Familial Breast Cancer

In May 2013 Angelina Jolie revealed that she had undergone preventative double mastectomy after tests showed that she carried the BRCA1 gene.

Familial breast cancer occurs in people with one or more family members affected by breast, ovarian or a related cancer such as colorectal cancer.

About 5 % of all breast cancers can be attributed to inherited mutations in specific high risk genes such as BRCA1, BRCA2 and TP53.

What is a mutation?

It is a change in the DNA code of a gene that prevents the gene from producing a fully functional protein.  Some mutations are more damaging than others. The genes that greatly increase the risk of cancer are ordinary human genes that have mutations in critical parts of their genetic code.

Cancer genes are human genes that are normally involved in critical cellular functions such as control of the cell cycle and DNA repair. When there is a mutation in one of these genes, the gene does not function normally. For the person who carries the mutation, this functional failure leads to an increased risk of them developing cancer.

The risk of cancer that these genes confer is organ specific. For example, mutations in the genes BRCA and BRCA2 increase the risk of the carrier developing breast and ovarian cancer. They do not cause a generalised increase in the risk of developing all types of cancer.

People who carry the mutated genes have an increased risk of developing cancer, but some may never develop cancer.

Most cancers with mutations are inherited in an autosomal dominant manner. This means that you only need to inherit a mutation from one parent in order to inherit the increased risk of developing cancer. So a mutation in only one copy of the gene will increase the risk of a person developing cancer.

Breast and ovarian cancer:

A high penetrance gene is a mutated gene that is very likely to cause clinical manifestations.

Two high penetrance genes – BRCA1 and BRCA2 are responsible for less than 10 % of breast cancers.

Although BRCa1 and BRCA2 are usually called the breast cancer genes, they should really be called the breast and ovarian cancer genes, because they increase the risk of developing both breast and ovarian cancer.

Women who carry a BRCA1 or BRCA2 mutation have a lifetime risk of developing breast cancer of up to 85%. The UK population risk in women who do not carry a mutation is about 12.5 % which means about 1 in 8 women will be affected by breast cancer in their lifetime.

Women with BRCA mutations also have a lifetime risk of developing ovarian cancer of up to 60%. The UK population risk is less than 2 % for women who do not carry these gene mutations.

About 1 in 400 people carry a mutation in one of these genes. The risk of carrying a mutation in one of these genes is much higher (about 1 in 50) for Ashkenazi  Jews.

Clusters of cancers in families:

With current medical knowledge there is an inability to explain why there are some families which have clusters of cancer which are not explained by the genes identified so far. . Some of these are probably just random clustering or “bad luck” or due to the fact that family members may be exposed to similar environmental factors.  But some appear to have a genetic basis that has not yet been identified.

2013 NICE (National Institute for Health and Care Excellence) guidance on people at risk of familial breast cancer – Clinical Guideline 164:

Initial assessment for people without a personal history of breast cancer:

• When a person with no personal history of breast cancer presents with breast symptoms or has concerns about relatives with breast cancer, the doctor should take a first and second degree family history. First degree relatives: mother, father, daughter, son, sister, brother with whom the patient shares 50 % of their genes. Second degree relatives: grandparent, grandchild, aunt, uncle, niece, nephew, half sister and half brother with whom they share 25 % of their genes. Third degree relatives are first cousins with whom they share an eighth (12.5 %) of their genes.
• Information should be as accurate as possible on age of diagnosis of any cancer in relatives, location of the tumour within the body, multiple cancers or Jewish ancestry.
• Referral for specialist breast cancer risk estimation should be made under the following circumstances:
• One first degree  female relative with breast cancer at less than 40 years of age
• One first degree male relative with breast cancer at any age
• One first degree relative with breast cancer in both breasts where the first primary cancer was diagnosed at less than 50 years of age
• Two first degree relatives or one first plus one second degree relative with breast cancer at any age
• One first degree or second degree relative with breast cancer at any age plus one first degree or second degree relative with ovarian cancer at any age. At least one of these has to be a first degree relative
• Three first degree or second degree relatives on the same side of the family with breast cancer at any age
• If more than one relative is involved they should be on the same side of the family.
• In certain circumstances, it may be important to gather information about first cousins and more distant relatives. For example, if a person’s mother has breast cancer, and her mother has brothers only, it is useful to find out if any of the person’s first cousins (the children of her mother’s brothers) have had cancer.
• Women who do not meet these criteria can be reassured that they are at near population risk (risk of developing cancer is similar to an average person’s risk that is they are not high risk) and do not require referral for specific breast cancer risk estimation.

Family history of cancer:

• Many families have cancers on both the maternal and the paternal sides of the family. Each side of the family is considered separately – maternal and paternal side cancers are not additive unless the mother and father are related to one another.
• Some cancers, such as cancer of the ovary, endometrium (lining of the womb) and prostate are sex specific.
• Both men and women can carry the genetic mutations that predispose to these cancers and they can pass on these genes to their children.
• If a man carries a mutation in the BRCA1 or BRCA2 gene, he will never develop ovarian cancer and he is very unlikely to develop breast cancer. But if he has a daughter, she will have a 1 in 2 chance of inheriting his BRCA mutation.
• Men who carry mutations in the BRCA2 gene have an increased risk of developing prostate cancer. The risk is highest under the age of 65. In men who develop prostate cancer under the age of 50 who have relatives with either breast or ovarian cancer, the family history should be assessed.
• When there is an “intervening man” ( a man between two affected female relatives) in a family with breast and/or ovarian cancer, for example a man with a sister and mother with breast cancer, he should be counted as though he was another affected woman in the family tree. This is because this man almost certainly carries the gene, even though he does not have cancer.
• Most genetic mutations in the cancer genes are not 100% penetrant- they increase the risk of cancer but do not always cause it. Some carriers live long healthy lives without developing cancer.

What is the value of discovering that a person has an increased risk of breast cancer?

Women who are at increased risk of breast cancer may benefit from interventions (surveillance using breast MRI and mammography) which have been shown to lead to early detection of breast cancer.  NICE recommends annual MRI to women aged 30-49years if they have a BRCA1 or BRCA2 mutation. Some patients may wish to consider surgery as an option. Mastectomy reduces the risk of breast cancer to less than 10 % when a BRCA1 or 2 mutation is present.

Recent trial results have shown a significant reduction in the risk of breast cancer for the drugs tamoxifen and raoxifene. NICE now has recommended that these may be offered to women at high risk of breast cancer after careful assessment. Both drugs can cause thrombosis and tamoxifen can cause endometrial cancer so the risks and benefits of treatment have to be discussed with each individual patient.

Hormone replacement therapy (HRT) and oral contraceptives have been associated with an increased risk of developing breast cancer so women who are considering or already taking these would need to discuss this with their doctor, bearing in mind that the combined oral contraceptive pill offers protection against ovarian cancer.

The benefits of ovarian screening are unproven but surgical removal of the fallopian tubes and ovaries reduces the risk of ovarian cancer in women with a BRCA mutation to less than the population risk. 

How does screening for familial breast cancer affect a patient’s ability to get insurance?

Currently UK insurance companies should not ask about predictive gene testing on application for life insurance up to £500,000 or critical illness cover up to £330,000 as agreed by a UK government moratorium that will be due for review in 2017.