Personalized treatment planning of stage II and IIIA colon cancr patients using genomic classifiers (COLOPRINT/MSI-PRINT)

Introduction: Adjuvant therapy for stage II patients is recommended for patients with high risk features, especially with T4 tumors, and recommended for all stage III patients. Adjuvant therapy is not indicated for patients with MSI-H status who are considered of being at low risk of disease relapse. However, this leaves the majority of stage II patients with an undetermined risk. ColoPrint is an 18-gene expression classifier that identifies patients at higher risk of disease relapse. Together with a genomic classifier to determine MSI-status, ColoPrint can help making treatment decisions for early stage colon cancer patients. Methods: ColoPrint was developed using whole genome expression data and was validated in public datasets (n = 322) and independent patient cohorts from 5 European hospitals (n = 341). Tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 70 months) for patients were available and the ColoPrint index was determined using validated diagnostic arrays. The 64-gene MSI-signature (MSI-Print) was developed using full genome expression data of 276 primary stage II and III colorectal tumors with known MSI-status (n = 29 MSI-H, n = 247 MSS). Uni-and multivariate analysis was performed on the pooled stage II and stage IIIA patient set and in the subsets of patients who were stage IIIA or stage II T3/ MSS. Results: In the analysis of all stage II and IIIA patients, ColoPrint classified two-third of stage II patients as being at lower risk. The 3-year Relapse-Free-Survival (RFS) was 91% for Low Risk and 74% for patients at higher risk with a HR of 2.9 (p = 0.001). Clinicopathological parameters from the 2012 NCCN guidelines (T4, perforation, <12 LN assessed, high grade and/ or angio-lymphatic invasion) did not predict a differential outcome for high risk patients (p< 0.20). In the subgroup of patients with T3 and MSS phenotype, ColoPrint classified 61% of patients at lower risk with a 3-year RFS of 91% (86-96%) and 39% of patients at higher risk with a 3-year RFS of 73% (63-83%) (p = 0.002). No clinical parameter was significantly prognostic in this subgroup. In the stage IIIA subgroup, most patients (76%) were also classified as low risk with a 3-year RFS of 90% (HR= 6.2; p = 0.008). The MSI-signature was validated in 130 stage II patients with known MSI-status and identified MSI-H patients with high sensitivity (93.1%) and high specificity (87.9%). Conclusion: The diagnostic MSI signature identifies patients with MSI-H status with high accuracy. Combined with ColoPrint, the prognostic accuracy in stage II and stage IIIA patients can be significantly improved, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.