Familial breast cancer

Several genetic risk factors have been identified, the most common being BRCA1 and BRCA2:¹

• BRCA1 mutation on chromosome 17: the lifetime risk of breast cancer for women with this mutation is 65-85% and the lifetime risk of ovarian cancer is 40-50%; men with this mutation may be at increased risk of breast cancer.

• BRCA2 mutation on chromosome 13: the lifetime risk of breast cancer for women with this mutation is 40-85% and the lifetime risk of ovarian cancer is 10-25%; for men with this mutation, the lifetime risk of breast cancer is 6%.

• TP53 mutation on chromosome 17: most women with this mutation develop breast cancer by 50 years of age.

• PTEN gene: Cowden's syndrome (predisposes to breast cancer, thyroid cancer, uterine cancer and hamartomatous lesions of the skin).

• ATM, CHEK2, BRIP1, and PALB2 genes: moderate risk of breast cancer.

A Cochrane review found favourable outcomes for patients after risk assessment for familial breast cancer.² Local protocols should exist (or be developed) for the care of women at risk of familial breast cancer. There should be clear referral mechanisms between primary, secondary and tertiary care.

When a family history of breast cancer is identified during a consultation, a careful family tree of affected individuals should be constructed and patients reassured or referred appropriately.

Management in primary care³

• A first- and second-degree family history should be taken in primary care when a woman presents with breast symptoms, or has concerns about relatives with breast cancer. This will assess risk and allow proper classification and care, as above.¹

• The woman should be given information concerning breast awareness and self-examination.

• The woman should be advised to return if her family history changes, or breast symptoms develop.

• Women should have access to psychological support and assessment where necessary. Information on local or national support groups should be available.

• Appropriate lifestyle advice should be offered regarding risk factors - eg, contraception, smoking and alcohol.

Genetic testing³

If possible, the development of a genetic test for a family should usually start with the testing of an affected individual (mutation searching/screening) to try to identify a mutation in the appropriate gene (such as BRCA1, BRCA2 or TP53).

Discuss the potential risk and benefits of genetic testing. Include in the discussion the probability of finding a mutation, the implications for the individual and the family, and the implications of either a variant of uncertain significance or a null result (no mutation found).

• Offer genetic testing in specialist genetic clinics to a relative with a personal history of breast and/or ovarian cancer if that relative has a combined BRCA1 and BRCA2 mutation carrier probability of 10% or more.

• Offer genetic testing in specialist genetic clinics to a person with no personal history of breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more and an affected relative is unavailable for testing.

• Offer genetic testing in specialist genetic clinics to a person with breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more.

• Offer people eligible for referral to a specialist genetic clinic a choice of accessing genetic testing during initial management or at any time thereafter.

Testing should only be carried out after the patient has received appropriate genetic counselling and they have given informed consent.

National Institute for Health and Care Excellence (NICE) recommendations for management³

Referral from primary care

People without a personal history of breast cancer who meet the following criteria should be offered referral to secondary care:

• 1 first-degree female relative diagnosed with breast cancer at younger than age 40 years.

• 1 first-degree male relative diagnosed with breast cancer at any age.

• 1 first-degree relative with bilateral breast cancer where the first primary was diagnosed at younger than age 50 years.

• 2 first-degree relatives, or 1 first-degree and 1 second-degree relative, diagnosed with breast cancer at any age.

• 1 first-degree or second-degree relative diagnosed with breast cancer at any age and 1 first-degree or second-degree relative diagnosed with ovarian

• cancer at any age (1 of these should be a first-degree relative).

• 3 first-degree or second-degree relatives diagnosed with breast cancer at any age.

Advice should be sought from the designated secondary care contact if any of the following are present in the family history in addition to breast cancers in relatives not fulfilling the above criteria:

• Bilateral breast cancer.

• Male breast cancer.

• Ovarian cancer.

• Jewish ancestry.

• Sarcoma in a relative younger than age 45 years.

• Glioma or childhood adrenal cortical carcinomas.

• Complicated patterns of multiple cancers at a young age.

• Paternal history of breast cancer (2 or more relatives on the father's side of the family).

Discussion with the designated secondary care contact should take place if the primary care health professional is uncertain about the appropriateness of referral because the family history presented is unusual or difficult to make clear decisions about, or where the person is not sufficiently reassured by the standard information provided.

Direct referral to a specialist genetics service should take place where a high-risk predisposing gene mutation has been identified (for example, BRCA1,
BRCA2 or TP53).

People without a personal history of breast cancer can otherwise be cared for in primary care if the family history shows only 1 first-degree or second-degree relative diagnosed with breast cancer at older than age 40 years (in most cases, this will equate to less than a 3% 10-year risk of breast cancer at age 40 years) and none of the above criteria apply.

Surveillance for women with no personal history of breast cancer

Offer annual mammographic surveillance to women:

• Aged 40-49 years at moderate risk of breast cancer.

• Aged 40-59 years at high risk of breast cancer but with a 30% or lower probability of being a BRCA or TP53 carrier.

