227P - Prognosis of phosphorylated-insulin growth factor receptor (p-IGF-1R) and metalloproteinase-3 (MMP3) expression in advanced gastrointestinal stroma...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer agents
GIST
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological Therapy
Presenter Joan Maurel
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors J. Maurel1, A. Lopez Pousa2, S. Calabuig3, S. Bagué2, X. Garcia Del Muro4, X. Sanjuan4, J. Rubio5, M. Cuatrecasas1, J. Martinez-Trufero6, C. Horndler6, J. Fra7, C. Valverde Morales8, A. Redondo9, A.M. Poveda10, I. Sevilla11, N. Lainez12, M. Rubini13, X. García Albéniz14, J. Martin Broto15, E. De Álava16
  • 1Oncology, Hospital Clínic i Provincial de Barcelona, 08036 - Barcelona/ES
  • 2Medical Oncology, l'Hospital de Sant Pau i de la Santa Creu, Barcelona/ES
  • 3Oncology, Hospital General de Valencia, Valencia/ES
  • 4Oncology, ICO Hospitalet, Barcelona/ES
  • 5Oncology, ICO Girona, Girona/ES
  • 6Oncology, Hospital Miguel Servet, Zaragoza/ES
  • 7Oncology, Hospital Rio Hortega, Valladolid/ES
  • 8Oncologia Médica, Vall d'Hebron University HospitalInstitut d'Oncologia, ES-08035 - Barcelona/ES
  • 9Medical Oncology, Hospital Universitario la Paz, Madrid/ES
  • 10-, Fundación Instituto Valenciano de Oncología, 46009 - Valencia/ES
  • 11Medical Oncology, C U Virgen de la Victoria, málaga/ES
  • 12Medical Oncology, Complejo Hospitalario de Navarra, Pamplona/ES
  • 13Oncology, Università degli studi di Ferrara, Ferrara/IT
  • 14Oncology, Harvard School of Public Health, Boston/US
  • 15Medical Oncology, Hospital Universitario Son Espases, ES-07010 - Palma de Mallorca/ES
  • 16Oncology, Hospital Virgen del Rocío, Sevilla/ES

Abstract

Aim

Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, with 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 expression of p-IGF-1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS)

Methods

Ninety-six advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF-1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF-1R system, we have used an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-1R. 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. Bidirecctional 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

MMP3 was overexpressed in 10% of cases and p-IGF-1R in only 2% of cases. 68% of patients had KIT mutations, 4% had PDGFRA mutations and 28% were WT for KIT and PDGFRA. At univariate analysis KIT exon 11/13 vs rest (WT/WT, KIT exon 9 mutations and PDGFRA mutations) had better PFS (p = 0.038; HR: 0.58; 95%CI (0.35-0.96). 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 positive expression of p-IGF-1R or MMP3 (HR 2.1; 95% CI 1.01-4,2) but not mutational analysis (HR 1.02; 95%CI 0.53-1.96) were the strongest prognostic factors for PFS in the multivariate analysis. For OS only PS, disease free-interval and number of metastatic sites remain significant.

Conclusions

Our findings suggest that p-IGF-1R (Y1316) and MMP3 expression have major prognostic significance for PFS in advanced GIST treated with imatinib therapy.

Disclosure

All authors have declared no conflicts of interest.