Genetic Testing For Breast Cancer

This is a wordy article but it really needs to be available in its entirety to be really helpful.

By Dr Helen Hanson, Consultant in Cancer Genetics, Royal Marsden Hospital

Recent media attention has led to a significantly increased demand for genetic testing for breast cancer predisposition genes. Referrals into clinical genetics departments have risen dramatically as a result. Many of these referrals are inappropriate as breast cancer is common and typically women overestimate their familial risk. However, even though the breast cancer susceptibility genes BRCA1 and BRCA2 were first discovered in the late 1990s and NHS genetic testing became available a few years later, many women eligible for a genetic test are not currently accessing or receiving testing. The aim of this short article is to summarise who is currently eligible for genetic testing, the genetic testing process, and the cancer risk and management strategy for a BRCA carrier.

Contribution of BRCA genes to breast and ovarian cancer
Inherited mutations in the BRCA1 and BRCA2 genes account for up to 5% of all cases of breast cancer and 10% of all cases of epithelial ovarian cancer. Therefore, most cases of breast or ovarian cancer are not caused by inherited mutations in these high-risk genes. However, the clinical utility of knowing an individual’s BRCA status is high, both for an individual affected with cancer and their wider family.

The chance of identifying a BRCA1 or BRCA2 mutation in a family is increased if there are multiple family members affected with breast cancer (commonly premenopausal) or ovarian cancer and in an individual if they are affected with bilateral or triple negative breast cancer (oestrogen receptor negative, progesterone receptor negative and HER2 receptor negative). The assessment of risk is complex, largely dependent on family history and generally undertaken within a clinical genetics clinic.

Eligibility and process of BRCA testing
Guidelines on familial breast cancer recently updated by the National Institute for Health and Care Excellence (NICE) now recommend that testing of BRCA1 and BRCA2 should be undertaken in individuals who are at 10% risk of having a mutation.1 Not widely appreciated outside clinical genetics is that the most appropriate way to initiate testing within a family is to undertake the initial mutation search of the BRCA genes in an individual affected with cancer (normally breast or ovarian). This maximises the likelihood of mutation detection and provides the most clinically informative 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 current guidelines is complex. Multiple risk assessment models are available but many clinical genetics centres use clinical criteria to determine eligibility.2 All women affected with cancer meeting one of the following categories should be referred to a genetics centre3 for assessment of eligibility for genetic testing:

  • Woman affected with triple negative breast cancer <50 years
  • Woman affected with bilateral breast cancer <50 years
  • Woman affected with breast and ovarian cancer
  • Woman affected with epithelial (non-mucinous) ovarian cancer
  • Woman and a close relative (first or second degree) both affected with premenopausal breast cancer (<50 years)
  • Woman affected with breast cancer and a close relative with ovarian cancer
  • Woman affected with breast cancer and two further cases of breast cancer in family
  • Woman with Ashkenazi Jewish heritage and breast or ovarian cancer at any age

In addition, it is appropriate to refer families with a male member of the family affected with breast cancer.

If a BRCA mutation is identified, unaffected family members can undertake a predictive genetic test (a targeted genetic 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 also having the mutation. Individuals who have inherited the mutation are at an increased lifetime risk of developing breast and ovarian cancer, whereas individuals who have not inherited the familial mutation return to population risk of breast and ovarian cancer.

If an unaffected family member is referred to a clinical genetics centre on the basis of a strong family history, testing will normally be recommended in the first instance in the most appropriate affected family member. NICE guidance now additionally 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 However, the value of a negative result (no mutation identified) in this situation is far less, as in this situation it will not be certain if the person did not inherit a familial BRCA mutation or if the cancer in the family is not attributable to a BRCA mutation. Consequently, the estimated cancer risk of an individual will not return to population level, although it would likely be appreciably lower than that of a BRCA carrier.