• Aged 40-59 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier.

• Aged 40-69 years with a known BRCA1 or BRCA2 mutation.

Offer annual MRI surveillance to women:

• Aged 30-49 years who have not had genetic testing but have a greater than 30% probability of being a BRCA carrier.

• Aged 30-49 years with a known BRCA1 or BRCA2 mutation.

• Aged 20-49 years who have not had genetic testing but have a greater than 30% probability of being a TP53 carrier.

• Aged 20-49 years with a known TP53 mutation.

Surveillance for women with a personal and family history of breast cancer

• Offer annual mammographic surveillance to all women aged 50-69 years with a personal history of breast cancer who remain at high risk of breast cancer (including those who have a BRCA1 or BRCA2 mutation), and do not have a TP53 mutation.

• Offer annual MRI surveillance to all women aged 30-49 years with a personal history of breast cancer who remain at high risk of breast cancer, including those who have a BRCA1 or BRCA2 mutation.

Risk reduction and treatment strategies³

• Hormonal contraceptives:¹

  • For women over 35 years with a family history of breast cancer have a further increased risk of breast cancer associated with taking the oral contraceptive pill, given that their absolute risk increases with age.

  • Advice to women up to age 35 years with a family history of breast cancer should be in keeping with general health advice on the use of the oral contraceptive pill.

  • Any other form of hormonal contraception or intrauterine device may be used.

  • For women who are known carriers of a gene mutation associated with breast cancer (such as BRCA1):
    

    • Discuss the use of combined hormone contraception with a specialist genetics service as views are conflicting on whether or not the protective effects of combined hormone contraception against ovarian cancer outweigh the increased risk of breast cancer.

    • The progestogen-only pill, depot medroxyprogesterone acetate, the etonogestrel-only implant or the levonorgestrel-releasing intrauterine system (Mirena®) may generally be used.

• Hormone replacement therapy (HRT):¹
  

  • If the woman is at low risk of breast cancer (ie they do not fulfil the referral criteria to secondary care), HRT may be prescribed.

  • If they are at increased risk of breast cancer (ie they fulfil the referral criteria to secondary care):

    • Ensure they have been referred to secondary care for assessment of their breast cancer risk.

    • Inform them of the increase in breast cancer risk with type and duration of HRT and refer them to secondary care for advice as to whether or not it is appropriate to prescribe HRT.

• Alcohol consumption - women with a family history should be informed that alcohol may increase their risk of breast cancer slightly.⁴

• Women should be advised not to smoke, in line with current health advice.

• Women should be advised on the probable increased postmenopausal risk of breast cancer from being overweight.

• Women should be advised about the potential benefits of physical exercise on breast cancer risk.

Chemoprevention for women with no personal history of breast cancer

Tamoxifen reduces the risk of breast cancer in women at increased risk of disease.⁵

The National Institute for Health and Care Excellence recommends:³

• Offer tamoxifen for 5 years to premenopausal women at moderate or high risk of breast cancer unless they have a past history or may be at increased risk
  of thromboembolic disease or endometrial cancer.

• Offer anastrozole for 5 years to postmenopausal women at moderate or high risk of breast cancer unless they have severe osteoporosis.

• For postmenopausal women at moderate or high risk of breast cancer who have severe osteoporosis or do not wish to take anastrozole:

  • Offer tamoxifen for 5 years if they have no history or increased risk of thromboembolic disease or endometrial cancer, or

  • Consider raloxifene for 5 years for women with a uterus if they have no history or increased risk of thromboembolic disease and do not wish to take tamoxifen.

• Do not offer chemoprevention to women who were at high risk of breast cancer but have had bilateral risk-reducing mastectomy.
  Do not continue chemoprevention beyond 5 years in women with no personal history of breast cancer.
  Women should stop tamoxifen at least 2 months before trying to conceive, and 6 weeks before elective surgery.

Risk-reducing mastectomy for women with no personal history of breast cancer

Bilateral risk-reducing mastectomy:

• Bilateral risk-reducing mastectomy is appropriate only for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team. Bilateral mastectomy should be raised as a risk-reducing strategy option with all women at high risk.

• Women considering bilateral risk-reducing mastectomy should have genetic counselling in a specialist cancer genetic clinic before a decision is made.

• Pre-operative counselling about psychosocial and sexual consequences of bilateral risk-reducing mastectomy should be undertaken.

• All women considering bilateral risk-reducing mastectomy should be able to discuss their breast reconstruction options (immediate and delayed) with a member of a surgical team with specialist oncoplastic or breast reconstructive skills.

Risk-reducing bilateral oophorectomy:

• Risk-reducing bilateral oophorectomy is appropriate only for a small proportion of women who are from high-risk families and should be managed by a multidisciplinary team. Information about bilateral oophorectomy as a potential risk-reducing strategy should be made available to women who are classified as high risk.

• The effects of early menopause and options for management of early menopause should be discussed with any woman considering risk-reducing bilateral oophorectomy.

• Women undergoing bilateral risk-reducing oophorectomy should have their fallopian tubes removed as well.