Familial breast cancer

Dr Helen Hanson discusses breast cancer surveillance and BRCA testing.

Coloured MRI scans of a 58-year old woman's right breast and thorax, showing adenocarcinoma (yellow area in the breast) (SPL)

Breast cancer is the most common cancer in women in the UK, with the average lifetime risk of developing the disease estimated at 12%.1

The aetiology of the disease is complex and multifactorial, including lifestyle, environmental factors, hormonal factors (including reproductive history) and inherited susceptibility.

Family history

Family history is an important risk factor for breast cancer. The risk for women with a single affected first-degree relative (mother, sister) is approximately twice that of the general population.

Clustering of breast cancer cases in a family may occur simply by chance, because breast cancer is a common disease, or may be due to shared lifestyle and/or environmental factors, or an inherited genetic susceptibility.

Although up to one-third of all breast cancer cases may be due to an inherited genetic susceptibility, only about 5% of breast cancer is due to the inheritance of highly penetrant breast cancer susceptibility genes.2,3

The remaining inherited susceptibility is now recognised to be due to polygenic inheritance, meaning a number of moderate and low penetrance genes or genetic factors can act multiplicatively to increase breast cancer risk.4

A number of these heritable factors have now been identified, but approximately 60-70% of familial risk remains unexplained and research is continuing to fully elucidate familial risk.4

Assessing familial risk

Breast cancer is common and often, patients and clinicians overestimate familial risk. However, it is important to identify a woman who is at increased familial risk, to organise appropriate breast surveillance and direct genetic testing in the family.

Taking a three-generation family history (maternal and paternal) is an essential part of assessing familial risk.2 The purpose is to answer two clinical questions:

  • Do female family members need increased breast surveillance?
  • Is there likely to be a mutation in a high penetrance breast cancer gene?

Breast cancer surveillance

NICE guidance1 on familial breast cancer identifies three levels of risk:

  • Women at population risk, who can be managed and reassured in the primary care setting.
  • Women at moderate risk who meet criteria for referral to secondary care (family history clinic) for increased breast surveillance.
  • Women at high risk who meet criteria for referral to tertiary care (specialist cancer genetics clinic) for increased breast surveillance and assessment of eligibility for genetic testing.

In general, if a woman has a first-degree relative with breast cancer under the age of 40 or with bilateral breast cancer, or at least two firstor second-degree (grandmother, aunt) relatives with breast cancer, or a male first-degree relative with breast cancer, they will meet at least the moderate risk criteria.

These women should be offered referral to secondary care and are eligible for annual mammography between the ages of 40 and 49, and three-yearly mammography, within the NHS Breast Screening Programme (NHSBSP), from age 50.1

It is important to note that if the history is on the paternal side, the father can essentially be removed when counting degrees of relationship.

If the family history is stronger, a woman may fall into the high-risk group, for example, two firstor second-degree relatives affected aged under 50, three relatives affected aged under 60 or four affected at any age. These women should be offered referral to tertiary care and may be eligible for annual mammography between the ages of 40 and 59 and three-yearly mammography, within the NHSBSP, from age 60.

For women in this category, the risk of a mutation in a high penetrance breast cancer gene in the family is increased and a family member with cancer may be eligible for genetic testing.

Genetic mutations

Inherited (germline) mutations in the BRCA1 and BRCA2 genes are associated with a high lifetime risk of developing breast cancer.4

Mutations in these genes are found in only 2-3% of all women with breast cancer, but in a higher proportion if there is a suggestive family history.

Although most cases of breast cancer are not caused by inherited mutations in these high-risk genes, the clinical utility of knowing an individual's genetic status is high, both for a patient with cancer and for their wider family.

