CINSARC Signature Outperforms Gold-Standard TNM Staging and Consensus Molecular Subtypes for Clinical Outcome in Stage II–III Colorectal Carcinoma

The outcome of stage II–III colorectal cancer (CRC) is highly variable and therapeutic choice is currently based on TNM staging with a few additional biomarkers. However, studies show that some stage III patients have a better prognosis than some stage II patients. A promising consensus molecular (CMS) classification with prognostic relevance has been developed, but it is not used in daily practice. Our team developed CINSARC, a 67-gene expression prognostic signature, whose prognostic value has been demonstrated in many cancer types. It is applicable to formalin-fixed, paraffin-embedded (FFPE) blocks using NanoString® technology. We investigated whether it could predict outcome in stage II–III CRC. We established the CINSARC classification on the TCGA retrospective cohort comprising 297 stage II–III CRC patients using RNA sequencing and on a second independent cohort comprising 169 cases using NanoString® technology. We compared its recurrence-free and overall survival prognostic value with TNM staging and CMS classification. In the TCGA cohort, we showed that CINSARC significantly splits the population of stage II–III CRC into two groups with different progression-free interval (P = 1.68 × 10−2; HR = 1.87 [1.11–3.16]) and overall survival (P = 3.73 × 10−3; HR = 2.45 [1.31–4.59]) and is a strong prognostic factor in multivariate analysis, outperforming TNM staging and CMS classification. We validated these results in the second cohort by applying CINSARC on FFPE samples with Nanostring® technology. CINSARC is a ready-to-use tool with a robust independent prognostic value in stage II–III CRC.