title: KIT, PDGFRA, and BRAF mutational spectrum impacts on the natural history of imatinib-naive localized GIST: a population-based study.
abstract: The mutation status of KIT or PDGFRA notoriously affects the response of advanced gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors. Conversely, it is currently still unclear whether mutation status impinges on the prognosis of localized, untreated GISTs. Hence, at present, this variable is not included in decision making for adjuvant therapy. A series of 451 primary localized GISTs were analyzed for KIT, PDGFRA, and BRAF mutations. Univariable and multivariable analyses and a backward selection procedure were used to assess the impact of mutation status on overall survival and to identify prognostically homogenous groups. Mutation was a significant prognostic indicator of overall survival in naive, localized GISTs (P<0.001): KIT-mutated patients had a worse outcome than PDGFRA-mutated or triple-negative (KIT, PDGFRA, BRAF wild-type) cases. Multivariable Cox regression models allowed us to identify 3 molecular risk groups: group I exhibited the best outcome and included PDGFRA exon 12, BRAF, and KIT exon 13-mutated cases; group II, of intermediate clinical phenotype (HR=3.06), included triple-negative, KIT exon 17, PDGFRA exon 18 D842V, and PDGFRA exon 14-mutated cases; group III displayed the worst outcome (hazard ratio=4.52), and comprised KIT exon 9 and exon 11 and PDGFRA exon 18 mutations apart from D842V. This study highlights the prognostic impact of mutation status on the natural course of GIST and suggests that the molecular prognostic grouping may complement the conventional clinicopathologic risk stratification criteria in decision making for adjuvant therapy.
authors.affiliation: *Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso †Experimental Oncology I, CRO Aviano National Cancer Institute, Aviano ‡Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale Tumori **Department of Pathology, IRCCS San Raffaele Hospital, Milano §Department of Pathology, Firenze University School of Medicine, Firenze ∥Department of Pathology, University of Marche, Ancona School of Medicine, Ancona ¶Department of Pathology, General Hospital, Bolzano #Department of Pathology, Macchi Foundation, Varese ††Department of Pathology, General Hospital, Bergamo ‡‡Department of Pathology, Perugia University, School of Medicine, Perugia §§Novartis Farma, Origgio Departments of ∥∥Surgery ¶¶Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rossi
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasparotto
authors.forename: Rosalba
authors.initials: R
authors.lastname: Miceli
authors.forename: Luisa
authors.initials: L
authors.lastname: Toffolatti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gallina
authors.forename: Enrico
authors.initials: E
authors.lastname: Scaramel
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marzotto
authors.forename: Elena
authors.initials: E
authors.lastname: Boscato
authors.forename: Luca
authors.initials: L
authors.lastname: Messerini
authors.forename: Italo
authors.initials: I
authors.lastname: Bearzi
authors.forename: Guido
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Arrigoni
authors.forename: Aurelio
authors.initials: A
authors.lastname: Sonzogni
authors.forename: Angelo
authors.initials: A
authors.lastname: Sidoni
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Paola
authors.initials: P
authors.lastname: Amore
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Dei Tos
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf