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Prediction of survival in patients with metastatic colorectal cancer treated with third-line cetuximab and irinotecan through changes in microRNA expression in whole blood during treatment.

3532 Background: MicroRNAs (miRNAs) have shown potential as predictive markers for disease outcome in patients with cancer. MiRNA profiling in whole blood from patients with metastatic colorectal cancer (CRC) before and during treatment was performed to identify a panel of deregulated miRNAs and changes in miRNA expression over time that could predict overall survival (OS).


METHODS
A total of 144 patients with metastatic CRC included in a prospective phase II study of third-line treatment with cetuximab and irinotecan every second week were studied. MiRNAs before and during treatment were isolated from whole blood collected in PAXgene Blood RNA tubes (Qiagen), and miRNA profiling was performed using TaqMan MicroRNA Array v2.0 (Applied Biosystems). The Cox proportional hazard (CPH) model was applied to study the absolute effect of miRNA expression on OS. Each miRNA expression for every measurement was included as a time varying covariate and each miRNA effect on OS was tested. All miRNA that met the 0.001 significance level was then included in a multivariate CPH model. Second, we studied the effect of miRNA change over time by calculating relative changes in miRNA for patients with at least two miRNAs (n=105).


RESULTS
At time of follow-up 132 (92%) of the patients were dead. High expression of miR-361-5p and miR-597, and low expression of miR-31, miR324-3p, let-7e and miR-24 predicted OS after controlling for KRAS mutation status, performance status, age and gender. Hazard ratios (HR) and 95% confidence interval (CI) were miR-31 (0.72; 0.55-0.94), miR-361-5p (2.01; 1.33-3.03), miR-597 (1.70; 1.27-2.27), miR324-3p (0.47; 0.31-0.70), let-7e (0.63; 0.44-0.90) and miR-24 (0.66; 0.44-0.99). During treatment, relative changes in miRNA expression for miR-31 (0.77; 0.62-0.95), let-7g (0.62; 0.43-0.89) and miR-424 (1.38; 1.08-1.76) predicted OS.


CONCLUSIONS
We identified 6 miRNAs that may be good biomarkers of value for OS in patients with metastatic CRC treated with cetuximab and irinotecan. MiR-31 was a predictor for OS at any time point during treatment, and relative change in miR-31 expression during treatment was a predictor for OS.