PURPOSE:

• The authors set out to answer a key question: What are the risks for breast cancer, ovarian cancer and contralateral breast cancer for those who carry pathogenic variants in BRCA1 and BRCA2 genes?
• What is different about this study?
  • Prospective not retrospective
  • Study large enough to provide more precise risk / penetrance estimates
  • Study includes an analysis of risk associated with number of 1st and 2nd degree relatives and location of the variants within the gene

METHODS:

• Large prospective cohort study
• BRCA1 and BRCA2 carriers recruited via 3 consortia and were followed over several years

RESULTS:

Breast Cancer risks, based on 3886 women (median age 38)

• BRCA1:
  • Peak breast cancer incidence increased rapidly until ages 30 to 40 then plateaus
  • Cumulative risk by age 80: 72% (95% CI, 65%-79%)
• BRCA2:
  • Peak breast cancer incidence increased rapidly until 40 to 50 then plateaus
  • Cumulative risk by age 80: 69% (95% CI, 61%-77%)

Ovarian Cancer risks, based on 5066 women (median age 38)

• BRCA1:
  • Cumulative risk by age 80: 44% (95% CI, 36%-53%)
• BRCA2:
  • Cumulative risk by age 80: 17% (95% CI, 11%-25%)

Contralateral Breast Cancer risks at 20 years of follow up after 1st diagnosis, based on 2213 women (median age 47)

• BRCA1:
  • Cumulative risk: 40% (95% CI, 35%-45%)
• BRCA2:
  • Cumulative risk: 26% (95% CI, 20%-33%)

Family History risks

• BRCA1:
  • Hazard ratio for ≥ 2 vs 0 affected relatives, 1.99 (95%CI, 1.41-2.82; P<.001)
• BRCA2:
  • Hazard ratio for ≥ 2 vs 0 affected relatives, 1.91 (95%CI, 1.08-3.37; P=.02)

Mutation Position risks

• BRCA1:
  • Higher if outside region bounded by positions c.2282-c.4071 (hazard ratio 1.46; 95%CI, 1.11-1.93; P=.007)
• BRCA2:
  • Higher if outside region bounded by positions c.2831-c.6401 (hazard ratio, 1.93; 95%CI, 1.36-2.74; P<.001)

KEY POINTS:

• Like previous studies, risk higher if first breast cancer diagnosed before age 40 vs after age 50 (P = .03)
• Cumulative risks for ovarian cancer were low up until age 40 for BRCA1 and age 50 for BRCA2
• Contralateral breast cancer risk lower in BRCA2 and may be due to increased estrogen receptor positive tumors, which are more receptive to hormonal therapies
• Mutations in exon 11 of either gene had lower breast cancer risk but may have higher ovarian cancer risk

CONCLUSION:

• The data in this study can be used to provide individualized counseling to BRCA1 and BRCA2 mutation carriers.

Learn More – Primary Sources:

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

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