Genetics of breast cancer

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

  • 5%–10% of female breast cancer is due to inheritance of a mutated copy of either BRCA1 or BRCA2.
  • Women who inherit a mutated copy of either gene have an elevated lifetime risk of breast cancer—up to 70% by the age of 70 years.
  • Particular risk of premenopausal breast cancer, often before the age of 40 years.
  • Associated risk of ovarian cancer (greater with BRCA1).
  • Male carriers are at risk for breast cancer and, for BRCA2 carriers, melanoma, prostate and pancreatic cancers.
  • Some ethnic groups are at particular risk for carriage of these mutations (an estimated 2% of U.S. Ashkenazi Jews).

Other genes contribute less often to familial breast cancer.

  • Risk is associated with mutation in PTEN (Cowden disease), p53 (Li–Fraumeni syndrome), CHEK2 (particularly *1000delC), STK11 (Peutz-Jegers syndrome), CDH1 (hereditary diffuse gastric cancer syndrome), and PALB2.
  • Whole genome association studies are increasingly identifying genes of low and moderate penetrance.

The management of hereditary breast cancer is essentially that of nonhereditary disease.

  • Controversial issues include management of the contralateral breast of index cases and care of asymptomatic female family members.
  • Published guidelines define groups of women at higher risk for breast cancer (see Box 28..) and recommend referral to medical genetic clinics for counseling, consideration of genetic testing, and further management.

Currently, the following options are available for women at higher risk for breast cancer.

Prophylactic surgery

Bilateral subcutaneous mastectomy (usually with immediate reconstruction) reduces the incidence of breast cancer in these women, but has no established impact on survival. It may be offered in conjunction with prophylactic oophorectomy.


In addition to annual screening mammography, recent guidelines recommend annual screening with breast magnetic resonance imaging (MRI) for women who carry, or are untested but have a first-degree relative who carries, a genetic mutation as listed above.

Breast cancer prevention trials

Clinical trials utilizing the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene as well as the aromatase inhibitor exemestane have demonstrated that these drugs reduce the incidence of breast cancer by approximately 50% in higher-risk populations of women. There is no evidence that any of these breast cancer prevention drugs reduce breast cancer mortality.

Box 28.1. Summary of NCCN Guidelines for Breast and/or Ovarian Cancer Genetic Assessment

An affected individual with one or more of the following:

  • Aknown mutation in a breast cancer susceptibility gene within the family
  • Breast cancer diagnosis ≤ age 50
  • Triple-negative (i.e., ER/PR/HER2-negative) breast cancer
  • Two breast cancer primaries
  • Ovarian cancer
  • Male breast cancer
  • Breast cancer at any age and a concerning family history (examples include ≥1 relative with breast cancer ≤ age 50 or epithelial ovarian cancer at any age)

An unaffected individual with a family history of one or more of the following:

  • Aknown mutation in a breast cancer susceptibility gene within the family
  • ≥2 breast primaries in a single individual
  • ≥2 individuals with breast primaries on the same side of the family
  • Ovarian cancer
  • Male breast cancer
  • Other concerning family history patterns (examples include first- or second-degree relative with breast cancer ≤ age 45; and ≥1 family members with a combination of cancers)

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