title: Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis.
abstract: BACKGROUND
  Studies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.
  
  
  METHODS
  We conducted a nested case-control study in a population-based cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. We collected clinical characteristics and information on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk.
  
  
  RESULTS
  Factors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16(+)COX-2(+)Ki67(+)) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were detected by mammography and were p16, COX-2, and Ki67 triple negative (p16(-)COX-2(-)Ki67(-)) (4.1%, 95% CI = 3.4% to 5.0%). In a multivariable model, DCIS lesions that were p16(+)COX-2(+)Ki67(+) or those detected by palpation were statistically significantly associated with subsequent invasive cancer, but nuclear grade was not. Eight-year risk of subsequent DCIS was highest for women with DCIS lesions that had disease-free margins of 1 mm or greater combined with either ER(-)ERBB2(+)Ki67(+) or p16(+)COX-2(-)Ki67(+) status (23.6%, 95% CI = 18.1% to 34.0%).
  
  
  CONCLUSIONS
  Biomarkers can identify which women who were initially diagnosed with DCIS are at high or low risk of subsequent invasive cancer, whereas histopathology information cannot.
authors.affiliation: University of California, San Francisco, CA 94121, USA. Karla.Kerlikowske@ucsf.edu [corrected]
authors.forename: Karla
authors.initials: K
authors.lastname: Kerlikowske
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.forename: Mona L
authors.initials: ML
authors.lastname: Gauthier
authors.forename: Hal K
authors.initials: HK
authors.lastname: Berman
authors.forename: Fred
authors.initials: F
authors.lastname: Waldman
authors.forename: James
authors.initials: J
authors.lastname: Bennington
authors.forename: Henry
authors.initials: H
authors.lastname: Sanchez
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jimenez
authors.forename: Kim
authors.initials: K
authors.lastname: Stewart
authors.forename: Karen
authors.initials: K
authors.lastname: Chew
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Ljung
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000453:epidemiology* / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis* / Q000453:epidemiology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry* / Q000601:surgery; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051546:Cyclooxygenase 2 / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D019394:Ki-67 Antigen / Q000032:analysis; D015412:Mastectomy, Segmental; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000453:epidemiology; D016017:Odds Ratio; D010173:Palpation; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051546:Cyclooxygenase 2; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; C000614131:CDKN2A protein, human; C508053:ERBB2 protein, human