Mammography is currently used to detect breast cancer

Earlier this week, the news was full of stories about a ‘blood test’ that can apparently predict a woman’s risk of breast cancer, years before she develops the disease.

This sounds exciting. Being able to work out someone’s risk of cancer well in advance of developing the disease could be incredibly powerful.

People at higher risk could take extra steps to change their lifestyle, be offered extra screening or other monitoring, or even take drugs to prevent the disease.

But how valid are these claims? How would such a test work? What’s the science behind it? And how does it fit into the bigger picture of breast cancer prevention and detection?

We’ve been poring over the research paper that led to the headlines, and spoke to Imperial College’s Dr James Flanagan, the researcher who led the study together with Cancer Research UK’s Professor Robert Brown – to get his take on it.

The bottom line is the ‘test’ reported here is more of a proof-of-concept than a fully developed ‘cancer blood test’.

The principles that underpin the research are definitely promising, and suggest that in future the way we understand a person’s cancer risk (and what we do with this info) will be much more sophisticated.

But there’s a long way to go before a clinically useful test can be built from these findings.

Let’s take a look at how it all fits together.

Cancer risk, gene faults, and genetic variation

Cancer is ultimately caused by faults in the genes in our DNA that cause cells to multiply out of control.

For much of the last half-century, cancer researchers have been trying to understand how these faulty genes cause cancer, and how to use this knowledge to prevent and detect the disease.

Because of this research, people with multiple cases of cancer in their family can now be tested for rare faults in genes like BRCA1, BRCA2 and APC – faults that are known to substantially increase a person’s chances of cancer. Carriers can be offered extra screening or other treatments, and this has undoubtedly saved many lives.

But, crucially, only a small proportion of people who develop cancer do so because of an inherited gene fault. So researchers have been looking for common, more subtle genetic differences that explain why some people are more likely to develop cancer.

These efforts have borne fruit, and researchers are now beginning to paint a detailed picture of scores of tiny, common, genetic variations between individuals, each of which seems to cause a small change in risk, but which can add up to something more significant.

All of us carry some of these variations – precisely which ones we carry, and how many, plays a role in our chances of developing cancer later in life.

But this is very much work in progress, and this picture isn’t yet complete. And we don’t fully understand precisely how these variations influence a person’s risk, how they interact with lifestyle factors like smoking or obesity, or why some variations are linked to certain types of cancer.

And unlike testing for faulty genes, tests that can accurately predict a person’s cancer risk based on genetic variation are still some years away.

On top of this, researchers are still trying to work out whether offering people more or less screening, monitoring, or other treatments, based on these subtle variations in their DNA, actually saves lives.

Nevertheless, both these types of test look for changes in our DNA sequence – the code that contains information about how to make proteins.

But over the last few decades, it’s become apparent that on top of our DNA lies a whole extra layer of information – so-called ‘epigenetic’ information. And it’s this that Dr Flanagan’s team – in particular, PhD student Kevin Brennan – has been studying

DNA molecules are like a twisted ladder

Beyond our DNA

DNA molecules are long, twisted ladder-like molecules that live in the nucleus of each of our cells. Before a gene in our DNA can be activated, (i.e. the information on the ‘rungs’ of the ladder are ‘read’), one or more proteins first needs to stick to the outside of the DNA ladder to physically untwist it.

Cells carefully control which genes are active (i.e. which bits of the ladder are ‘untwisted’) at any given point in time by adding tiny chemical ‘tags’ to the DNA, known as epigenetic markers.

Some tags – called methyl groups – attract clusters of proteins that keep the DNA ladder tightly closed, meaning that genes can’t be switched on. The process of adding these methyl groups is known as methylation.

Scientists studying DNA methylation have discovered that it tends to occur in clumps along the length our DNA, and that these patterns are copied from cell to cell as they divide.

Researchers have also found evidence that exposure to various things over the course of our lives can influence our epigenetic patterns – things like tobacco smoke, radiation, alcohol and diet.

And they’ve also discovered that these patterns go completely, catastrophically awry in cancer. This allows cancer cells to turn on genes that should be off (and vice versa), and grow and divide out of control.

Putting all this together raises an interesting question. Can looking at these epigenetic patterns before cancer develops – and at differences in these patterns between individuals – yield any clues about a person’s chances of subsequently developing the disease?

Epigenetics and cancer risk

Several studies in recent years have suggested that the answer could be yes. For example, in 2008, blood samples from bladder cancer patients in a Spanish study were found to have different methylation patterns from people without the disease. And last year, a US study, also of bladder cancer, found a similar thing .

One important point about all these studies is that they looked at DNA from white blood cells – the cells of our immune systems. But although the immune system is heavily involved in cancer (as we’ve blogged about before), this wasn’t why researchers looked here. It was because they had no choice – the red cells in our blood don’t contain any DNA. In Dr Flanagan’s words, “they’re all we can get our hands on for this type of research”.

In 2009, Dr Flanagan’s team published results of a study of methylation patterns in the DNA from breast cancer patients’ white blood cells. They looked at epigenetic ‘tags’ on a whole range of genes involved in cancer, and found that one gene in particular seemed to be methylated in patients but not in women without the disease – a gene called ATM, which is known to be involved in several types of cancer.

