Blockade of the epidermal growth factor receptor (EGFR) with cetuximab or panitumumab monoclonal antibodies is effective in a subset of colorectal cancers (CRCs), but the efficacy of these therapeutic agents can be limited due to the emergence of resistances. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. A recent study found that patients who experience greater and longer responses to EGFR blockade preferentially developed EGFR-ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR-ECD variants. Subclonal RAS but not EGFR-ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.
