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Genetics, BRCA and the Angelina Jolie Connection

Angelina Jolie’s bold op-ed regarding her recent decision to undergo a mastectomy in the New York Times last Tuesday has sparked significant debate regarding the difficult choices women with a “faulty” BRCA1/2 gene face. As Jolie writes herself: “Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness.” A personal story from a celebrity often galvanises debate and encourages people to seek medical advice.

Experts have applauded the manner in which she discussed the reasons behind her decision, saying that by discussing such a personal and difficult choice, she might inspire some women with family histories of breast cancer to get genetic tests. That’s no mean feat for such a high profile actress, especially one whose body image has been subject to intense media scrutiny.

Who should get tested?

Cancer is a multifactorial disease with genetic, environmental and lifestyle factors all playing a role in producing a malignance and in the likelihood of an individual’s risk of contracting the disease. A family history of cancer may identify people with an increased risk and lead to the identification of an inherited predisposition that confers a high lifetime risk of cancer, such as BRCA1/2 mutations.

The average lifetime risk for a UK woman of getting breast cancer is around 1:8 (12.5%) whereas the risk of ovarian cancer is about 1 in 50 (2%). However, heritable, highly penetrant germline mutations such as BRCA1/2, which are associated with significantly increased risk of cancer are estimated to account for only 5-10% of breast cancers and around 10% of ovarian cancers overall.

Ms. Jolie’s situation might currently be a high profile story, but the majority of breast and ovarian cancer cases that occur in the general population are not the result of an inherited mutation in the BRCA1 or BRCA2 genes, although with around 1 in 900 women carrying a BRCA1 mutation and 1 in 450 a BRCA2 carrier, it is a fairly common occurrence.

The importance of genetic testing is highlighted by a much greater risk of getting cancer for those with a BRCA1/2 mutation for breast cancer (60-90% for BRCA1 and 45-85% for BRCA2) and ovarian cancer (10-15% for BRCA1 after age 40 and 5-10% for BRCA2 after age 50). These risks are different for each woman, as illustrated by Ms. Jolie’s estimated risk of 87% of breast cancer and 50% of ovarian cancer.

These figures highlight the importance of genetic testing for BRCA1/2 mutations in women with a moderate to high probability risk based on family history. Current NICE guidelines on familial breast cancer state that women with 20% probability of carrying a BRCA mutation are eligible for the genetic test – a figure set to halve to 10%.

It must also be noted that even with a strong family history of breast or ovarian cancer, not every woman in such families carries a harmful BRCA1/2 mutation, and not every instance of cancer within such families is linked to a harmful BRCA mutation. What’s more, not every woman who has a harmful mutation will develop breast and/or ovarian cancer.

The options

Ms. Jolie’s op-ed highlights that the most important result of genetic testing for women who do have an inherited mutation is the ability to make informed treatment decisions.

NICE guidance indicates that women who are known BRCA1 and BRCA2 mutation carriers aged 30–49 years should be offered annual MRI. It also states that risk-reducing surgery, bilateral mastectomy and/or bilateral salpingo-oophorectomy (removal of the ovaries) is appropriate only for a small proportion of women who are from high-risk families.

Bilateral risk-reducing mastectomy has been shown to reduce the risk of breast cancer by approximately 90-95%, whereas prophylactic ovary removal has been demonstrated to reduce ovarian cancer risk in BRCA1/2 carriers by up to 96%. This procedure – which is much less invasive and traumatic than a bilateral mastectomy – is also associated with a reduction in lifetime breast cancer risk of approximately 50%. The risk reduction following both procedures is so dramatic that the risk of developing breast or ovarian cancer is reduced to below the average risk and further screening is not required.

The hunt for other mutations and treatments

BRCA1 and 2 are not the only genes where hereditary mutations increase a woman’s risk of (breast) cancer, there are others such as inherited mutations in TP53, accounting for around 1% of breast cancers, and the rarer inherited PTEN and STK11 mutations, together mutations in these five genes account for less than 25% of the familial risk of breast cancer. The remainder of the familial risk of breast cancer is likely to be the result of mutations in several genes, each with a small effect but in combination and environmental factors significantly altering breast cancer risk, necessitating further research, development of genetic tests and treatments aligned to address these.

Aridhia’s work at the Stratified Medicine Scotland Innovation Centre, and the Decipher Health project, is very closely aligned to this work. Both aim to integrate clinical records with information from the patient’s own genome sequence. This is different from a specific gene test currently available on the NHS because it creates a record of the whole genome. It also allows research to perform statistical analysis on massive datasets of linked clinical and “omic” data. Over time, links between response rates and specific variations of genomes can be better understood and as a result, allow identification of subgroups which are more or less likely to respond well to particular treatments.

The aim is to find efficient ways of introducing high-quality, inexpensive genetic testing routinely into the NHS, to support lifesciences companies to develop new diagnostic tests, and pharmaceutical companies to develop new targeted drugs.

There is a growing sense of excitement that cancer treatment paradigms are about to change for good. If, by working collaboratively, we can gain greater insights into how to test and treat patients like Angelina Jolie, we’ll benefit both the individual patient and clinical research.