But despite these tantalising results, a glaring weakness in all of the studies to date has been that they looked at the blood of people who already had cancer.

Cancer – and its treatment – can cause all sorts of changes to our bodies, so no-one could be sure that these epigenetic differences were caused by the cancer itself, or whether they’d existed before. So it wasn’t clear whether epigenetic markers could help predict a person’s risk.

Prospective studies

To try to address these flaws, with funding from Breast Cancer Campaign and Cancer Research UK, Dr Flanagan’s team turned to three large forward-looking (or ‘prospective’) studies – the European Prospective Investigation into Cancer (EPIC), the UK’s Breakthrough Generations Study, and the Australian KConFab study. These studies have been running for several years, collecting blood samples from healthy people, and following what subsequently happened to them.

This allowed Dr Flanagan’s team to identify women on these studies who had developed breast cancer, and then to go back and analyse blood samples taken many years before they were diagnosed.

The researchers identified 640 women who developed breast cancer in the three studies, and Brennan painstakingly measured whether the ATM gene in each of their blood samples was methylated.

They then repeated the process on a similar number of women on the studies who didn’t have breast cancer. And then, with the assistance of The Institute of Cancer Research’s genetic epidemiologist, Professor Montse Garcias-Closas, they put all their results into a computer to crunch the numbers.

They found that women who had the highest levels of methylation in the ATM gene in their white blood cells were nearly twice as likely to have subsequently developed breast cancer. And the effect was even more apparent in younger women. But it’s important to point out: not every women who had a methylated ATM gene developed breast cancer, and not every women who developed breast cancer had a methylated ATM gene.

What does all this mean?

According to Dr Flanagan, this is the first study with sufficient size and rigour to be able to find a definite link between an epigenetic marker in the blood and cancer risk.

“To be honest, most of the previous studies to try to look at this have been too small – we haven’t been able to measure this with any certainty,” he told us, adding “but this isn’t a ‘blood test’ yet. We need to look at how this fits in with other factors”.

How could this finding be used to help patients in future? Currently, people are offered cancer screening based on their age. But many researchers think that this ‘one-size-fits-all’ approach won’t last forever, and one day genetic testing will be used to offer people more tailored screening.

Dr Flanagan thinks that, in future, epigenetics could also help determine from what age, and how often, women should be offered screening. “That’s absolutely where we’re heading with this research,” he said, “but we’re not there yet.”

Next, Flanagan plans to look at how these epigenetic markers affect risk in people with different DNA variations, and he plans to collaborate with researchers at the Institute of Cancer Research to do so. Another plan is to look at the type of breast cancer women with methylated ATM genes develop, and to look in detail at the type of white blood cells that contain these modifications, to find clues as to how this marker actually increases risk.

So some of the media reports of an imminent ‘blood test’ that can “predict a woman’s breast cancer risk” were wide of the mark. Although it’s early days, this research suggests that epigenetic markers that can be measured in our blood – along with variations in our DNA – are a significant piece of the complex and fascinating jigsaw puzzle that is cancer risk.

Henry

Reference:

• Brennan, K. et al (2012). Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk Cancer Research, 72 (9), 2304-2313 DOI: 10.1158/0008-5472.CAN-11-3157

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This month, we hear how a landmark study could revolutionise breast cancer treatment, and take a look at the growing evidence on aspirin and cancer.

We also hear how obesity may be driving rises in kidney and womb cancer rates, while smoking patterns of the past mean that lung cancer continue to rise in women.

Plus, scientists develop the first snap-shot of tiny brain tumours, and we talk to Stephanie Moore MBE about how treatment for bowel cancer has changed since her husband, footballer Bobby Moore, died from the disease.

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We hope you enjoy it – please do let us know what you think of the podcast in the comments below, or email us at podcast@cancer.org.uk.

Kat

Lots in the news this week

• A major Cancer Research UK study published this week could revolutionise the way women with breast cancer are diagnosed and treated in the future. It reclassifies the disease into 10 completely new categories based on their genetic make-up. We’ve got an extensive analysis of the paper on the blog. And watch our chief executive Harpal Kumar and study leader Carlos Caldas talk about the implications of the study.

• Another big study funded by us – this time a bladder cancer trial – showed that patients given low doses of chemotherapy with radiotherapy are nearly 50 per cent less likely to relapse with the most lethal form of the disease compared to those given radiotherapy alone. This could mean fewer patients need their bladder removed and provides an alternative for frailer patients who are too weak for surgery.

• The government launched a public consultation on plain packaging of cigarettes on Monday. The idea is to standardise all packaging to ensure children are protected from the ‘silent salesman’ of branded packs, and give them one less reason to start smoking. A YouGov poll found strong public support for the policy. The BBC has a nice video feature about the consultation.

• An experimental sound-wave treatment for certain types of prostate cancer may have fewer side effects than current therapies, according to new UK research published on Tuesday. It’s fascinating and encouraging research, but we’ll have to wait for the results of much larger trials before current clinical practice is changed.

