title: Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.
abstract: BACKGROUND
  Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ~30-40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively.
  
  
  METHODS
  Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ(2), Fischer's exact test and Mann-Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and survival curves of subgroups were compared with log-rank test.
  
  
  RESULTS
  Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5-13.4 months) and 22 months (95% CI, 9.9-34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6-34 months) and 12.1 months (95% CI, 7.9-16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3-40.4 months) and 29.1 months (95% CI, 8.6-43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5-40.1 months) and 26.8 months (95% CI, 8.1-42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2-4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1-3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18-4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14-3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis.
  
  
  CONCLUSIONS
  Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Medical Oncology, 34098 Istanbul, Turkey.
authors.forename: D
authors.initials: D
authors.lastname: Tural
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Medical Oncology, 34098 Istanbul, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Serdengecti
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Medical Oncology, 34098 Istanbul, Turkey.
authors.forename: F
authors.initials: F
authors.lastname: Demirelli
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Pathology, 34098 Istanbul, Turkey.
authors.forename: T
authors.initials: T
authors.lastname: Öztürk
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Pathology, 34098 Istanbul, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: İlvan
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Medical Oncology, 34098 Istanbul, Turkey.
authors.forename: H
authors.initials: H
authors.lastname: Turna
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Medical Oncology, 34098 Istanbul, Turkey.
authors.forename: M
authors.initials: M
authors.lastname: Özgüroglu
authors.affiliation: Istanbul University Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Medical Oncology, 34098 Istanbul, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Büyükünal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D053492:Elafin / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053492:Elafin; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D051567:Proto-Oncogene Proteins c-vav; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C506806:PI3 protein, human; C496618:VAV1 protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human