Pathway activation strength is a novel independent prognostic biomarker for cetuximab sensitivity in colorectal cancer patients

Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), was shown to be active in colorectal cancer. Although some patients who harbor K-ras wild-type tumors benefit from cetuximab treatment, 40 to 60% of patients with wild-type K-ras tumors do not respond to cetuximab. Currently, there is no universal marker or method of clinical utility that could guide the treatment of cetuximab in colorectal cancer. Here, we demonstrate a method to predict response to cetuximab in patients with colorectal cancer using OncoFinder pathway activation strength (PAS), based on the transcriptomic data of the tumors. We first evaluated our OncoFinder pathway activation strength model in a set of transcriptomic data obtained from patient-derived xenograft (PDx) models established from colorectal cancer biopsies. Then, the approach and models were validated using a clinical trial data set. PAS could efficiently predict patients’ response to cetuximab, and thus holds promise as a selection criterion for cetuximab treatment in metastatic colorectal cancer. The gene expression profile of a patient’s colorectal tumor can help doctors predict how they will respond to therapy using the drug cetuximab. Colorectal cancer patients without a mutation on a gene called K--ras have the potential to respond well to cetuximab treatment, but up to 60% of such patients do not. A research team led by David Sidransky from Johns Hopkins University School of Medicine in the USA used a bioinformatic program called OncoFinder to analyze the genes activated in colorectal tumor tissue taken from patients and patient-derived mice models to identify a prognostic marker for cetuximab treatment. For both the mouse model and retrospective clinical data, the OncoFinder PAS correlated well with the sensitivity of tumors to cetuximab, providing a promising selection criterion for cetuximab treatment in metastatic colorectal cancer.