How BRCA research could lead to new ways to prevent breast cancer

by Sydney Ghazarian

Microscopic image of human breast tissue from stained to visualise different cell markers against a black background. Microscopic image of human breast tissue from stained to visualise different cell markers against a black background.

Dr Sara Pensa, University of Cambridge

Dr Sara Pensa, University of Cambridge

Researchers’ discovery of the BRCA genes, BRCA1 and BRCA2, has allowed us to think differently about cancer.

When the genes were discovered over 30 years ago, scientists finally had the evidence to explain why sometimes breast cancer appeared to run in families. And now, thanks to BRCA testing, doctors can spot people with a higher risk of developing breast cancer and diagnose them earlier, when treatment is most likely to be successful.

But, despite all this progress, doctors still don’t have many options for preventing breast cancers linked to BRCA gene changes.

“At the moment, the only really available options for individuals that are known to be at high risk of breast cancer are surgical,” explains Professor Walid Khaled, a Cancer Research UK-funded BRCA expert at Cambridge University.

Having a mastectomy, or the surgical removal of one or both breasts, is currently the most effective way to prevent breast cancer in people who have a high risk because of BRCA mutations.

Choosing to have a mastectomy, however, can be a difficult decision. As they’ve discussed their work with women who have BRCA gene mutations, Khaled and his colleagues have found that many want ways of reducing their cancer risk without changing their bodies. So, Khaled’s team have dedicated themselves to finding new options.

Microscopic image of human breast tissue from stained to visualise different cell markers against a black background.

Dr Sara Pensa, University of Cambridge

Dr Sara Pensa, University of Cambridge

The search for the earliest signs of breast cancer

Khaled’s research focuses on understanding how BRCA mutations alter cells at the molecular level. One of his goals is to pinpoint the earliest signs of cancer and find ways to intervene before it takes hold.

His work began 10 years ago in mouse models, where he looked at how faulty BRCA genes impacted their cells before they developed cancer.

The mice had distinct changes in their breast tissue early on in their lives that could be linked to breast cancer.

Then, Khaled went looking for similar changes in people through the Human Breast Cell Atlas project. As the project’s co-lead, he and his team mapped out the different types of cells in human breast tissue and identified key changes in the cells of people with BRCA mutations.

“What was really interesting,” Khaled says, “is that you could see a lot of the changes that we saw in the mouse models were also happening in the human tissue.”

One change he saw was something called immune cell exhaustion. This is when immune cells try to mount an attack against abnormal or dangerous cells, but for various reasons, are unable to.

“We were surprised because this is normally associated with late-stage tumours, but it seems like it's happening quite early in these high-risk individuals.”

Now that he’s identified the cellular changes that accompany faulty BRCA genes, Khaled and his team are looking for drugs that could treat or prevent them in the first place.

Walid Khalid smiling in front of a blurred background. He's wearing a tan blazer, pink button-down shirt, white Cancer Research UK lanyard and silver-framed glasses.

Professor Walid Khaled

Professor Walid Khaled

The search for the earliest signs of breast cancer

Khaled’s research focuses on understanding how BRCA mutations alter cells at the molecular level. One of his goals is to pinpoint the earliest signs of cancer and find ways to intervene before it takes hold.

His work began 10 years ago in mouse models, where he looked at how faulty BRCA genes impacted their cells before they developed cancer.

Walid Khalid smiling in front of a blurred background. He's wearing a tan blazer, pink button-down shirt, white Cancer Research UK lanyard and silver-framed glasses.

Professor Walid Khaled

Professor Walid Khaled

The mice had distinct changes in their breast tissue early on in their lives that could be linked to breast cancer.

Then, Khaled went looking for similar changes in people through the Human Breast Cell Atlas project. As the project’s co-lead, he and his team mapped out the different types of cells in human breast tissue and identified key changes in the cells of people with BRCA mutations.

