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Familial breast cancer

GP Dr Andrew Maurice outlines the important messages of the NICE guidelines

on familial breast cancer that are pertinent to primary care

Breast cancer is the most common cancer in women, affecting around one in 10 women in the UK in their lifetime. While family history is one of the strongest risk factors for developing breast cancer, most sufferers will not be aware of an affected close relative. Only 3-5 per cent of breast cancers are thought to be related to mutations in the BRCA1, BRCA2 and TP53 genes. However, with breast cancer being so common in the general population it can be difficult for women to know whether any case in their extended family indicates a significant personal risk and can lead to considerable anxiety. Therefore, there is a need for accurate initial assessments in primary care and also an awareness of the important aspects of the further management of women at increased risk. The updated NICE guidelines on familial breast cancer give recommendations for the classification and care of women who are at risk.

How should we deal with concerns over a family history of breast cancer?

Studies suggest the issue of a family history of breast cancer is directly raised by the patient in only about 0.5 per cent of consultations. However, in many other circumstances, a family history becomes relevant, such as presentations with breast symptoms or discussions over contraception in the over-35s and long-term HRT. In each case, a first and second-degree family history should be taken, with as much attention being paid to the paternal side of the family as maternal. Involving other relatives in constructing the pedigree is frequently required and a return appointment with a simple sketched family tree is often revealing.

Accurate assessment will require further information on:

• age at diagnosis of any cancer in relatives

• site of tumours

• multiple cancers (including bilateral diagnoses)

• Jewish ancestry.

The flow diagram on page 47 summarises the referral decision process, which will often lead to simple management in primary care or referral to secondary care for advice. Women who are not at significant risk should be reassured, but advised to return if there is a change in their family history or obviously if they develop any breast symptoms. The guidelines recommend this be included in a written information leaflet, which should also advise on:

• levels of population and family risk

• lifestyle issues regarding breast cancer risk

• details of support groups.

For some women, who would not seem to be eligible for referral on risk grounds, reassurance in primary care may not be enough to allay their cancer worries and referral may be required for further risk/psychological counselling. Similarly, referral for advice on complex or unusual family histories is entirely reasonable. It is worth bearing in mind that women at moderate risk outside the 40-49 year age group will not generally be offered additional screening, other than as part of research, and this may influence the timing of referral. Women who are referred undergo a detailed risk assessment, are advised on risk-reducing strategies and, if eligible, are entered into the recently updated surveillance programmes.

What are the implications of the new screening guidelines?

The recommendation of magnetic resonance imaging (MRI) for detecting breast cancer is the main change to the 2006 guidelines. Four major studies published recently have shown greater sensitivity of MRI over mammography in detecting breast cancer at an early stage in high-risk women. In addition, MRI was shown to be more effective than mammography in screening younger women because of breast tissue density issues. However, these benefits of MRI in the studies were at the cost of reduced specificity and all the significant sequelae associated with an increased number of false-positive results. In addition, mammograms still seemed to have a greater sensitivity than MRI for detecting ductal carcinoma in situ. Therefore, in keeping with the available evidence, the guidelines recommend MRI in conjunction with mammography for younger women at very high risk, and the decision to undertake such screening will generally be taken in tertiary care.

Even though the indications for MRI are relatively few the resource implications are considerable, and it remains to be seen whether the services will be readily available. Hence, the mainstay of breast cancer surveillance remains mammography alone and there is evidence for the benefit of screening women at moderate and high risk in the 40-49 year age groups.

How does genetic testing work?

There is a wide expectation from women who are concerned about their family history of breast cancer that gene testing is readily available and useful. However, this is not the case; with only a small percentage of all breast cancers being related to mutations in the known predisposing genes, genetic testing is reserved for very high-risk women.

These women will have been referred to specialist cancer genetics

clinics and be from families deemed to have a 20 per cent or greater chance of carrying a mutation in BRCA1, BRCA2 or TP53. In order to initiate testing, a blood sample is required from a surviving affected family member, which sadly in these families is frequently the limiting step. Several hundred mutations in BRCA1 and BRCA2 have been identified and these occur throughout their sequence. No one mutation predominates in the UK (as for example in the case of cystic fibrosis) and consequently testing for faults requires screening the entire coding sequence of these very large genes. Thus, searching for sequence alterations in BRCA1 and BRCA2 is complex and time consuming.

The use of all the latest techniques provides sensitivity approaching 95 per cent, but taking into account the threshold for testing, in many families a fault will not be found. Only if a mutation is identified in an affected family member can predictive genetic testing be offered to blood relatives. Studies estimate that a quarter of women may have inherited faults in as yet undetermined genes, that to some degree predispose them to breast cancer, which may extend the scope of testing in future. However, for most women with a family history of breast cancer, definitive genetic tests are not available and they embark on risk-reducing strategies based on statistical estimates.

Reducing risk

The presence of a family history of breast cancer frequently provides motivation to undertake steps to reduce risk. Bilateral risk-reducing mastectomy has understandably attracted considerable media attention. It is a highly effective intervention, but the extensive implications and nature of the surgery make it only appropriate for a small proportion of women from high-risk families. Access to surgery should be via specialist cancer genetic clinics which have the facilities for the necessary counselling.

Research continues into drugs that may reduce the risk of breast cancer, but at present none have gained sufficient evidence to be recommended in the guidelines. The types of risk factors for developing breast cancer for women with a family history are probably the same as for women in the general population but while the relative risk may also be similar, the absolute risk will be greater. The risks associated with taking exogenous hormones are well documented and the modifications of the other risk factors are broadly in accordance with good general health advice. With the increasing incidence of breast cancer they are something we could perhaps all heed rather more.

Andrew Maurice is a GP in Disley, Cheshire, and

a cancer genetics research fellow in Manchester

Competing interests None declared

Key points

• Most cases of breast cancer are not related to a family history

• Most women can be appropriately reassured in primary care by following the guidelines

• Women eligible for entry in a surveillance programme will still be screened by mammography

• Additional screening with MRI has been recommended for women at very high risk

• Genetic testing still only helps a small number

of families

• Simple advice on risk reduction is probably relevant to all

gene facts

• BRCA1 and BRCA2 mutations account

for most cases of familial breast cancer

• Mutations confer lifetime risks of breast cancer approaching 85 per cent

• The risk of ovarian cancer is up to 40 per cent for BRCA1 and can be a high as 20 per cent for BRCA2.

• There is some associated risk of other cancers (prostate, bowel, and male breast cancer, particularly in BRCA2).

• The TP53 tumour suppressor gene encodes a (tumour) protein involved in cell cycle control.

• Li-Fraumeni syndrome is the result of germline mutations in TP53. It is characterised by families with very early onset (95 per cent risk by 50 years) sarcomas, brain tumours and adrenocortical carcinomas, in addition to breast cancers

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