title: Prognostic value of phosphorylated HER2 in HER2-positive breast cancer patients treated with adjuvant trastuzumab.
abstract: BACKGROUND
  Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab.
  
  
  METHODS
  The study subjects were 78 HER2-positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan-Meier/log-rank test and Cox proportional hazards model, respectively.
  
  
  RESULTS
  The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors.
  
  
  CONCLUSIONS
  This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker.
authors.affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, kure@med.kawasaki-m.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kurebayashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanomata
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Yamashita
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shimo
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizutoh
authors.forename: Takuya
authors.initials: T
authors.lastname: Moriya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sonoo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D010766:Phosphorylation; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate; D000068878:Trastuzumab / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C587689:ERBB4 protein, human