title: The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study.
abstract: BACKGROUND
  HER2 is a well-established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that HER2 is mainly related to in situ recurrences. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS with long-term follow-up.
  
  
  METHODS
  All 458 patients diagnosed with a primary DCIS 1986-2004 in two Swedish counties were included. Silver-enhanced in situ hybridisation (SISH) was used for detection of HER2 gene amplification and protein expression was assessed by immunohistochemistry (IHC) in tissue microarrays. HER2 positivity was defined as amplified HER2 gene and/or HER2 3+ by IHC. HER2 status in relation to new ipsilateral events (IBE) and Invasive Breast Cancer Recurrences, local or distant (IBCR) was assessed by Kaplan-Meier survival analyses and Cox proportional hazards regression models.
  
  
  RESULTS
  Primary DCIS was screening-detected in 75.5% of cases. Breast conserving surgery (BCS) was performed in 78.6% of whom 44.0% received postoperative radiotherapy. No patients received adjuvant endocrine- or chemotherapy. The majority of DCIS could be HER2 classified (N=420 (91.7%)); 132 HER2 positive (31%) and 288 HER2 negative (69%)). HER2 positivity was related to large tumor size (P=0.002), high grade (P<0.001) and ER- and PR negativity (P<0.001 for both). During follow-up (mean 184 months), 106 IBCRs and 105 IBEs were identified among all 458 cases corresponding to 54 in situ and 51 invasive recurrences. Eighteen women died from breast cancer and another 114 had died from other causes. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P=0.03, (HR) 0.60 (95% CI 0.38-0.94)). Remarkably, the curves did not separate until after 10 years. In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P=0.003), but not for women with ER positive DCIS.
  
  
  CONCLUSIONS
  Improved prognostic tools for DCIS patients are warranted to tailor adjuvant therapy. Here, we demonstrate that HER2 positive disease in the primary DCIS is associated with lower risk of recurrent invasive breast cancer.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Medicon Village Building 404:B3, Scheelevägen 2, SE-223 81, Lund, Sweden. signe.borgquist@med.lu.se.
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
authors.affiliation: Department of Surgical Science, Uppsala University, Uppsala, SE-75105, Sweden. wenjing.zh@gmail.com.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Medicon Village Building 404:B3, Scheelevägen 2, SE-223 81, Lund, Sweden. karin.jirstrom@med.lu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden. Rose-Marie.Amini@igp.uu.se.
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Amini
authors.affiliation: Department of Pathology, Örebro University, Örebro, Sweden. thomas.sollie@orebroll.se.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sollie
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway. Therese.Sorlie@rr-research.no.
authors.forename: Therese
authors.initials: T
authors.lastname: Sørlie
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. Carl.Blomqvist@helsinki.fi.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Surgery, Clinical Sciences, Lund University, Malmö, Sweden. salma.butt@med.lu.se.
authors.forename: Salma
authors.initials: S
authors.lastname: Butt
authors.affiliation: Department of Surgical Science, Uppsala University, Uppsala, SE-75105, Sweden. fredrik.warnberg@surgsci.uu.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wärnberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human