“What was really interesting,” Khaled says, “is that you could see a lot of the changes that we saw in the mouse models were also happening in the human tissue.”

One change he saw was something called immune cell exhaustion. This is when immune cells try to mount an attack against abnormal or dangerous cells, but for various reasons, are unable to.

“We were surprised because this is normally associated with late-stage tumours, but it seems like it's happening quite early in these high-risk individuals.”

Now that he’s identified the cellular changes that accompany faulty BRCA genes, Khaled and his team are looking for drugs that could treat or prevent them in the first place.

The challenge with prevention trials

The search for preventative treatments comes with many challenges, but some of the biggest ones lie in how drugs are tested through clinical trials.

Researchers need to test how safe and effective a drug is by giving it to people who could benefit.

When it comes to a prevention clinical trial, this means giving the drug to someone who is at a higher risk of cancer but is currently cancer-free.

In other words, Khaled says, “You’re going to give the drug to someone who’s healthy.”

That can be risky — there’s a chance the drug could cause difficult, unpredictable side effects for a person who may never have developed cancer anyway.

So, instead of looking for new drugs, some researchers are turning their attention towards ones that are already approved, or nearly approved, for other uses. By repurposing drugs that have already been tested for safety, researchers can minimise the risks to participants. 

Based on Khaled’s research, one option could be to adapt immunotherapy drugs, which are currently used to treat advanced cancers, to "wake up" exhausted immune cells in people with BRCA changes.

But, as intriguing as that might be, it's still a long way off. Today's immunotherapies come with too many risks to be used preventatively, so researchers will have to work out if smaller, less frequent doses can help the immune system prevent cancer without causing serious side effects.

And even when the risk of side effects is minimised, Khaled explains that finding people to join a clinical trial to test a preventative treatment can still be a challenge.

“Let's say you tell BRCA carriers, ‘We want to run a trial that’ll run for 10 years. You're going to be on this drug, and we don't know if it's going to work, and you still might have a risk of getting cancer. Are you okay with that?’”

Because clinical trials can take years of study, researchers need participants to remain in the trials for long periods of time. And during that time, participants can’t seek other preventative treatments that could potentially interfere with the study, like mastectomies, unless they drop out.

“This a very difficult conversation to have with someone and it's a very difficult decision for them to make,” says Khaled.

But sometimes, researchers can (quite literally) find a window of opportunity that doesn’t interfere.

Microscopic image of human breast tissue from stained to visualise different cell markers against a black background.

Dr Sara Pensa, University of Cambridge

Dr Sara Pensa, University of Cambridge

The challenge with prevention trials

The search for preventative treatments comes with many challenges, but some of the biggest ones lie in how drugs are tested through clinical trials.

Researchers need to test how safe and effective a drug is by giving it to people who could benefit.

When it comes to a prevention clinical trial, this means giving the drug to someone who is at a higher risk of cancer but is currently cancer-free.

In other words, Khaled says, "You're going to give the drug to someone who's healthy."

That can be risky — there’s a chance the drug could cause difficult, unpredictable side effects for a person who may never have developed cancer anyway.

Microscopic cross section of a breast tumour showing blue, green, and red cells against a black background.

Section of breast tumour.

Section of breast tumour.

So, instead of looking for new drugs, some researchers are turning their attention towards ones that are already approved, or nearly approved, for other uses. By repurposing drugs that have already been tested for safety, researchers can minimise the risks to participants. 

Based on Khaled’s research, one option could be to adapt immunotherapy drugs, which are currently used to treat advanced cancers, to "wake up" exhausted immune cells in people with BRCA changes.

But, as intriguing as that might be, it's still a long way off. Today's immunotherapies come with too many risks to be used preventatively, so researchers will have to work out if smaller, less frequent doses can help the immune system prevent cancer without causing serious side effects.

And even when the risk of side effects is minimised, Khaled explains that finding people to join a clinical trial to test a preventative treatment can still be a challenge.

