title: PTEN deficiency as a predictive biomarker of resistance to HER2-targeted therapy in advanced gastric cancer.
abstract: BACKGROUND
  To investigate the role of the phosphoinositide 3-kinase (PI3K) pathway activation in human epidermal growth factor receptor 2 (HER2)-targeted therapy.
  
  
  METHODS
  We evaluated the predictive roles of PI3K, catalytic alpha (PIK3CA), and phosphatase and tensin homolog (PTEN) in HER2-based therapy (either trastuzumab or lapatinib). PTEN expression and PIK3CA mutation were analyzed using immunohistochemistry and pyrosequencing.
  
  
  RESULTS
  Forty-eight patients received trastuzumab (n = 39) or lapatinib (n = 9) combination chemotherapy. PTEN loss was found in 47.9% (n = 23), but no PIK3CA mutations were identified. Twenty-six (54.1%) patients responded to HER2-based therapy, without a significant difference between patients with PTEN loss and those without (52.2 vs. 56.0%). Among the patients with responsive disease, time to best response did not differ by PTEN status, but the duration of response was significantly shorter for patients with PTEN loss (median 4.2 vs. 6.1 months, p = 0.04). In addition, patients with PTEN loss had a significantly shorter progression-free survival time (median 4.9 vs. 7.3 months, p = 0.047).
  
  
  CONCLUSIONS
  PTEN deficiency is an important predictive marker for early resistance to HER2 inhibitor treatment in gastric cancer patients. This finding may be useful for the development of drug combinations and identification of patients who need a modified treatment strategy.
authors.affiliation: Oral Cancer Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Zhang
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Park
authors.forename: Kyu Hyun
authors.initials: KH
authors.lastname: Park
authors.forename: Ki Hyang
authors.initials: KH
authors.lastname: Kim
authors.forename: Minkyu
authors.initials: M
authors.lastname: Jung
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Hyo Song
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000172:deficiency*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality
chemical_list: D015415:Biomarkers; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human