In combination with their response to cetuximab treatment, our data show that patients carrying at least one of SMAD4 or NF1 mutations had a higher possibility of a poor response to EGFR blockade with a shorter progression-free survival (PFS), suggesting that SMAD4 and NF1 mutations may play an important role in tumor progression and might function as biomarkers for poor prognosis to cetuximab-based therapy in mCRC patients. The gene discussed is SMAD4; the disease is neoplasm.