Although cancer is not usually inherited, certain types, including breast and ovarian, can be triggered by inherited gene faults, meaning they can run in families. Now that we can test for these mutations, could – and should – we be testing as many people as possible to identify those at higher risk? Isy Godfrey spoke with Beth Torr, Scientific Programme Manager in Cancer Genetics, to find out.
Our mission at The Institute of Cancer Research, London – to defeat cancer – is not a simple one. Cancer is a highly complex condition that can be driven by genetic, environmental and lifestyle factors. There are more than 200 different types, and it can affect any part of the body. What’s more, each case of cancer is unique, so treatments that work for one person may not work for another – even if they are the same age and sex, with the same cancer type.
The long-term goal is to have such a wide range of effective, targeted treatments at our disposal that we can treat all cancers – at least those caught early enough. Until then, one of the best ways to save lives is to prevent the disease from developing in the first place.
Although people can take steps to reduce their risk of cancer, the disease is never fully preventable, which means it can affect anyone. So, prevention is also a significant challenge. However, it is possible to identify some of the people who have additional known risk factors for cancer and intervene to reduce their likelihood of developing the disease.
Common risk factors include certain genetic alterations known as cancer driver mutations. These occur in genes with various roles, including DNA repair and tumour suppression. Examples of genes that can drive cancer when they are mutated include TP53, KRAS and EGFR.
These names may not be familiar to everyone. However, many people are likely to be aware of the BRCA1 and BRCA2 genes (BReast CAncer 1 and 2) thanks to media coverage and celebrities such as Angelina Jolie talking about their personal experiences.
Why are the BRCA genes so important?
BRCA1 was identified in 1994, and researchers at The Institute of Cancer Research (ICR) identified BRCA2 a year later. Mutations in both genes were originally linked to breast cancer, but they can also increase the risk of other cancer types, including ovarian, pancreatic and prostate.
It is possible to check people’s BRCA genes to find out whether they have inherited a harmful gene fault that increases their risk of cancer. Armed with this knowledge, a person can be more alert to changes in their body and ensure that they seek medical advice immediately for any new symptoms.
This is particularly important in ovarian cancer, which often goes undetected until the later stages because its early symptoms overlap with those produced by conditions such as urinary tract infections and irritable bowel syndrome. Once ovarian cancer has progressed and spread, it is much more difficult to treat and, as a result, it is much more likely to be fatal. There are also no reliable screening programmes for the disease.
People who are identified to have an inherited gene fault in the BRCA genes may also be offered preventive surgery to significantly reduce their risk – for instance, a bilateral mastectomy to remove both breasts or a bilateral salpingo-oophorectomy (BSO) to remove the ovaries and fallopian tubes. Whatever course of action they decide on, the knowledge of their increased risk gives them options.
The results are also useful for healthcare professionals. They can inform treatment decisions, as inherited BRCA gene faults can make cancer respond better to certain treatments, such as platinum-based chemotherapy.
What’s more, in contrast to 30 years ago – when these genes were first identified, and testing them took months or years – the BRCA gene test is now technically a relatively straightforward procedure requiring little preparation. A healthcare professional takes a sample of blood or saliva or performs a cheek swab to collect some cells. DNA extracted from the sample is then analysed to check for harmful gene faults in BRCA1 or BRCA2. The most time-consuming part is the clinical consultation to make sure that the patient having the test has all the information required to provide informed consent.
Why are we not offering BRCA gene testing to everyone in the UK?
Currently, across the UK, the NHS only offers testing to people with a high likelihood of having an inherited gene fault, based on their personal diagnosis of a relevant cancer and a very strong family history of a relevant cancer.
There are two main reasons why not everyone can and should undergo BRCA gene testing. Firstly, only about one in every 250 people in the UK have a BRCA gene fault. Although it would be reassuring for the other 249 people to learn that their BRCA genes are unaffected, this knowledge won’t change their likelihood of getting cancer. It is also difficult to justify testing that many people for a relatively low number of actionable results.
Secondly, this type of test is not suitable for everyone. Some people might prefer not to know that they – and potentially their children and other blood relatives – have an increased genetic risk of cancer, which can cause anxiety and have other effects on mental health. For this reason, it is recommended that people undergo genetic counselling before making a decision about the test.
However, access to clinical professionals and capacity for genetic counselling act as barriers to expanding testing. Beth Torr, Scientific Programme Manager in the Translational Genetics Group at the ICR, explained:
“Historically, laboratory testing was labour-intensive and slow, and the costs were high. Now, although there’s much better capacity and the tests are cheaper, the clinical pathways are still a limiting factor. The current pathway requires everyone to undergo both pre- and post-test genetic counselling, which means we can’t make BRCA gene testing cost-effective for the general population.”
Can we expand BRCA gene testing at all?
Researchers at the ICR recently completed a BRCA gene testing study called BRCA-DIRECT, which they designed to evaluate whether a new patient-centred pathway could help expand testing capacity and reduce the turnaround time for results.
The team divided the participants – all of whom had received a diagnosis of high-grade ductal carcinoma in situ (DCIS) or invasive breast cancer – into two groups. While those in the first group had the standard pre-test genetic counselling consultation, those in the second group received their pre-test information on a newly created digital platform. The platform also included documentation of consent, postal saliva sampling, return of negative results and access to a genetic counsellor hotline.
