title: Clinicopathologic Significance of the Intratumoral Heterogeneity of HER2 Gene Amplification in HER2-Positive Breast Cancer Patients Treated With Adjuvant Trastuzumab.
abstract: OBJECTIVE
  Although intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been associated with a poor prognosis for primary HER2-positive breast cancer and metastatic HER2-positive breast cancer treated with trastuzumab, the clinicopathologic significance in a setting involving trastuzumab treatment as an adjuvant treatment has not been studied in patients.
  
  
  METHODS
  We retrospectively investigated 443 patients with HER2-positive breast cancer treated with surgery, adjuvant chemotherapy, and 1 year of trastuzumab. Three areas that showed different levels of HER2 protein expression were chosen, and silver in situ hybridization was performed.
  
  
  RESULTS
  HER2 regional and genetic heterogeneity was found in 6.2% and 6.8% of tumors, respectively. Both types of heterogeneity were significantly associated with hormone receptor positivity, HER2 immunohistochemistry score of 2+, a low level of HER2 gene amplification, and absence of an extensive intraductal component. Genetic heterogeneity also showed strong correlation with a lower histologic grade. In the hormone receptor-positive group, the regional heterogeneity affected disease-free survival of patients (hazard ratio, 4.869; 95% confidence interval, 1.424-16.646; P = .005), whereas genetic heterogeneity did not.
  
  
  CONCLUSIONS
  Evaluation of intratumoral heterogeneity, especially in cases with hormone receptor positivity, may be valuable for assessing the prognosis of HER2-positive patients anticipating treatment with adjuvant systemic therapy and trastuzumab.
authors.affiliation: From the Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea;
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea;
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Korea; and.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: From the Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea;
authors.forename: In Ah
authors.initials: IA
authors.lastname: Park
authors.affiliation: From the Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea;
authors.forename: In Hye
authors.initials: IH
authors.lastname: Song
authors.affiliation: Departments of Surgery and.
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: From the Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; gygong@amc.seoul.kr.
authors.forename: Gyungyub
authors.initials: G
authors.lastname: Gong
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D000068878:Trastuzumab / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068878:Trastuzumab
keywords: Adjuvant chemotherapy; Breast carcinoma; Gene amplification; HER2; Heterogeneity; Trastuzumab