title: Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: a WECARE study report.
abstract: BACKGROUND
  Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.
  
  
  METHODS
  A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.
  
  
  RESULTS
  Among women treated with radiation, the mean radiation dose was 1.1 Gy (range = 0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR = 4.5, confidence interval, CI = 3.0-6.8), and also among those treated with RT (RR = 1.2, CI = 1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.
  
  
  CONCLUSIONS
  Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations.
  
  
  BACKGROUND
  All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Bernstej@mskcc.org
authors.forename: Jonine L
authors.initials: JL
authors.lastname: Bernstein
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.forename: Roy E
authors.initials: RE
authors.lastname: Shore
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: John D
authors.initials: JD
authors.lastname: Boice
authors.forename: Marilyn
authors.initials: M
authors.lastname: Stovall
authors.forename: Michael
authors.initials: M
authors.lastname: Andersson
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Malone
authors.forename: Anne S
authors.initials: AS
authors.lastname: Reiner
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.forename: Susan A
authors.initials: SA
authors.lastname: Smith
authors.forename: Lina
authors.initials: L
authors.lastname: Tellhed
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Teraoka
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
authors.forename: Jorgen H
authors.initials: JH
authors.lastname: Olsen
authors.forename: Lene
authors.initials: L
authors.lastname: Mellemkjaer
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Liang
authors.forename: Anh T
authors.initials: AT
authors.lastname: Diep
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001940:Breast / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D011829:Radiation Dosage; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA1/BRCA2; Contralateral breast cancer; Radiotherapy