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

Beth O. Van Emburgh, Sabrina Arena, Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Giorgio Corti, Benedetta Mussolin, Federica Baldi, Michela Buscarino, Alice Bartolini, Emanuele Valtorta, Joana Vidal, Beatriz Bellosillo, Giovanni Germano, Filippo Pietrantonio, Agostino Ponzetti, Joan Albanell, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Clara Montagut () and Alberto Bardelli ()
Additional contact information
Beth O. Van Emburgh: Candiolo Cancer Institute—FPO, IRCCS
Sabrina Arena: Candiolo Cancer Institute—FPO, IRCCS
Giulia Siravegna: Candiolo Cancer Institute—FPO, IRCCS
Luca Lazzari: Candiolo Cancer Institute—FPO, IRCCS
Giovanni Crisafulli: Candiolo Cancer Institute—FPO, IRCCS
Giorgio Corti: Candiolo Cancer Institute—FPO, IRCCS
Benedetta Mussolin: Candiolo Cancer Institute—FPO, IRCCS
Federica Baldi: Candiolo Cancer Institute—FPO, IRCCS
Michela Buscarino: Candiolo Cancer Institute—FPO, IRCCS
Alice Bartolini: Candiolo Cancer Institute—FPO, IRCCS
Emanuele Valtorta: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda
Joana Vidal: Hospital del Mar
Beatriz Bellosillo: Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar
Giovanni Germano: Candiolo Cancer Institute—FPO, IRCCS
Filippo Pietrantonio: Fondazione IRCCS Istituto Nazionale dei Tumori
Agostino Ponzetti: Colorectal Cancer Unit, San Giovanni Battista Hospital
Joan Albanell: Hospital del Mar
Salvatore Siena: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda
Andrea Sartore-Bianchi: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda
Federica Di Nicolantonio: Candiolo Cancer Institute—FPO, IRCCS
Clara Montagut: Hospital del Mar
Alberto Bardelli: Candiolo Cancer Institute—FPO, IRCCS

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13665

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