The findings, which were published in the British Journal of Cancer, showed that the digital platform was a viable alternative to conventional genetic counselling, producing similar outcomes in terms of patient knowledge, anxiety and satisfaction. In addition, the 37 healthcare professionals who provided feedback on the pathway all ‘agreed’ or ‘agreed strongly’ that all aspects of the pathway were equivalent to or better than the current one.
Beth said: “Our study showed that it’s both feasible and acceptable to use this patient-directed pathway, with standardised pre-test information about genetic testing, to allow more people to undergo testing. In a follow-up pilot project at the North Thames Genomics Laboratory Hub, the pathway has been implemented as the ‘standard of care’, and the feedback from breast units has been really encouraging. It’s great to see that the pathway has not only ensured better accessibility and inclusivity but also brought testing into more mainstream oncology units and conversations.”
Who would benefit most from testing?
These BRCA gene faults are heritable, which means they run in families. As not everyone with these faults goes on to develop cancer, they can pass down through several generations without affecting anyone. However, their hereditary nature means that these faults are more common within some communities than in others.
People with Jewish heritage are particularly at risk, with as many as one in 40 people affected in certain populations. Researchers have managed to demonstrate that more than 90 per cent of the BRCA gene faults among Jewish people are one of three ‘founder mutations’, which likely first occurred more than 500 years.
The significantly higher incidence of BRCA gene faults among these groups justifies a targeted BRCA gene testing programme. Until recently, there was no workable infrastructure by which to deliver community-based genetic testing. However, thanks to the pioneering BRCA-DIRECT study, a new NHS-run testing programme became a possibility. The Jewish BRCA Programme has been established to make testing available to people with Jewish ancestry across England. It will be delivered by the North Thames Genomics Laboratory Hub at The Royal Marsden Hospital.
Beth Torr is involved, alongside Professor Clare Turnbull, Professor of Translational Cancer Genetics at the ICR and Chief Investigator for the BRCA-DIRECT study. Beth explained the link:
“We are deploying a very similar pathway to BRCA-DIRECT. The main difference is that the participants in the NHS Jewish BRCA Testing Programme are out in the community while those in the BRCA-DIRECT programme were at a hospital undergoing diagnosis, treatment and/or follow-up for a breast cancer diagnosis. Many elements of the pathway are similar, though, including the home-based saliva testing, the provision of multiple information resources and the genetic counselling expert telephone hotline.”
The aim of this programme is to test 30,000 people with Jewish ancestry, as they have the highest chance of having a BRCA gene fault. Jnetics and Chai Cancer Care – two community-specific charities – are helping by raising awareness of the programme and managing ongoing engagement with the community.
Researchers will use modelling tools to determine the long-term impact of this wide-scale testing on early diagnosis and prevention. As the first programme of this kind to be provided by the NHS in England, the project will also provide baseline data on important statistics, such as uptake, resource requirements, patient satisfaction and impact on downstream services.
The data from the first year of the programme were recently published in the Journal of Medical Genetics. These showed that 2.3 per cent of the 4,274 returned samples revealed an inherited, harmful BRCA gene mutation, which is in line with previously reported figures from Jewish population testing. Over the period, 827 calls were made to the programme hotline – 557 for administrative purposes and 270 for genetic counselling.
If this programme proves successful in the longer term, it could set a precedent for how we approach BRCA gene testing more widely in the UK going forwards.
How is BRCA gene testing likely to look in the future?
Although the BRCA-DIRECT study showed that it was feasible to offer expanded testing using a more efficient digital pathway, BRCA gene testing does still require resources, placing a burden on healthcare providers. So, any roll-out of these programmes must consider these implications in the short-to-medium term.
To date, there is not enough evidence to confirm that BRCA gene testing reduces overall mortality rates. This may be due to the historical limitations on genetic testing or the relatively low number of people affected, but it does indicate that the extent to which testing is implemented needs to be weighed carefully against the likely benefits.
Beth agreed that there are multiple factors to consider. She said: “Offering people the choice for testing, particularly if they have concerns about their family history, can be reassuring for people, and it empowers them by giving them access to more options. Most of the BRCA-DIRECT participants, who had a personal diagnosis of breast cancer, said they were testing because of family members, so for someone with a family history of cancer, a negative result can help alleviate concerns.
“I do think we have to be cautious in not over-emphasising the power of expanding testing, but at least for BRCA1 and BRCA2 genes, there is more of an argument for testing given we know we are not currently identifying everyone for whom interventions can be beneficial. The biggest area of evidence for impact is around prevention of cancers due to surgical intervention. We have also observed a stage shift in cancer diagnoses.”
Overall, she is optimistic that expanding BRCA gene testing will be beneficial.
“I’m really proud of our work,” she said. “From early data in the current pilot, we’ve found the pathway implemented to be cost-effective overall for offering expanded testing to people diagnosed with breast cancer, and it is identifying people with BRCA gene faults who would otherwise not be eligible for testing. I hope that the pathway we created can allow more potentially at-risk individuals to access BRCA gene testing. I believe that once increased numbers of people are undergoing testing, we could see an effect on survival. And that really is our ultimate goal – to extend and save as many lives as possible.”
Our research is helping more women survive ovarian and breast cancer. Please donate today and support the vital work our scientists are doing to defeat cancer.
Image credit: Melissa from Pixabay