title: Co-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: a GEMCAD study.
abstract: BACKGROUND
  By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I.
  
  
  METHODS
  A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses.
  
  
  RESULTS
  Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis.
  
  
  CONCLUSIONS
  Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR.
authors.affiliation: Pathology Department, Hospital Miguel Servet, Zaragoza, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hörndler
authors.forename: Rosa
authors.initials: R
authors.lastname: Gallego
authors.forename: Xabier
authors.initials: X
authors.lastname: García-Albeniz
authors.forename: Virginia
authors.initials: V
authors.lastname: Alonso-Espinaco
authors.forename: Vicente
authors.initials: V
authors.lastname: Alonso
authors.forename: Pilar
authors.initials: P
authors.lastname: Escudero
authors.forename: Mireya
authors.initials: M
authors.lastname: Jimeno
authors.forename: Javier
authors.initials: J
authors.lastname: Ortego
authors.forename: Jordi
authors.initials: J
authors.lastname: Codony-Servat
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Martos
authors.forename: Ana
authors.initials: A
authors.lastname: Calatrava
authors.forename: Mercedes
authors.initials: M
authors.lastname: Marín-Aguilera
authors.forename: Jenifer
authors.initials: J
authors.lastname: Muñoz
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Michele
authors.initials: M
authors.lastname: Rubini
authors.forename: Pere
authors.initials: P
authors.lastname: Gascón
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008875:Middle Aged; D000077544:Panitumumab; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D007334:Insulin-Like Growth Factor I; D000077544:Panitumumab; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020783:Matrix Metalloproteinase 7; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab