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Breast cancer gene mutations and implications for patients

Key learning points:

 - Women and families with the BRCA1/2 mutation need adequate support and time to make decisions about their various options

 - Both primary and secondary care have a huge role to play in assessing and caring for   such patients who can often have very complex issues

 - Risk-reducing mastectomy is life-changing and can lead to psychosocial problems

Although time has passed since Angelina Jolie first came out and discussed her double mastectomy, which was widely seen as a positive step, families at high risk of breast and ovarian cancer remain anxious about their options. One could argue that the media coverage has forced families to think about their risk where they had previously chosen not to. This of course has been heightened by the recent guidance from the National Institute for Health and Care Excellence (NICE) who state that women at high risk and those who are post-menopausal should now be offered the preventative drugs Tamoxifen or Raloxifene which will reduce the risk of breast cancer by up to 40%. Tamoxifen can be given to pre- and post-menopausal women. 

BRCA1/2 stands for breast cancer susceptibility genes 1 and 2 and account for 5-10% of all breast cancers.1 They are human genes that play a major part in the genetic material within our cells by providing a stable environment and producing tumour suppressor proteins which repair any damaged DNA within the cell. If DNA is not repaired properly because there is a mutation which means the protein is missing or non functional, cancer can develop. Specific mutations in BRCA1/2 can greatly increase the risk of breast and ovarian cancer and these mutations account for about 20-25% of hereditary breast cancer.2 Furthermore, there has also been a change in the threshold for genetic testing, from 20% to 10%, which means that if a relative has been estimated to have a greater than 10% of carrying the BRCA1/2 mutation, testing can be offered, enabling greater numbers of people to be tested. The implications for practice are that more women and their families are seeking testing and consultation on their options. The fact that options are increasing for such families can only be seen as a positive move. In some clinical areas, where testing is not yet available or there is a prolonged wait, women are paying privately for the test at a personal cost of £500. To ensure accuracy when calculating a person's risk of getting breast cancer, according to the guidance, packages such as the Manchester scoring or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) should be used.

Both primary and secondary care has a role to play in caring for such potential patients. The first priority is to take a thorough family history from those who have a personal history of breast and ovarian cancer or those who are worried that they may be at risk. Breast cancer development will depend on many factors including:

 - The nature of the family history.

 - The number of relatives who developed breast and/or ovarian cancer.

 - The age at onset of either breast or ovarian cancer.

 - The age of the person at risk.

The risk of breast cancer is calculated on a lifetime risk usually from the age of 20 years. The categories are population risk, moderate risk and high risk:

For those aged 20 and over, population risk is having a lifetime risk of less than 17%. Moderate risk is over 17% but less than 30%. High risk is greater than 30%.

For those aged between 40 and 50 years, population risk is less than 3%, moderate risk is 3-8% and high risk is greater than 8%.

First-degree relatives are defined as parents, siblings, sons and daughters. Second-degree relatives are grandparents, grandchildren, aunts, uncles, nieces, nephews, and half-siblings. Third-degree relatives are great-grandparents, great aunt and uncle, first cousins, great grandchildren, great nephews and great nieces.

According to the updated NICE guidelines, people without a personal history of breast cancer can be cared for in primary care if the family history shows only one first-degree or second-degree relative diagnosed with breast cancer over the age of 40 years, provided that none of the following are present in the family history:

 - 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 (two or more relatives on the father's side of the family).

People without a personal history of breast cancer should be offered referral to secondary care if there is:

 - One first-degree female relative with breast cancer below the age of 40 years.

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

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

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

 - 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.

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

Options for women at high risk

There are a number of options for women at high risk of breast cancer. Hereditary breast cancer accounts for 5-10% of all breast cancers and those women given a diagnosis of the BRCA1/2 gene have a lifetime risk of up to 90% for breast cancer and 60% for ovarian cancer.3-5 Those with the BRCA2 gene have a slightly lower chance of ovarian cancer - in the region of 40%. 

Changes in the TP53 gene greatly increase the risk of developing breast cancer as part of a rare inherited cancer syndrome called Li-Fraumeni syndrome, but they account for less than 1% of all breast cancers. Women with at TP53 mutation have a high risk of many cancers including breast cancer.

The options therefore include bilateral risk-reducing mastectomy with or without reconstruction, surveillance in the form of mammography and magnetic resonance imaging (MRI), or chemo-prevention in the form of Tamoxifen and Raloxifene. It is however noteworthy that neither drug is licensed as yet for this indication, and the side-effects of the drugs should not be under-estimated. There are also issues to consider, such as who will prescribe and monitor the drugs and who will counsel the patients regarding the options. Although the drugs are thought to reduce the risk of breast cancer by up to 40%, the risk reduction with bilateral mastectomy is in the region of 95%.

