title: Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status.
abstract: BACKGROUND
  Assessment of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) might be an important tool in identifying human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients unlikely to derive benefit from anti-HER2 therapies. However, studies to date have failed to demonstrate its predictive role in any treatment setting.
  
  
  METHODS
  Prospectively collected baseline core biopsies from 429 early-stage HER2-positive breast cancer patients treated with trastuzumab, lapatinib, or their combination in the Neo-ALTTO study were stained using two anti-PTEN monoclonal antibodies (CST and DAKO). The association of PTEN status and PI3K pathway activation (defined as either PTEN loss and/or PIK3CA mutation) with total pathological complete response (tpCR) at surgery, event-free survival (EFS), and overall survival (OS) was evaluated.
  
  
  RESULTS
  PTEN loss was observed in 27% and 29% of patients (all arms, n = 361 and n = 363) for CST and DAKO, respectively. PTEN loss was more frequently observed in hormone receptor (HR)-negative (33% and 36% with CST and DAKO, respectively) compared with HR-positive tumours (20% and 22% with CST and DAKO, respectively). No significant differences in tpCR rates were observed according to PTEN status. PI3K pathway activation was found in 47% and 48% of patients (all arms, n = 302 and n = 301) for CST and DAKO, respectively. Similarly, tpCR rates were not significantly different for those with or without PI3K pathway activation. Neither PTEN status nor PI3K pathway activation were predictive of tpCR, EFS, or OS, independently of treatment arm or HR status. High inter-antibody and inter-observer agreements were found (>90%). Modification of scoring variables significantly affected the correlation between PTEN and HR status but not with tpCR.
  
  
  CONCLUSIONS
  These data show that PTEN status determination is not a useful biomarker to predict resistance to trastuzumab and lapatinib-based therapies. The lack of standardization of PTEN status determination may influence correlations between expression and relevant clinical end points.
  
  
  RESULTS
  This trial is registered with ClinicalTrials.gov: NCT00553358.
authors: Molecular Oncology Laboratory, Vall D'Hebron Institute of Oncology, Barcelona, Spain pnuciforo@vhio.net.
authors: P G
authors: PG
authors: Nuciforo
authors: Molecular Oncology Laboratory, Vall D'Hebron Institute of Oncology, Barcelona, Spain.
authors: C
authors: C
authors: Aura
authors: Frontier Science Scotland, Kincraig, UK.
authors: E
authors: E
authors: Holmes
authors: Molecular Oncology Laboratory, Vall D'Hebron Institute of Oncology, Barcelona, Spain.
authors: L
authors: L
authors: Prudkin
authors: Molecular Oncology Laboratory, Vall D'Hebron Institute of Oncology, Barcelona, Spain.
authors: J
authors: J
authors: Jimenez
authors: Molecular Oncology Laboratory, Vall D'Hebron Institute of Oncology, Barcelona, Spain.
authors: P
authors: P
authors: Martinez
authors: BrEAST Data Centre, Jules Bordet Institute, Brussels, Belgium.
authors: H
authors: H
authors: Ameels
authors: SOLTI Breast Cancer Research Group, Barcelona, Spain.
authors: L
authors: L
authors: de la Peña
authors: GlaxoSmithKline, Collegeville, USA.
authors: C
authors: C
authors: Ellis
authors: University Hospital Kiel, Kiel, Germany.
authors: H
authors: H
authors: Eidtmann
authors: Department of Medical Oncology, Jules Bordet Institute, Brussels, Belgium.
authors: M J
authors: MJ
authors: Piccart-Gebhart
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York.
authors: M
authors: M
authors: Scaltriti
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York Breast Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors: J
authors: J
authors: Baselga
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D006801:Humans; D007124:Immunoenzyme Techniques; D000077341:Lapatinib; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012074:Remission Induction; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000077341:Lapatinib; D051059:PTEN Phosphohydrolase; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C494929:PTEN protein, human
keywords: HER2-positive; PIK3CA; PTEN; breast cancer; lapatinib; trastuzumab