Epidermal Growth Factor Receptor Mutations May Confer Resistance Or Cross-Resistance To Cetuximab And Panitumumab And Can Be Detected In Circulating Tumor Dna

3549 Background: Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. Methods: We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by targeted next-generation sequencing (“tumor tissue” cohort). Binding, signaling and drug sensitivity studies were performed in Ba/F3 cells stably transduced with wt and mutant EGFR. Results were validated in circulating tumor DNA (ctDNA) of an independent “liquid biopsy” cohort of 27 patients. Results: We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab in the “tumor tissue” cohort. This mutation introduces a ...