MiRNA expression as a predictor of survival in patients with metastatic colorectal cancer treated with EGFR inhibitors.

Abstract

e14059 Background: The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. EGFR inhibitors have been tested for treatment of a variety of cancers but they are generally plagued by low response rates, leading to ineffective or non-optimal chemotherapy, unnecessary drug toxicity and expense. In colorectal cancer, KRAS mutations are clearly associated with resistance to anti-EGFR antibodies. A major challenge is to identify, in non-mutated KRAS patients, markers that can predict response to this therapy. This study aimed to develop a miRNA expression-based model for evaluating the responsiveness of patients with KRAS wild-type metastatic colorectal cancer to one or more EGFR inhibitors prior to treatment. Methods: miRNA profiling of KRAS wild-type tumors was performed on a discovery set of 44 patients with metastatic colorectal cancer treated with anti-EGFR inhibitors. A miRNA expression-based predictor of survival risk group was calculated by combining a Cox proportional hazards model and a supervised principal component method. Results: miRNA profiling of the discovery set identified hsa-miRNA-31* whose expression in tumor samples was highly correlated with survival and displayed prediction prospective for disease-free and overall survivals. Parameters of the hsa-miRNA-31* expression-based prediction model were determined on a subgroup of 23 patients. Its discriminative ability was evaluated on the complementary 21 samples that included 19 events. In this validation set, 4 of the 6 patients classified as “low risk” by the model survived for more than 25 weeks as disease-free whereas 11 of the 13 patients classified as “high risk” displayed disease progression within 25 weeks, suggesting a specificity of 85% [95% CI: 54%-98%] and a sensitivity of 67% [95% CI: 22%-96%] for the prediction model. These values were associated with a PPV of 67%, [95% CI: 22%-95%] and a NPV of 85% [95% CI: 54%-98%]. Conclusions: Our findings demonstrated that a prediction model based on the level of expression of hsa-miRNA-31* could evaluate whether a patient with a KRAS wild-type metastatic colorectal cancer is likely to respond to an EGFR inhibitor.