Abstract 1281: Exploratory analysis of microRNAs as predictive markers of benefit from cetuximab in metastatic colorectal cancer

Global miRNA expression profiling has become increasingly common in cancer research, and miRNA signatures that are correlated to stage of disease or to clinical outcomes are now available for a variety of cancer types. Expression profiling of miRNA may be useful also in identifying molecular markers for the prediction of drug-responses and for prospective stratification. Due to their cancer-type specific deregulation and to their stability, miRNAs can be detected in frozen tissue, formalin-fixed paraffin-embedded tissue (FFPET), and in plasma samples from cancer patients. In the current study, we evaluated the use of FFPET for generating miRNA signatures and sought to identify novel predictive markers of benefit from the anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in metastatic colorectal cancer (mCRC). Global miRNA expression profiling was completed using RNA isolated from FFPE tumors obtained from thirty-two patients who received cetuximab monotherapy as part of the CA225-045 clinical trial. Biomarker analyses from this study had previously demonstrated that patients with tumors expressing high levels of the EGFR ligands epiregulin and amphiregulin and/or possessing wild-type KRAS were more likely to show benefit from cetuximab than patients with low expression of the ligands or with mutant KRAS (J Clin Oncol 25:3230-37). MicroRNA signatures were generated using Agilent human miRNA Rel 12.0 microarrays and were correlated to best clinical responses. By comparing the miRNA profiles of nonresponders (progressive disease) to the miRNA profiles of those with disease control (DC = stable disease or partial responses), approximately 30 differentially-expressed miRNAs were identified, many of which were recognized previously for their association with CRC or with other cancers. Among the most interesting were miRNAs regulating genes in the RAS signaling pathway or identified as downstream targets and effectors of the Myc transcription network. On a relative scale and as compared to nonresponders, the DC group possessed high levels of RAS-associated miRNAs and low levels of Myc-target miRNAs. This pattern is suggestive of a lower proliferation index in tumors derived from subjects in the DC group. This study demonstrated that it is feasible to obtain high-quality miRNA signatures from FFPET. Despite the small number of samples analyzed, several interesting, cancer-relevant miRNAs were identified as potential prognostic markers and/or pr