title: Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer.
abstract: How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient.
  
  
  CONCLUSIONS
  Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Corti
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Crisafulli
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Leanne G
authors.initials: LG
authors.lastname: Ahronian
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mussolin
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Buscarino
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lazzari
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Jessop
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Robinson
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.|Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Hong
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Thabet
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000097:blood; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009154:Mutation; D000077544:Panitumumab; D057285:Precision Medicine; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D000077544:Panitumumab; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab