title: Phosphorylated-insulin growth factor I receptor (p-IGF1R) and metalloproteinase-3 (MMP3) expression in advanced gastrointestinal stromal tumors (GIST). A GEIS 19 study.
abstract: BACKGROUND
  Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated the immunohistochemical (IHC) expression of p-IGF1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS).
  
  
  METHODS
  Ninety-two advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF1R system, we have used an antibody (anti-pY1316) that specifically recognizes the active phosphorylated form of the IGF1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9, 11, 13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirectional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p < 0.10 and criterion to keep the variable in the model of p < 0.05. PFS was computed as the date of imatinib initiation to progression or death. Overall survival was defined as the time from imatinib initiation to death.
  
  
  RESULTS
  Phospho-IGF1R was expressed only in 9 % (2/22) of cases without KIT mutation. MMP3 expression was detected in 2/5 patients (40 %) with PDGFRA mutation, 1/16 patients (6 %) with WT genotype and 7/71 patients (10 %) of KIT mutant patients. At univariate analysis KIT exon 11/13 mutation had better PFS than patients with exon 9 mutation, PDGFRA mutation or WT genotype (p = 0.021; HR: 0.46; 95 %CI (0.28-0.76). Less than 24 months disease free-interval (HR 24.2, 95 % CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95 % CI 2.5-15.9), extension of disease; >1 organ (HR 1.89; 95 % CI 1.03-3.4) and genotype analysis (HR 0.57, 95 % CI 0.37-0.97) but not immunophenotype analysis (HR 1.53; 95 % CI 0.76-3.06) were the strongest prognostic factors for PFS in the multivariate analysis.
  
  
  CONCLUSIONS
  Our results do not support p-IGF-1R and MMP3 evaluation in non-selected GIST patients but evaluation of this immunophenotype in WT and mutant PDGFR mutation in larger group of GIST patients, deserve merits.
authors.affiliation: Department of Medical Oncology, Hospital Clinic, CIBERehd, Translational Genomics and Targeted Therapeutics in Solid Tumors (IDIBAPS), Barcelona, Spain.
authors.forename: Joan
authors.identifier: 0000-0002-9413-5592
authors.initials: J
authors.lastname: Maurel
authors.affiliation: Department of Medical Oncology, Hospital Universitario Sant Pau, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: López-Pousa
authors.affiliation: Molecular Oncology Laboratory, Fundación de Investigación del Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Calabuig
authors.affiliation: Pathology Department, Hospital Universitario Sant Pau, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagué
authors.affiliation: Department of Medical Oncology, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain.
authors.forename: Xavier Garcia
authors.initials: XG
authors.lastname: Del Muro
authors.affiliation: Pathology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sanjuan
authors.affiliation: Department of Medical Oncology, Institut Català d'Oncologia de Girona, Girona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rubió-Casadevall
authors.affiliation: Pathology Department, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain.
authors.forename: Miriam
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authors.lastname: Cuatrecasas
authors.affiliation: Department of Medical Oncology, Hospital Universitario Miguel Servet, Saragossa, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Trufero
authors.affiliation: Pathology Department, Hospital Universitario Miguel Servet, Saragossa, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Horndler
authors.affiliation: Department of Medical Oncology, Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Fra
authors.affiliation: Department of Medical Oncology, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Valverde
authors.affiliation: Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Redondo
authors.affiliation: Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Poveda
authors.affiliation: Department of Medical Oncology, Hospital Universitario Virgen de la Victoria y Regional de Málaga, Málaga, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Sevilla
authors.affiliation: Department of Medical Oncology, Hospital de Navarra, Pamplona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lainez
authors.affiliation: Department of Experimental and Diagnostic Medicine, Department of Epidemiology, University of Ferrara (UNIFE), Emilia-Romagna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Rubini
authors.affiliation: Harvard T.H. Chan School of Public Health, Boston, MA USA.
authors.forename: Xabier
authors.initials: X
authors.lastname: García-Albéniz
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín-Broto
authors.affiliation: Pathology Department, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: de Alava