title: PTEN, Akt, MAPK, p53 and p95 expression to predict trastuzumab resistance in HER2 positive breast cancer.
abstract: OBJECTIVE
  Mutations that activate the PIK3CA oncogene and inhibit the tumor suppressor gene PTEN action are commonly found in breast tumors. Akt is a key activator of cell survival. p53 is frequently found mutated in human tumors, and mutant p53 protein actively contributes to tumorigenesis. In selected cases of breast cancer, trastuzumab (TZMB) is incorporated in the primary treatment in the adjuvant and metastatic settings. Many studies have reported that selected patients are resistant to TZMB due to the presence of p95 HER2 fragments. To address this, we analysed PTEN, Akt, MAPK, p53 and p95 expression in breast cancer patients treated with TZMB.
  
  
  METHODS
  Out of 90 patients histologically diagnosed with breast cancer between 2004 and 2011, analysed were 25 patients with HER2 positive, and estrogen (ER) and progesterone receptors (PR) negative, metastatic or locally advanced disease. All 25 patients were treated with TZMB and resistance to TZMB was assessed. All patients were on anthracycline-and taxane-containing regimens. Tissue samples were obtained from paraffin blocks and evaluated immunohistochemically for PTEN, Akt, MAPK, p53, and p95 expression.
  
  
  RESULTS
  TZMB resistance was detected in 5 (20%) patients. Akt expression was positive in 2 patients (8%) and MAPK, p95, and p53 expression was positive in 1 patient (4%); PTEN expression was negative in 3 patients (12%). No significant differences were found between TZMB resistance and PTEN, Akt, MAPK, p53, and p95 expression. Subgroup analysis was carried out in the neoadjuvant treatment group. Complete pathologic response was detected in 3 patients (21.4%). Statistically significant differences were not found between the complete response rate and PTEN, Akt, MAPK, and p95 expression. There was a statistically significant correlation between p53 expression and complete pathologic response (p=0.02).
  
  
  CONCLUSIONS
  No statistically significant correlation between TZMB resistance and the expression of these biomarkers was noted. In patients with HER2-positive breast cancer that were treated with 4 dose-dense sequential cycles of doxorubicin and cyclophosphamide, followed by TZMB and paclitaxel combination therapy in the neodjuvant setting, p53 expression could predict complete response to chemotherapy.
authors.affiliation: Department of Medical Oncology, Cukurova University Medical Faculty, Adana, Turkey. berboz@hotmail.com
authors.forename: B B
authors.initials: BB
authors.lastname: Duman
authors.forename: B
authors.initials: B
authors.lastname: Sahin
authors.forename: A
authors.initials: A
authors.lastname: Acikalin
authors.forename: M
authors.initials: M
authors.lastname: Ergin
authors.forename: S
authors.initials: S
authors.lastname: Zorludemir
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis*; D020360:Neoadjuvant Therapy; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D012307:Risk Factors; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human