“Let's say you tell BRCA carriers, ‘We want to run a trial that’ll run for 10 years. You're going to be on this drug, and we don't know if it's going to work, and you still might have a risk of getting cancer. Are you okay with that?’”

Because clinical trials can take years of study, researchers need participants to remain in the trials for long periods of time. And during that time, participants can’t seek other preventative treatments that could potentially interfere with the study, like mastectomies, unless they drop out.

But sometimes, researchers can (quite literally) find a window of opportunity that doesn’t interfere.

A window of opportunity

Under the right circumstances, researchers can run something called a window trial. These types of clinical trials run for weeks rather than years, giving researchers a chance to see the effects of a drug before they commit to a longer-term study.

“So that means you're not going to necessarily change the trajectory that the patient is going to go on anyway, but it gives you an opportunity to test something within that trajectory,” explains Khaled.

And this was the case for one window trial Khaled helped work on, which was led by another Cancer Research UK-funded researcher, Dr Sacha Howell.

The team wanted to test whether ulipristal acetate (UA), a drug currently used as an emergency contraceptive and to treat fibroids, could help reduce people’s risk of developing breast cancer.

UA blocks the effects of progesterone, a hormone that may help certain cells linked to breast cancer grow. To quickly investigate how it might work, the team recruited a small group of women with a family history of breast cancer and denser breast tissue to take part in a trial called BC-APPS1.

The women on the trial took daily UA tablets for 12 weeks. By comparing breast tissue samples taken before and after treatment, the team found that UA reduced breast density in some women, which suggests it has the potential to lower cancer risk over time.

“That trial was really important, because it showed that these types of trials can be run safely and you can see an outcome that is quite meaningful,” says Khaled.

Although window trials themselves are not new, Khaled believes that Howell’s innovative ‘window prevention’ approach could make it easier to run more full-length trials that could help change how we deal with cancer risk.

“It tackles the problem with most prevention trials, which is how do you know that the treatment’s working without having to wait?”

Mammogram scan showing scan of both breasts side by side.

SimoneN/Shutterstock

SimoneN/Shutterstock

Microscopic image of human breast tissue from stained to visualise different cell markers against a black background.

Dr Sara Pensa, University of Cambridge

Dr Sara Pensa, University of Cambridge

A window of opportunity

Under the right circumstances, researchers can run something called a window trial. These types of clinical trials run for weeks rather than years, giving researchers a chance to see the effects of a drug before they commit to a longer-term study.

“So that means you're not going to necessarily change the trajectory that the patient is going to go on anyway, but it gives you an opportunity to test something within that trajectory,” explains Khaled.

And this was the case for one window trial Khaled helped work on, which was led by another Cancer Research UK-funded researcher, Dr Sacha Howell.

Mammogram scan showing scan of both breasts side by side.

SimoneN/Shutterstock

SimoneN/Shutterstock

The team wanted to test whether ulipristal acetate (UA), a drug currently used as an emergency contraceptive and to treat fibroids, could help reduce people’s risk of developing breast cancer.

UA blocks the effects of progesterone, a hormone that may help certain cells linked to breast cancer grow. To quickly investigate how it might work, the team recruited a small group of women with a family history of breast cancer and denser breast tissue to take part in a trial called BC-APPS1.

The women on the trial took daily UA tablets for 12 weeks. By comparing breast tissue samples taken before and after treatment, the team found that UA reduced breast density in some women, which suggests it has the potential to lower cancer risk over time.

“That trial was really important, because it showed that these types of trials can be run safely and you can see an outcome that is quite meaningful,” says Khaled.

Although window trials themselves are not new, Khaled believes that Howell’s innovative ‘window prevention’ approach could make it easier to run more full-length trials that could help change how we deal with cancer risk.

“It tackles the problem with most prevention trials, which is how do you know that the treatment’s working without having to wait?”