Cancer risk for BRCA 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.4-6 Women with BRCA2 mutations have a similar lifetime breast cancer risk (45-85%), but slightly lower lifetime ovarian cancer risk (10-30%).4-6 Women affected with a unilateral breast cancer are also at a significantly increased risk of developing breast cancer in the contralateral breast. Cancer 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 both breast and prostate cancer.

Management of BRCA carriers
For women affected with cancer, the result of BRCA testing (positive-mutation detected or negative-no mutation detected) has important implications for their current and future cancer management and prognosis. For example, a BRCA carrier with breast cancer may choose to have mastectomy rather than breast-conserving surgery and BRCA carriers with ovarian cancer display a better response to platinum-based chemotherapy agents and have a better prognosis compared to sporadic patients.7

BRCA carriers, who are unaffected with cancer, need to consider their future cancer risk and the appropriate clinical management for them. Their decision may be influenced and indeed change with time due to their personal experience of cancer within their family, whether they are planning/have children and their support network.

BRCA carriers are eligible for increased breast screening compared to women at population breast cancer risk. Current NICE guidance advises annual breast MRI between 30 and 50 years and an annual mammogram between 40-70 years.1 However, some women will wish to consider a bilateral risk-reducing mastectomy as this surgery minimises the lifetime risk of developing breast cancer.

At present there is no proven method of ovarian cancer screening. Therefore risk-reducing salpingo-oophorectomy is discussed with all BRCA carriers who are in their 40s and have completed their families. This surgery has the benefit of minimising ovarian cancer risk and furthermore if undertaken before the menopause, it can significantly reduce lifetime breast cancer risk.8

Considerations prior to undertaking a genetic test
When making a decision whether to have a genetic test the considerations are very different for women affected with cancer and considering a diagnostic genetic test, compared to women unaffected with cancer considering a predictive genetic test. Of course, personal circumstances for both groups of women also play a large role.

Women affected with cancer need to consider how they will deal with the knowledge that they could be at an increased risk of developing a further cancer in the future and the knowledge they may have passed on a mutation to their children. However, for many women the clinical utility of the test and the potential to have an explanation for their cancer diagnosis outweigh any negative considerations.

Timing of testing is very important for individuals undertaking a predictive genetic test. Breast screening does not begin until a woman’s 30s and therefore many individuals do not want to know they are at increased risk before any action will be taken, whereas others may prefer to plan for the future, for example, when they may have children, as this may affect decisions regarding risk-reducing surgery. Insurance implications are often a concern, however, at present there is a moratorium agreed between the Association of British Insurers and the Department of Health, which means that patients do not need to disclose results of a predictive genetic test for BRCA1 or BRCA2 to take out any type of insurance.9

Future changes to model of genetics testing
Genetic testing has traditionally been undertaken through clinical genetics centres, however due to the clinical utility of a genetic test result in the oncology setting, some genetic testing is now being undertaken directly in oncology clinics and this will likely expand in the near future. Genetic testing in unaffected individuals will continue to be performed within clinical genetics centres as this generally requires different and more complex counselling.

New genetic sequencing technologies are just emerging from research to the clinical setting. These technologies have the potential for huge decreases in time, cost and labour intensity of genetic testing and therefore it is widely anticipated that genetic testing for BRCA and other cancer predisposition genes will be part of routine cancer care in the near future.


  1. National Institute for Health and Care Excellence (NICE). Clinical guideline 164. 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. June 2013
  2. The Institute of Cancer Research. Cancer genetics clinical protocols. Available at: Accessed September 2013
  3. The British Society for Genetic Medicine (BSGM). UK Genetics Centres. Available at: Accessed September 2013
  4. Easton D F, Ford D, Bishop D T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56:265-271
  5. Ford D, Easton D F 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;62:676-689
  6. Antoniou A, Pharoah P D 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;72:1117-1130
  7. Cass I, Baldwin R L et al. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003;97:2187-2195
  8. Kauff N D, Domchek S M et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1– and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008;26:1331-1337
  9. Association of British Insurers (ABI). Genetic testing. Available at: Accessed September 2013
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