title: Molecular characterization of EGFR and EGFR-downstream pathways in triple negative breast carcinomas with basal like features.
abstract: Triple negative breast cancer with basal like features (TN-BCBL) do not benefit from hormonal and anti-HER2 therapies. As a considerable fraction of TN-BCBLs shows EGFR deregulation, EGFR-targeted therapies have been proposed as an option. The characterization of EGFR and EGFR-downstream members may therefore provide important predictive information.
  
  
  
  Based on morphological and immunophenotypic features, we identified 38 TN-BCBLs that were subsequently investigated for alterations in EGFR signaling pathways. EGFR and PTEN protein levels were studied by immunohistochemistry, EGFR gene status by FISH, EGFR, H-Ras, K-Ras, N-Ras, BRAF and PIK3CA gene mutations by direct sequencing. EGFR overexpression and loss of PTEN expression characterized the majority of TN-BCBLs (76% and 74% of patients, respectively). EGFR gene copy number gain (FISH+) was identified in 51% of analyzable patients. PIK3CA gene mutations were detected in three cases (8%), whereas EGFR, H-Ras, K-Ras, N-Ras and BRAF genes showed no mutations. Overall, out of 17 patients classified as FISH+, 12 cases (70%) showed a concomitant alteration in PI3K/PTEN pathway.
  
  
  
  These results provide evidence that the efficacy of anti-EGFR drugs in TN-BCBL patients could be impaired by frequent alterations in the PI3K/PTEN axis, and suggest that TN-BCBLs could benefit from tailored treatments against this axis.
authors.affiliation: Institute of Pathology, Locarno, Switzerland. vittoria.martin@ti.ch
authors.forename: V
authors.initials: V
authors.lastname: Martin
authors.forename: F
authors.initials: F
authors.lastname: Botta
authors.forename: E
authors.initials: E
authors.lastname: Zanellato
authors.forename: F
authors.initials: F
authors.lastname: Molinari
authors.forename: S
authors.initials: S
authors.lastname: Crippa
authors.forename: L
authors.initials: L
authors.lastname: Mazzucchelli
authors.forename: M
authors.initials: M
authors.lastname: Frattini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002277:Carcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000032:analysis; D018579:Patient Selection; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016133:Polymerase Chain Reaction; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human; C494929:PTEN protein, human; C501009:HRAS protein, human