title: Selection bias influences reported contralateral breast cancer incidence and survival in high risk non-BRCA1/2 patients.
abstract: OBJECTIVE
  The results of studies comparing survival in familial and sporadic breast cancer (BC) are inconsistent. A higher incidence of contralateral breast cancer (CBC) has been reported in familial BC. Ascertainment bias may influence both the reported familial CBC and survival.
  
  
  METHODS
  We assessed CBC incidence, distant disease free (DDFS) and overall survival (OS) in 327 BC patients who had > or =3 breast and/or ovarian cancers in the family but no BRCA1/2 gene mutation (non-BRCA1/2). They were matched to 327 sporadic controls for year and age at detection. To correct for ascertainment bias, we analyzed also separately the results (1) Of the 250 non-BRCA1/2 patients with DNA testing performed before diagnosis or within 2 years ('unselected') and (2) Of the 77 with testing > or =2 years after diagnosis (late-tested).
  
  
  RESULTS
  Median follow-up of non-BRCA1/2 patients was 6.1 yrs. Ten years CBC incidence was 11% in non-BRCA1/2 versus 6% in sporadic patients (p = 0.002). At multivariate analysis CBC incidence was increased in late-tested non-BRCA1/2 (HR 4.6; p = 0.001) not in 'unselected' (HR 1.8; p = 0.1). Increased CBC occurred in non-BRCA1/2 patients mainly before genetic testing, suggesting ascertainment bias. Tumors were < or =T1 in 62% of non-BRCA1/2 versus 50% of sporadic patients (p = 0.003), node-negative in 55% versus 52% respectively (p = 0.5). After correction for stage and therapy, OS did not differ between 'unselected' non-BRCA1/2 and sporadic patients (HR 0.8; p = 0.3), but was improved in late-tested non-BRCA1/2.
  
  
  CONCLUSIONS
  Overall survival and contralateral breast cancer incidence were similar in 'unselected' non-BRCA1/2- and sporadic patients. Reports of higher CBC incidence and better survival in non-BRCA1/2 patients may substantially be caused by DNA testing selection-bias.
authors.affiliation: Department of Surgical Oncology, Erasmus University Medical Centre, Rotterdam, The Netherlands. m.tilanus-linthorst@erasmusmc.nl
authors.forename: Madeleine M A
authors.initials: MM
authors.lastname: Tilanus-Linthorst
authors.forename: Karina C M
authors.initials: KC
authors.lastname: Bartels
authors.forename: Celina
authors.initials: C
authors.lastname: Alves
authors.forename: Bonnie
authors.initials: B
authors.lastname: Bakri
authors.forename: Ellen
authors.initials: E
authors.lastname: Crepin
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Cecile T M
authors.initials: CT
authors.lastname: Brekelmans
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality*; D005260:Female; D006801:Humans; D015994:Incidence; D015412:Mastectomy, Segmental / Q000379:methods; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors; D015983:Selection Bias; D015996:Survival Rate
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein