Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer

Beth O. Van Emburgh1,7,8, Sabrina Arena1,7, Giulia Siravegna1,7, Luca Lazzari1,7, Giovanni Crisafulli1,7, Giorgio Corti1, Benedetta Mussolin1, Federica Baldi1,7, Michela Buscarino1, Alice Bartolini1, Emanuele Valtorta2, Joana Vidal3,9, Beatriz Bellosillo3, Giovanni Germano1, Filippo Pietrantonio4, Agostino Ponzetti5, Joan Albanell3,9, Salvatore Siena2,6, Andrea Sartore-Bianchi2, Federica Di Nicolantonio1,7, Clara Montagut3, Alberto Bardelli1,7

1.Candiolo Cancer Institute—FPO, IRCCS, 10060 Candiolo, Torino, Italy
2.Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy
3.Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, 08003 Barcelona, Spain
4.Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy
5.Colorectal Cancer Unit, Medical Oncology Division 1, San Giovanni Battista Hospital, 10133 Torino, Italy
6.Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy
7.Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy
8.FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy
9.Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain
10.Pathology Department, Hospital del Mar, 08003 Barcelona, Spain
Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop 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.