Looking beyond BRCA

Khaled hopes that his research will lead to more studies like Howell’s window trial. But for now, he's testing eight potential therapeutics in mouse models thanks to funding from Cancer Research UK Biology to Prevention Awards.

“Once we know which ones that we want to pursue, we’ll go for these window trials. And I think that will open up the opportunity to run longer-term prevention studies.”

These long-term trials also have the potential to help others with a higher risk of breast cancer, like those with changes to a gene called PALB2, and even those with an average level of cancer risk.

“The accelerated changes that are happening in BRCA carriers might also be happening in the general population, but at a slower pace.”

“Rather than people having more mutations, the problem could be that the mechanisms that hold mutated cells back from becoming cancers are getting tired, which might explain why ageing is a major risk for all cancers”

In their own way, BRCA genes are a window scientists can look through to understand cancer risk. And, three decades since they were discovered, Khaled is hopeful that researchers are close to finding new ways of preventing BRCA-linked breast cancer without the need for surgery.

“We might not be able to completely eliminate the risk, but I think we might at least be able to offer an alternative option to surgery. That would be amazing.”

Microscopic image of human breast tissue from stained to visualise different cell markers against a black background.

Dr Sara Pensa, University of Cambridge

Dr Sara Pensa, University of Cambridge

Looking beyond BRCA

Khaled hopes that his research will lead to more studies like Howell’s window trial. But for now, he's testing eight potential therapeutics in mouse models thanks to funding from Cancer Research UK Biology to Prevention Awards.

Microscopic image of cell sample from BRCA2 mouse model showing blue and red cells against a black background.

Sample from BRCA2 mouse model, with cells missing the BRCA2 gene shown in red. Photo taken by Julius Schmiegelow, PhD student at Cambridge Universtiy.

Sample from BRCA2 mouse model, with cells missing the BRCA2 gene shown in red. Photo taken by Julius Schmiegelow, PhD student at Cambridge Universtiy.

“Once we know which ones that we want to pursue, we’ll go for these window trials. And I think that will open up the opportunity to run longer-term prevention studies.”

These long-term trials also have the potential to help others with a higher risk of breast cancer, like those with changes to a gene called PALB2, and even those with an average level of cancer risk.

“The accelerated changes that are happening in BRCA carriers might also be happening in the general population, but at a slower pace.”

“Rather than people having more mutations, the problem could be that the mechanisms that hold mutated cells back from becoming cancers are getting tired, which might explain why ageing is a major risk for all cancers”

In their own way, BRCA genes are a window scientists can look through to understand cancer risk. And, three decades since they were discovered, Khaled is hopeful that researchers are close to finding new ways of preventing BRCA-linked breast cancer without the need for surgery.

“We might not be able to completely eliminate the risk, but I think we might at least be able to offer an alternative option to surgery. That would be amazing.”

Gillian's story

Gillian (right) with her daughter, Gaby (left).

Gillian (right) with her daughter, Gaby (left).

One year after her mother died of breast cancer, Gillian was diagnosed with breast cancer herself at 38, and later with ovarian cancer.

Following her surgery and treatment, she tested positive for the BRCA1 gene mutation.

“I was told there’s a very slim chance of the ovarian cancer coming back but because of the gene fault I’ve got quite a high risk of the breast cancer returning.”

After many years weighing up the risks and benefits, Gillian ultimately made the difficult decision to have preventative surgery – a double mastectomy with reconstruction.

She hopes Khaled’s research could offer alternative treatment options to others, including her daughter Gaby, who also tested positive for the BRCA1 gene mutation.

“This research sounds amazing and would be a real gamechanger for BRCA1 gene carriers. The potential for less invasive prevention options makes me feel so happy to think that in the future women may not have to make the difficult choice – with all the emotions that it entails –  of whether to opt for risk-reducing surgery.”

Microscopic image of human breast tissue from stained to visualise different cell markers against a black background.

Dr Sara Pensa, University of Cambridge

Dr Sara Pensa, University of Cambridge

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