC, but if present, it substantially increases the risk for lymph node metastasis (LNM) and recurrent cancer
Summary
The prognosis and therapeutic decision making in patients with colorectal cancer (CRC) rely on the TNM classification, concerning tumor invasion and metastasis [1]. An international consortium has evaluated genomewide gene-expression data to classify patients into four consensus molecular subtypes (CMS) [3]. CMS1, 13% of CRCs, represents immune-active tumors with highmutational load, Microsatellite instability (MSI) or BRAFmutations, and has been recognized as a favorable prognostic subtype in early-stage CRC [4]. CMS2, the canonical type and comprising 37% of CRCs, is characterized by activated WNT- and MYC-pathways, high somatic copynumber alterations, and increased EGFR expression with a mutated TP53 gene. CMS3, the metabolic type and comprising 13% of CRCs, is characterized by low somatic copy-number alterations, KRAS mutations, and elevated metabolic signatures. CMS4, representing 23% of CRC, is characterized by tumors with epithelial-mesenchymal transition, TGF-beta pathway, and stromal activation. A residual group of 13% represents unclassified patients or patients with a mixed subtype [3, 7]
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