title: Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas.
abstract: BACKGROUND
  Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.
  
  
  METHODS
  We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.
  
  
  RESULTS
  We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P≤0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P≤0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P≤0.019; Cox analysis).
  
  
  CONCLUSIONS
  Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gallardo
authors.forename: E
authors.initials: E
authors.lastname: Lerma
authors.forename: D
authors.initials: D
authors.lastname: Escuin
authors.forename: A
authors.initials: A
authors.lastname: Tibau
authors.forename: J
authors.initials: J
authors.lastname: Muñoz
authors.forename: B
authors.initials: B
authors.lastname: Ojeda
authors.forename: A
authors.initials: A
authors.lastname: Barnadas
authors.forename: E
authors.initials: E
authors.lastname: Adrover
authors.forename: L
authors.initials: L
authors.lastname: Sánchez-Tejada
authors.forename: D
authors.initials: D
authors.lastname: Giner
authors.forename: F
authors.initials: F
authors.lastname: Ortiz-Martínez
authors.forename: G
authors.initials: G
authors.lastname: Peiró
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C494929:PTEN protein, human