The monoclonal antibodies cetuximab and panitumumab are capable of blocking EGFR activity and have shown clinical activity in patients with metastatic CRC (mCRC). However, the efficacy of these agents is significantly limited by mechanisms of intrinsic and acquired resistance. In this respect, the S492R mutation of the extracellular domain of the EGFR is a peculiar mechanism of acquired resistance that limits the binding of cetuximab, but not panitumumab, to the EGFR.

This study is the first to demonstrate that the S492R EGFR ectodomain mutation is never present in patients that have not been exposed to EGFR monoclonal antibodies. In particular, a large cohort (505 patients) of KRAS exon 2 wild type mCRC cases, potential candidates for treatment with cetuximab, were screened to test for the S492R EGFR mutation; a sensitive test that failed to identify any mutation.

These findings suggest that the S492R EGFR mutation is not involved in primary resistance to cetuximab in CRC and have important consequences on the molecular assessment of mCRC patients. Based on these findings patients with mCRC should not be routinely screened for the S492R mutation prior therapy with cetuximab.