title: Impact of Age at Primary Breast Cancer on Contralateral Breast Cancer Risk in BRCA1/2 Mutation Carriers.
abstract: OBJECTIVE
  To determine prospectively overall and age-specific estimates of contralateral breast cancer (CBC) risk for young patients with breast cancer with or without BRCA1/2 mutations.
  
  
  METHODS
  A cohort of 6,294 patients with invasive breast cancer diagnosed under 50 years of age and treated between 1970 and 2003 in 10 Dutch centers was tested for the most prevalent BRCA1/2 mutations. We report absolute risks and hazard ratios within the cohort from competing risk analyses.
  
  
  RESULTS
  After a median follow-up of 12.5 years, 578 CBCs were observed in our study population. CBC risk for BRCA1 and BRCA2 mutation carriers was two to three times higher than for noncarriers (hazard ratios, 3.31 [95% CI, 2.41 to 4.55; P < .001] and 2.17 [95% CI,1.22 to 3.85; P = .01], respectively). Ten-year cumulative CBC risks were 21.1% (95% CI, 15.4 to 27.4) for BRCA1, 10.8% (95% CI, 4.7 to 19.6) for BRCA2 mutation carriers and 5.1% (95% CI, 4.5 to 5.7) for noncarriers. Age at diagnosis of the first breast cancer was a significant predictor of CBC risk in BRCA1/2 mutation carriers only; those diagnosed before age 41 years had a 10-year cumulative CBC risk of 23.9% (BRCA1: 25.5%; BRCA2: 17.2%) compared with 12.6% (BRCA1: 15.6%; BRCA2: 7.2%) for those 41 to 49 years of age (P = .02); our review of published studies showed ranges of 24% to 31% before age 40 years (BRCA1: 24% to 32%; BRCA2:17% to 29%) and 8% to 21% after 40 years (BRCA1: 11% to 52%; BRCA2: 7% to 18%), respectively.
  
  
  CONCLUSIONS
  Age at first breast cancer is a strong risk factor for cumulative CBC risk in BRCA1/2 mutation carriers. Considering the available evidence, age-specific risk estimates should be included in counseling.
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: van den Broek
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van 't Veer
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Hooning
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Sten
authors.initials: S
authors.lastname: Cornelissen
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Emiel J
authors.initials: EJ
authors.lastname: Rutgers
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Cornelisse
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Mike
authors.initials: M
authors.lastname: van Beek
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Maryska L
authors.initials: ML
authors.lastname: Janssen-Heijnen
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Westenend
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Jobsen
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Siesling
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands.
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
authors.affiliation: Alexandra J. van den Broek, Laura J. van 't Veer, Sten Cornelissen, Annegien Broeks, Emiel J. Rutgers, Flora E. van Leeuwen, and Marjanka K. Schmidt, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; Maartje J. Hooning and Caroline Seynaeve, Erasmus MC Cancer Institute, Rotterdam; Vincent T.H.B.M. Smit, Cees J. Cornelisse, and Rob A.E.M. Tollenaar, Leiden University Medical Center, Leiden; Mike van Beek, PAMM, Catharina Hospital, Eindhoven; Maryska L. Janssen-Heijnen, Netherlands Comprehensive Cancer Organization, Eindhoven, and VieCuri Medical Centre, Venlo; Pieter J. Westenend, Laboratory for Pathology, Dordrecht; Jan J. Jobsen, Medisch Spectrum Twente, Enschede; and Sabine Sieling, Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands. mk.schmidt@nki.nl.
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D000367:Age Factors; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology*; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human