title: Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases.
abstract: BACKGROUND
  Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs.
  
  
  METHODS
  p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method.
  
  
  RESULTS
  Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival.
  
  
  CONCLUSIONS
  The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.
authors: Department of Medicine, Division of Hematology-Oncology, CB 7305, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Barbara
authors: B
authors: Adamo
authors: Allison M
authors: AM
authors: Deal
authors: Emily
authors: E
authors: Burrows
authors: Joseph
authors: J
authors: Geradts
authors: Erika
authors: E
authors: Hamilton
authors: Kimberly L
authors: KL
authors: Blackwell
authors: Chad
authors: C
authors: Livasy
authors: Karen
authors: K
authors: Fritchie
authors: Aleix
authors: A
authors: Prat
authors: J Chuck
authors: JC
authors: Harrell
authors: Matthew G
authors: MG
authors: Ewend
authors: Lisa A
authors: LA
authors: Carey
authors: C Ryan
authors: CR
authors: Miller
authors: Carey K
authors: CK
authors: Anders
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D051059:PTEN Phosphohydrolase