title: Association of phosphatase and tensin homolog low and phosphatidylinositol 3-kinase catalytic subunit alpha gene mutations on outcome in human epidermal growth factor receptor 2-positive metastatic breast cancer patients treated with first-line lapatinib plus paclitaxel or paclitaxel alone.
abstract: BACKGROUND
  Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) has been shown to enhance breast cancer cell survival and confer resistance to chemotherapeutic agents. We studied the prognostic and predictive value of PIK3CA mutations and PTEN low in patients receiving paclitaxel alone or in combination with lapatinib.
  
  
  METHODS
  Immunohistochemistry and mutation analyses were used to evaluate PTEN and PIK3CA, respectively. Kaplan-Meier analysis with log-rank tests, logistic regression and Cox models were used in analyses of these biomarkers with efficacy endpoints.
  
  
  RESULTS
  In the overall population, PIK3CA mutations were associated with poorer overall survival (OS) (hazard ratio (HR) = 1.87; 95% confidence interval (CI): 1.22, 2.88; P = 0.001). PTEN expression was not associated with OS (P = 0.474). In the PIK3CA wild-type subgroup, lapatinib plus paclitaxel reduced risk of progression compared with paclitaxel alone (HR = 0.44; 95% CI: 0.28, 0.69; P <0.0001); progression-free survival (PFS) was not significantly improved within the PIK3CA mutation subgroup (P = 0.179). In the PTEN low group, OS was improved with addition of lapatinib (P = 0.039). In both PTEN subgroups, addition of lapatinib was associated with improvements in PFS (P <0.050). PIK3CA and PTEN were not predictive of treatment based on interaction tests (P >0.05).
  
  
  CONCLUSIONS
  PTEN was neither a significant prognostic nor predictive factor. PIK3CA mutations were an adverse prognostic factor for survival but not predictive for lapatinib benefit.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00281658 (registered 23 January 2006).
authors: Binghe
authors: B
authors: Xu
authors: Zhongzhen
authors: Z
authors: Guan
authors: Zhenzhou
authors: Z
authors: Shen
authors: Zhongshen
authors: Z
authors: Tong
authors: Zefei
authors: Z
authors: Jiang
authors: Junlan
authors: J
authors: Yang
authors: Michelle
authors: M
authors: DeSilvio
authors: Mark
authors: M
authors: Russo
authors: Meggan
authors: M
authors: Leigh
authors: Catherine
authors: C
authors: Ellis
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016017:Odds Ratio; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D017239:Paclitaxel / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D000077341:Lapatinib; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human; C494929:PTEN protein, human