title: Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction.
abstract: BACKGROUND
  Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO.
  
  
  METHODS
  We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO.
  
  
  RESULTS
  Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77).
  
  
  CONCLUSIONS
  In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: B A M
authors: BA
authors: Heemskerk-Gerritsen
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: C
authors: C
authors: Seynaeve
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: C J
authors: CJ
authors: van Asperen
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: M G E M
authors: MG
authors: Ausems
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: J M
authors: JM
authors: Collée
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: H C
authors: HC
authors: van Doorn
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: E B
authors: EB
authors: Gomez Garcia
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: C M
authors: CM
authors: Kets
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: F E
authors: FE
authors: van Leeuwen
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: H E J
authors: HE
authors: Meijers-Heijboer
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: M J E
authors: MJ
authors: Mourits
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: T A M
authors: TA
authors: van Os
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: H F A
authors: HF
authors: Vasen
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: S
authors: S
authors: Verhoef
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: M A
authors: MA
authors: Rookus
authors: Department of Medical Oncology (BAMHG, CS, MJH), Department of Clinical Genetics (JMC), and Department of Gynecology (HCvD), Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Genetics, Leiden University MC, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, University MC Utrecht, Utrecht, the Netherlands (MGEMA); Department of Clinical Genetics, Maastricht University MC, Maastricht, the Netherlands (EBGG); Department of Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands (CMK); Department of Epidemiology (FEvL, MAR), and Department of Clinical Genetics (SV), Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Human Genetics, VU University MC, Amsterdam, the Netherlands (HEJMH); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (HEJMJ, TAMvO); Department of Gynecology, University MC Groningen, Groningen, the Netherlands (MJEM); Foundation for Detection of Hereditary Tumours, Leiden, the Netherlands (HFAV).
authors: M J
authors: MJ
authors: Hooning
mesh_terms: D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000453:epidemiology* / Q000235:genetics / Q000517:prevention & control*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D010052:Ovariectomy; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D040242:Risk Reduction Behavior; D058994:Salpingectomy; D013997:Time Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen