Does nature trump nuture?

Does our genetic footprint determine who gets what cancer when, or can we change this Sword of Damocles inheritance by diet and lifestyle improvements?

Back to basics

From the time of conception, we receive a genetic profile and our family history determines the types of diseases that we could inherit. We must ask ourselves, is this particularly relevant when looking at our predictive risk of developing breast cancer? If the answer is yes, then why is it that 60% of all women who get breast cancer have no identifiable risk factors?

As a worldwide population, women are thought to have a one in eight statistical lifetime risk of developing breast cancer. However, this risk does not discriminate between those women at high, average or low risk. Part of managing breast disease is to attempt to have an understanding of each individual woman’s risk of getting breast cancer. Clinicians and women themselves should learn to recognise who may be at a higher risk for breast cancer. It is part of a health care provider’s task to counsel and refer patients for risk-assessing and risk-reducing strategies.

Risk Assessment: how and how accurate

Risk assessment is not as time-consuming as often thought and merely involves getting the patient’s history. This involves identifying factors from the patient’s family history, personal history and medical history that may increase their risk of breast cancer. These factors, defined by the American Cancer Society (ACS) are discussed below.

In addition to formulating a subjective idea of a patient’s breast cancer risk based on their history, various models based on large population-based studies can be used to aid the process. These risk assessment tools include the National Cancer Institute model (otherwise known as the Gail model), which uses personal and medical history, or the Claus model which relies more on family history and genetic factors.

Although these models are good at predicting population – based risk, they have poor predictability for an individual patient. In addition, they are based on specific populations, such as white women, which may have poor concordance with our population in South Africa. In addition, most risk assessment tools were developed before BRCA genes were discovered. A BRCA-specific tool (BRCA-PRO) can be used to identify risk of genetic breast cancer. Most recently BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) has been developed for estimating both risk of genetic breast cancer and age-specific risk in familial breast cancer.

The risk assessment process should not only identify a patient’s individual risk but also address their fears and concerns about breast cancer, while putting into context perceived versus actual risk.

Risk Stratification

Following risk assessment patients can be classified according to their risk profile:

  •  High risk of breast cancer: Genetic or strong family history.

o Personal history of breast cancer.

o Presence of some risk lesions on biopsy.

  • Increased risk of breast cancer:

o Radiation exposure to the chest wall at a young age.

o Presence of some risk lesions on biopsy.

  •  Average risk of breast cancer:

o Patients with no or few risk factors.

Genetic risk factors

The following genetic risk factors are critical for us to know, so that we can be more vigilant with our monthly breast self-examinations and our clinical examinations by our GP or gynaecologist. Women need to ensure that they go for routine mammograms and ultrasounds at good units – they should offer radiology reviews, counselling prior to biopsies and access to multi-disciplinary care units that offer individualised and well-thought out care.

Know this about your family

Family history of breast carcinoma in the following circumstances:

1. Breast carcinoma in a first-degree relative (doubles risk).

2. Especially a mother or sister who is premenopausal.

3. Having two first-degree relatives increases the risk five-fold.

4. Family history of bilateral breast carcinomas.

5. Father or brother with breast cancer.

6. Known BRCA 1 and 2 mutation.

These are the most common inherited mutations:

1. BRCA mutations are more commonly found in Jewish women of Ashkenazi (Eastern Europe) descent. They are also found in African American women, Afrikaner (Dutch descent), Scottish, Hispanic and do probably occur in any racial, or ethnic group.

2. BRCA 1 carries up to an 80% chance of developing breast cancer in the patient’s lifetime, with an increased risk in ovarian cancer as well.

3. BRCA 2 has a similar breast cancer risk, as well as a higher risk of developing GIT, malignancies, melanoma and gynaecological malignancies.

It is important to understand that our ability to test genetic profiling is not as simple as looking at a family with large numbers of documented cancers and strolling into a pathology lab and asking “while you check my cholesterol, thyroid function, fasting glucose, and insulin, just add a BRCA test, two of my aunts have had breast cancer under the age of 35”.

Performing a random, genetic test on yourself may fill you with a false sense of security. Your test results may come back negative, but so might the results of your two aunts. Testing Aunty may result in a positive result or a negative, and a negative means that in your family the cause of the breast cancer may not be BRCA or we may not be able to identify the genetic abnormalities.

This is because

• The ability to test BRCA 1 and 2 mutations in certain population groups is difficult, both from a genetic and financial perspective in South Africa.

• Ideally the index case should be tested.

• A negative BRCA test in an index case does not exclude a genetic (inherited) breast carcinoma, but merely our inability to detect the causative gene or gene combination.

There are other genes at play, or combinations thereof in certain families that are more difficult to detect.

1. ATM gene: this usually promotes damaged DNA repair, and the gene has been documented in certain families with breast cancer.

2. CHEK2: This gene is seen in some women with a strong family history, and greatly increases risk when present, as it has a two-fold risk when mutated.

3. Li-Fraumeni syndrome (P53): The P53 suppressor gene is associated with multiple types of cancers such as leukemia, sarcomas, brain tumours and breast carcinomas.

4. Cowden’s Syndrome (PTEN): This gene regulates cell growth and causes increased risk for both benign and malignant breast tumours, as well as tumours of the digestive tract, uterus and ovaries.

Genetic testing can be used to look for certain mutations, however testing may not result in positive results even in women with significant family histories and the pros and cons should be discussed in detail with patients.
How genetic testing is done

A saliva swab or blood sample is sent for analysis. A full gene-sequencing test that looks for BRCA 1 and 2 abnormalities may cost anything from around R6000 to R10 000, while the results may take one to three months. NO tests should be done without thorough pre-and post-test counselling, which should include consideration around what the options are, should the test results be positive. Genetic testing is now available in most South African centres, both in government and private multi-disciplinary units.

30% of women who develop breast cancer may have a history of breast or other cancers on both the maternal and paternal side of the family. In this group of women, genetic profiling and testing often does not result in a positive test for a gene mutation.

What should one do if you are faced with this type of family history?

Diet and lifestyle modification and close screening are extremely important. The first step is to ensure that all safety precautions are undertaken, a consultation in a unit that specialises in high-risk surveillance is essential. Knowing the age of the youngest member of the family with breast or other cancer is also important.

Having mammograms and ultrasounds done in a unit that offers digital mammography, breast tomosynthesis, and good quality breast ultrasound is vital. Often the density of the mammogram, and the presence of other benign breast masses, cysts and fibroadenomas will clue the treating clinician in how often clinical breast examination and breast radiology is warranted.

Benign breast problems do not indicate a higher risk of developing breast cancer, but they do make self and clinical examinations more difficult, and more stressful for the patient.

Open access clinics are important for women who have strong family histories of breast cancer. If you are not sure of what you feel when you self-examine your breasts, this can result in high levels of anxiety, and access to breast ultrasound is an easy way to confirm if the mass felt is sinister or not.

Lifestyle modification

Various lifestyle modifications have been associated with either a decrease in breast cancer risk or minimising that risk. There is no doubt that it can also improve your health and wellbeing and should be recommended to all patients.

• Avoid obesity (particularly in post-menopausal women, and maintain a healthy Body Mass Index of 19-25).

• Reduction in alcohol consumption to less than two units of alcohol per day.

• Increase in exercise to at least 30 minutes, five times per week.

• Increased dietary intake of fruit and vegetables (at least five portions per day).

Can drugs decrease breast cancer risks: 


Two medications, Tamoxifen and Raloxifene, have been found beneficial in reducing breast cancer in high and increased risk patients. Tamoxifen, which is a Selective Oestrogen Receptor Modulator (SERM), has been found to reduce the incidence of breast cancer by 50% in women at high risk, but can be associated with side effects such as higher risk of thromboembolic disease (deep vein thrombosis, PE and stroke) and endometrial cancer. Although it benefits both pre and post-menopausal women, there are fewer side effects in pre-menopausal women making it a more promising choice.

Raloxifene, a medication used to prevent osteoporosis in post-menopausal women, also reduces the chance of getting breast cancer. In comparison to Tamoxifen, it does not have the same impact and does not prevent Ductal carcinoma in situ (DCIS) but has fewer side effects during treatment. Each drug should be given for five years, and studies show the benefits of prevention continue beyond cessation of treatment.

Because both drugs modify oestrogen receptivity in the breast cells, it is of little benefit in preventing oestrogen receptor negative cancers. Patients at high risk of these tumours, such as those with BRCA 1 and 2 mutations see little or no benefit.

Take care: Playing with knives

Risk-reducing surgery

The decision to undergo a risk-reducing mastectomy must be taken only after careful consideration, extensive counselling and multi-disciplinary unit guidance. This procedure is usually performed with an immediate reconstruction. If the patient is unsure, it is always advisable to delay the decision.

The current gold standard for risk-reducing mastectomy and reconstruction is a skin sparing mastectomy and immediate bilateral breast reconstruction by expander, or definitive implant with skin flap preservation. This traditionally includes removal of the nipple areolar complex (NAC). Recently the retention of the NAC has become more common, as the incidence of cancer in the retained nipple after risk-reducing mastectomy is documented at less than one per cent.

A contralateral risk-reducing mastectomy, although on the increase, should be entirely a patient based decision, and only taken after extensive counselling. This is because the risk of contralateral cancer is low and most breast carcinomas once spread to axillary lymph nodes, are more likely to reoccur elsewhere in the body, than for a second primary to develop in the contralateral breast.

Risk-reducing surgery should only be offered in multi-disciplinary units, after careful consideration is given to all the cons of the procedure and it should never be offered as an emergency.

Regular screening

Ideally, one should go for radiology screening twice a year. This usually consists of a mammogram once a year and an ultrasound twice a year. If possible, a breast MRI yearly makes for a good radiological seatbelt. This should be alternated with two annual clinical examinations. So the year is divided into four quarters:

For example:

1. January: Mammogram and ultrasound

2. April: Clinical examination

3. July: Ultrasound and MRI

4. October: Clinical breast exam

1. January: Repeat…


Women with a family history of breast cancer should be regularly screened from ten years before the youngest diagnosis of breast cancer in their family. All women should be encouraged to carry out breast self-examinations on a monthly basis. Many women feel that more regular mammographic screening may reduce their risk, however it is important to remember that mammograms will only pick up cancers earlier, and not prevent them. There is little data to support more regular screening than annually with mammography; however, the addition of Magnetic Resonance Imaging (MRI) may be a useful tool, particularly in young women. The current ACS guidelines suggest yearly MRI (staggered at six month intervals with mammography) is beneficial in women with BRCA mutations, and may be of use where risk lesions are present.

The reason for such stringent clinical and radiological follow-up is that 50% of women who do develop breast cancer in the high-risk group develop the breast cancer in the interim between their annual mammograms.


Prof Carol-Ann Benn heads up breast cancer centres at Helen Joseph Hospital and Netcare Milpark Hospital. She lectures at Wits University and, in 2002, established the Breast Health Foundation.

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