title: Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families.
abstract: Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, VIC 8006, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Harvey
authors.forename: R L
authors.initials: RL
authors.lastname: Milne
authors.forename: S A
authors.initials: SA
authors.lastname: McLachlan
authors.forename: M L
authors.initials: ML
authors.lastname: Friedlander
authors.forename: K E
authors.initials: KE
authors.lastname: Birch
authors.forename: P
authors.initials: P
authors.lastname: Weideman
authors.forename: D
authors.initials: D
authors.lastname: Goldgar
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: K A
authors.initials: KA
authors.lastname: Phillips
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D018570:Risk Assessment; D055815:Young Adult