The chance of identifying a BRCA1 or BRCA2 mutation in a family is increased if there are multiple family members with breast (commonly premenopausal) or ovarian cancer and in a patient if they have bilateral or triple negative breast cancer (estrogen receptor, progesterone receptor and HER2 receptor negative).4

It is important to note that mutations in BRCA1 and BRCA2 account for a higher proportion of ovarian cancer than breast cancer, with mutations being detected in approximately 15% of women with epithelial ovarian cancer.5

Eligibility for testing

The guidelines for familial breast cancer, recently updated by NICE, now recommend that testing of BRCA1 and BRCA2 should be undertaken in individuals who have at least a 10% risk of a mutation.1

The most appropriate way to initiate testing within a family is to undertake the initial mutation search of the BRCA genes in a patient with cancer (normally breast or ovarian). This maximises the likelihood of mutation detection and provides the most clinically useful information.

This is known as a diagnostic genetic test and involves a full screen of both BRCA genes for a change in the DNA sequence.

Determining who is eligible for a genetic test under the current guidelines is complicated.3 Multiple risk-assessment models are available, but many clinical genetics centres use clinical criteria to determine eligibility. All women with cancer who fall into one of the categories listed in box 1 should be referred to a genetics centre for assessment of eligibility for genetic testing.2,3

In addition, it is appropriate to refer families if a male family member has breast cancer.

If a BRCA mutation is identified, unaffected family members can undertake a predictive genetic test (a targeted test for a specific mutation), to determine if they have inherited the familial mutation.

Siblings and children of individuals with a BRCA mutation are at 50% risk of having the mutation. Individuals who have inherited the mutation have an increased lifetime risk of developing breast and ovarian cancer, whereas those who have not inherited it return to population risk of breast and ovarian cancer.6

If an unaffected family member is referred to a clinical genetics centre on the basis of a strong family history, testing is normally recommended in the first instance in the most appropriate affected family member.6

NICE guidance now also recommends that the initial mutation search of the BRCA genes can be undertaken in an unaffected family member, if affected family members are not available.1

Cancer risk for carriers

Women with a BRCA1 mutation have an approximate 60-90% lifetime risk of developing breast cancer and a 40-60% lifetime risk of developing ovarian cancer.5

Women with BRCA2 mutations have a similar lifetime breast cancer risk (45-85%), but slightly lower lifetime ovarian cancer risk (10-30%).6

Women with unilateral breast cancer are also at a significantly increased risk (approximately 50%) of developing breast cancer in the contralateral breast.

The risks are lower for males. Male BRCA1 carriers do not have a significantly increased cancer risk, whereas male BRCA2 carriers have small increased lifetime risks of breast and prostate cancer.

Management of carriers

For women with cancer, the result of BRCA testing (positive: mutation detected, or negative: no mutation detected) has implications for their current and future cancer management and prognosis.1

For example, a BRCA carrier with breast cancer may choose to have mastectomy rather than breast- conserving surgery, and chemotherapy may be tailored to use a platinum-based agent.

BRCA carriers who do not have cancer need to consider their future risk and the appropriate clinical management. Their decision may change with time, depending on their personal experience of cancer within their family, whether they are planning, or have, children, and their support network.

BRCA carriers are eligible for increased breast screening. Current NICE guidelines advise annual breast MRI between the ages of 30 and 50 and an annual mammogram between the ages of 40 and 70.1 Some women may consider bilateral risk-reducing mastectomy, as this minimises the lifetime risk of developing breast cancer.

At present, there is no proven method of ovarian cancer screening. Risk-reducing salpingo-oophorectomy is discussed with all BRCA carriers in their 40s who have completed their families.7 This has the benefit of minimising ovarian cancer risk. Furthermore, if undertaken premenopausally, it can significantly reduce lifetime breast cancer risk.

  • Dr Hanson is consultant in cancer genetics at The Royal Marsden NHS Foundation Trust


1. NICE. Familial breast cancer: Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. CG164. London, NICE, June 2013.

2. Institute of Cancer Research. Cancer Genetic Clinical Protocols.

3. British Society for Genetic Medicine. Genetics Centres.

4. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998; 62: 676-89.

5. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995; 56: 265-71.

6. Antoniou A, Pharoah PD, Narod S et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72: 1117-30.

7. Kauff ND, Domchek SM, Friebel TM et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008; 26(8): 1331-7.

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