title: Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer.
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.
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Beth O
authors.initials: BO
authors.lastname: Van Emburgh
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lazzari
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Crisafulli
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.
authors.forename: Giorgio
authors.identifier: 0000-0001-6379-4117
authors.initials: G
authors.lastname: Corti
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mussolin
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Baldi
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Buscarino
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.affiliation: Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain.|Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, 08003 Barcelona, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Vidal
authors.affiliation: Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, 08003 Barcelona, Spain.|Pathology Department, Hospital del Mar, 08003 Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Germano
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pietrantonio
authors.affiliation: Colorectal Cancer Unit, Medical Oncology Division 1, San Giovanni Battista Hospital, 10133 Torino, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Ponzetti
authors.affiliation: Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain.|Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, 08003 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy.|Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, 20122 Milano, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.identifier: 0000-0001-9618-2010
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain.|Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, 08003 Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Montagut
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy.|Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use*; D060965:Clonal Evolution; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D018773:Genes, erbB-1; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D000074322:Antineoplastic Agents, Immunological; D066246:ErbB Receptors