Breast cancer screening

Contributed by Dr Imogen Locke, clinical research fellow in cancer genetics and Dr Rosalind Eeles, consultant and reader in clinical cancer genetics, Royal Marsden NHS Foundation Trust

Germline mutations in genes cause the inherited susceptibility to breast cancer

1. Aetiology and epidemiology  

Breast cancer is the commonest cancer in women in the UK. It is estimated that one in nine women in the general population will develop breast cancer during their lifetime. Breast cancer is a multifactorial disease linked to lifestyle and environmental factors, reproductive history and inherited susceptibility.  

Family history  

Family history is an important risk factor for both breast and ovarian cancer. The breast cancer risk of women with a single affected first degree relative 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, be due to shared lifestyle  and/or environmental factors or due to a genetic susceptibility.  

Twin studies predict that up to 27 per cent of breast cancer may be due to an inherited susceptibility. Only about 5 per cent of all breast cancer is thought to be due to the inheritance of highly penetrant breast cancer susceptibility genes. The remainder of heritable susceptibility may be the polygenic effect of a number of lower penetrance genes yet to be identified.  

Germline mutations  

Germline mutations in the BRCA1 and BRCA2 genes are the most important known causes of inherited susceptibility to breast and ovarian cancer. Mutations in these highly penetrant dominant genes account for the majority of striking multiple case breast and ovarian cancer families, especially those with ages of diagnosis younger than 40 years. 

Understanding the age specific cancer risks, or penetrance, associated with BRCA1 and BRCA2 mutations is fundamental to the risk assessment and genetic counselling of mutation carriers. It is estimated that women carrying pathogenic mutations in one of the BRCA genes have a lifetime risk for developing breast cancer up to 80 per cent by age 80 years.  

Women who have developed a BRCA gene-related breast cancer also have an elevated cumulative risk of developing contralateral breast cancer. Knowledge of an underlying genetic predisposition and the consequent residual risk to remaining breast tissue is important in guiding decisions about therapeutic options, including the use of breast conserving surgery with radiotherapy and prophylactic contralateral mastectomy.  

The majority of familial ovarian cancer is due to mutations in the BRCA1 gene and these families are therefore considered at increased risk for developing breast cancer.  

BRCA1 mutations predispose more strongly than BRCA2 to ovarian cancer.  

2. Triaging risk  

Taking a first- and second-degree family history on both sides of the family is an essential part of assessing cancer risk. Some mutations are more common in specific populations such as Icelandic and Ashkenazi Jewish, and rare in other populations, consistent with descent from a single founder.  

Breast cancers arising in BRCA1 mutation carriers tend to be high grade, oestrogen receptor negative and are less frequently associated with ductal carcinoma in situ (DCIS). Male breast cancer and prostate cancer are important manifestations of the BRCA2 phenotype.  

NICE guidance on familial breast cancer identifies three categories of risk: women who can be managed and reassured in the primary care setting, women who meet threshold criteria for referral to secondary care and women who meet threshold criteria for referral to tertiary care within the Regional Cancer Genetics Centre.  

Referral criterion  

Women at moderate or greater risk should be referred for assessment and mammographic surveillance in the secondary care setting if they meet the criteria, below.  

Criteria for referral to secondary care  

One first-degree relative diagnosed with breast cancer under 40 years.   

Two first-degree relatives, or one first-degree and one second- degree relative, diagnosed with breast cancer at any age.  

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

One first-degree relative with male breast cancer at any age.  

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

Two second-degree paternal relatives.  

One first-degree or second-degree relative diagnosed with breast cancer at any age and one first-degree or second-degree relative diagnosed with ovarian cancer at any age. 

A 3–8 per cent risk of developing breast cancer between the ages of 40 and 50 years or a lifetime risk of developing breast cancer of 17 per cent or greater, but less than 30 per cent.  

3. Screening and genetics  

Mammographic screening  

Women at moderate or greater risk should be offered annual mammographic screening between the ages of 40 and 49 years and three-yearly mammography, within the National Health Service Breast Screening Programme (NHSBSP), from the age of 50 years. Women from BRCA1, BRCA2 or TP53 mutation carrying families (or women at equivalent breast cancer risk) should have their mammographic screening protocol individualised on the basis of their family history.  

In these families, mammographic screening may commence at a younger age if there are early onset cases in the family and may be continued more frequently than the NHSBSP after the age of 50.  

Mammographic screening is less sensitive in younger women who typically have denser breast tissue, making microcalcification more difficult to visualise and breast cancers arising in BRCA1 gene mutation carriers are less likely to be associated with DCIS.  

Mammography is not recommended before the age of 30 years. Further data from clinical trials of MRI screening might influence future screening recommendations.  

The results of the UK-based MARIBS study that was published in 2005, demonstrated that overall breast MRI was more sensitive than mammography for detecting breast cancer.  

Referral to tertiary care  

Only a small proportion of women will fulfil the criteria for referral to the Regional Cancer Genetics Service.  

For these women, a personal risk assessment can be made and information provided about how heritability may contribute to the pattern of cancers in the family.  

The counsellee may wish to explore the pros and cons of genetic testing or discuss the risks and benefits of risk-reducing surgical options such as prophylactic mastectomy and prophylactic oophrectomy. BRCA gene mutation carrying families are also offered targeted ovarian and prostate cancer screening.  

Genetic testing  

Women who come from families where there is a 20 per cent or greater chance of finding mutation in the BRCA1, BRCA2 or TP53 genes should be offered genetic testing.  

Criteria for referral to tertiary care 

Two first- or second-degree relatives diagnosed with breast cancer at an average age of 50 years or younger. 

Three first- or second-degree relatives diagnosed with breast cancer at an average age of 60 years or younger .  

Four relatives diagnosed with breast cancer at any age.  

In the above, one affected relative must be first degree. 

One ovarian (any age) and one first- or second-degree relative with breast cancer under the age of 50 years or two breast cancers under the age of 60 years.  

Two or more ovarian cancers on the same side of the family (any age).  

One bilateral breast both diagnosed before 50 years of age in a first-degree relative.  

One bilateral breast cancer and one breast cancer under the age of 60 years in a first- or second-degree relative.  

Male breast cancer at any age and one breast cancer under 50 years or two breast cancers under 60 years in first- or second-degree relatives. 

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