MRI and age

Surveillance will depend on the age of the person. Those women with a TP53 mutation will not benefit from mammography, and MRI should be offered annually for those aged 20-49 years with a known TP53 mutation or those who are over 30% probable carriers, and be considered annually for women aged 50-69 with a known TP53 mutation. It is recommended that from age 30-49, those with a known BRCA1/2 mutation or a calculated risk of over 30% of being a probable carrier and personal history of breast cancer are also offered MRI.6

Age and Mammography

Annual mammography should be offered to those at moderate risk age 40-49 years and considered for those who are aged 50-59. Those with a known BRCA1/2 mutation age 40-69 and considered for those age 30-39. Women at high risk age 40-59 but with a 30% or lower probability of BRCA1/2 or TP53 and those with a greater than 30% probable risk of being a BRCA carrier should be offered annual mammography. Those women age 50-69 years with a personal history of breast and who remain at high risk or carry a BRCA1/2 mutation and do not have a TP53 mutation should be offered annual mammography. It should also be considered for women age 30-39 at high risk but with a 30% or lower chance of being a BRCA or PT53 carrier and age 30-39 greater than 30% chance of being a BRCA carrier.6

For those who choose to have risk-reducing surgery, there are many things to consider. Some surgeons for example remove the nipple areolar complex, while others are happy to preserve it. The cosmetic results are obviously superior if the nipple stays but some argue that this is not truly risk-reducing as cells within the ducts leading to the nipple may in future lead to breast cancer, although further research is recommended. There are also many different reconstruction techniques. The simplest method involves using an implant. This could be an expander, or expander followed by a more permanent and shaped implant. There is also a new technique that offers a good cosmetic result by providing extra support and a lower positioning of the implant. This is called Strattus and involves a layer of pig skin. Other methods involve using muscle/fat flaps from either the back or the abdomen, and are classed as more major surgery, often involving micro-vascular surgery. Patients will need time to recover and often experience pain or discomfort and loss of mobility for a time. The important thing to consider is that none of the methods replace the normal breast in terms of either the appearance or feeling. Many of the pictures on the internet often do not resemble the final cosmetic appearance that BRCA1/2 women eventually end up with. 

Research has shown that despite anxiety being reduced post surgery, women who have a risk-reducing mastectomy have psychological issues that can be long-standing and include issues of body image change, sexual dissatisfaction and poor quality of life.7-10 Despite genetic counselling and input from breast care nurses' pre and post surgery in those units that can offer such support, women and their partners struggle with recovery and adjustment. This is often underestimated by the medical and nursing profession as much of the focus is on women with breast cancer. The most important aspect of the journey for the patient and the family is time. Women need time to assimilate the diagnosis, consider their options including their children and ensure that they embark on the right reconstructive surgery. They also need their husband and partner fully engaged. Many units now have joint clinics with plastic surgeons offering women a choice of techniques. It is also good practice and very wise for the patient and partner to see photographs of the surgery and discuss the pre- and post-surgical care with the team, but especially the specialist nurse. Most units now offer a multidisciplinary approach.

Often there are many family disclosure issues regarding testing and surgery that need addressing before a woman feels ready for the surgery. There are also issues of ovarian risk-reducing surgery, family planning and timing of the breast surgery that influence a woman's overall reconstructive decision. It is fair to say therefore that the whole journey for the patient and their family is very complex. Patients often need many consultations with the surgical team before the surgery and it varies considerably when the final surgery takes place following diagnosis of the BRCA1/2 mutation. Genetic counsellors have a huge role to play in preparing the patient for the BRCA1/2 diagnosis as well as other family member disclosure. It is reassuring that this group of women are being taken seriously and are being given time and support to make such a huge life-changing decision.



 1. Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary  breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008;124(1):31-42.

2. National Cancer Institute. 2013. 

3. Antoniou A, Pharoah P, Narod S. Average risk of breast cancer and Ovarian Cancer associated with BRACA1 or BRACA2 mutations detected in case series unselected for family history. A combined analysis of 22 studies. American Journal Of Human Genetics 2003;72(11):17-30.

4. Cancer Research UK. Breast cancer genes. 2013. 

5. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003;302:643-6.

6. National Institute of Health and Care Excellence. 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. London: NICE; 2013. 

7. Brandberg Y, Sandelin K, Erikson S, et al. Psychological Reactions, Quality of life,Body Image After Bilateral Prophlactic Mastectomy in Women At High Risk For Breast Cancer:A prospective1-Year Follow up Study. Journal of Clinical Oncology 2008;26(24):3943-8.

8. Geiger A, Nekhlyudov L, Herrinton L. Quality of life after Prophylactic Mastectomy Annals Of surgical Oncology 2007;14(2):686-94.

9. Van Oostrum, et al. Long term Psychological impact of carrying a BRCA1/2 Mutation and prophylactic surgery: A 5 year follow up. Journal of Clinical Oncology 2003;21(20):3867-74.

10. Patenaude A, Orozco S, Li X, et al. Support needs and acceptability of psychological and peer consultation: attitudes of 108 women who had undergone or were considering prophylactic mastectomy. Pycho-oncology 2008;(17):831-43.