• We launched a new partnership with the Royal Collage of GPs to improve cancer diagnosis and care in general practice. The programme aims to develop ways to help doctors confidently diagnose more cancers at an earlier stage, which should save more lives from the disease.

• Bringing in a minimum price of 40 pence per unit of alcohol could cut deaths and hospital admissions, according to a UK economist. We know that about 12,500 cases of cancer in 2010 were down to alcohol, so welcome the introduction of minimum pricing as part of a wider strategy to reduce the consumption of alcohol and help prevent cancer.

• A new ‘nanoparticle’-based imaging technique could improve the accuracy of brain tumour surgery, according to lab work by US scientists.

• A team of Cancer Research UK scientists at UCL showed that increasing pressure ejects surplus healthy cells from overcrowded tissues, revealing a possible link between this process and the spread of cancer. Dr Kat Arney talked with the Huffington Post about the work.
• And finally, congratulations to Prof Shankar Balasubramanian at our Cambridge Research Insitute, Prof Tony Kouzarides at The Gurdon Institute, and Dr Julian Lewis at our London Research Institute – who have all been elected as fellows of the Royal Society.

New research has examined breast cancer in even more detail

The emotion and anxiety aroused by a single word – ‘cancer’ – spans ages, sexes, nations, races and classes.

But as we understand more about the disease, the idea that cancer is a single, common enemy, is increasingly being challenged.

In late 2009, the publication of the first complete cancer genomes showed the extraordinary chaos present in the DNA inside cancer cells. But they also highlighted the molecular differences between different types of cancer – in this case, skin cancer and lung cancer

Other large gene studies have revealed even more differences between types of cancer, but have also increased out understanding of the differences between the ‘same’ cancer type in different people – the foundation of ‘personalised medicine’.

For example, last week a team of Canadian and British researchers, writing in the journal Nature, analysed the DNA from 104 ‘triple-negative’ breast cancers – a particularly hard-to-treat form of the disease.

As this in-depth post on the Respectful Insolence blog describes, they found that no two women’s cancers were alike – there were differences across all the tumour samples. Even a subcategory like ‘triple-negative’ breast cancer doesn’t seem to be a single disease (a point we’ll return to later). And genetic differences also appeared between cells from the same tumour – known as ‘intratumour heterogeneity’.

This point was emphasised a few weeks earlier by researchers at our London Research Institute. They analysed multiple samples from the same patient’s kidney tumour and secondaries (where the cancer had spread to other parts of the body).

No two samples were identical, suggesting that there’s significant variation even inside a tumour. As we discussed in this blog post, it looks like tumours can be highly varied, creating new challenges in the search for personalised medicine.

A video about METABRIC (click to open in a new window)

Which brings us to today’s news, of a landmark Cancer Research UK-funded study published in Nature.

Through intricate genetic analysis, the same British and Canadian researchers, led by Professor Carlos Caldas from our Cambridge Research Institute and Professor Sam Aparicio from the British Columbia Cancer Centre in Canada, have uncovered crucial new information about breast cancer.

Their study group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), looked at the patterns of molecules inside tumours from nearly two thousand women, for whom information about the tumour characteristics had been meticulously recorded.

They compared this with the women’s survival, and other information, like their age at diagnosis.

While many other studies have highlighted differences between cancers, the METABRIC study looked at so many tumours that they could spot new patterns and ‘clusters’ in the data.

Their conclusion is that what we call ‘breast cancer’ is in fact at least ten different diseases, each with its own molecular fingerprint, and each with different weak spots.

This is simultaneously daunting and heartening – daunting because each of these diseases will likely need a different strategy to overcome it; and heartening because it opens up multiple new fronts in our efforts to beat breast cancer.

Let’s look at the background to the study, then in detail at what the researchers actually did, what they found, and what this means for the future of breast cancer treatment and diagnosis.

A changing view

Researchers studying breast cancer down the ages have long suspected it’s a complicated disease.

The first clue came more than a hundred years ago. Scientists found that most breast cancers make too much of a protein called the oestrogen receptor (or ‘ER’), and this allowed the hormone oestrogen to drive their growth.

As a result, ‘anti-oestrogen’ drugs like tamoxifen and anastrozole were invented. And now women are routinely given tests for levels of ER in their tumours. This helps decide whether to prescribe these drugs alongside standard treatments like surgery, radiotherapy and chemotherapy.

The progesterone receptor (PR) was discovered next.

Women whose breast cancers are ‘PR+’ are also likely to respond to anti-oestrogen drugs, and those whose tumours are both PR+ and ER+ tend to have the best outlook.

This suggested three ‘types’ of breast cancer –

• ‘double-positive’ cancers that had high levels of both hormone receptors
• Cancers with high levels of either ER or PR
• ‘double-negative’ cancers

But the idea was soon shown to be simplistic. For example, some women with ‘double-positive’ cancer did better on tamoxifen than others. And this variable response was seen for other types of breast cancer. Clearly something else was going on in at a deeper level.

In the late 90s – underpinned by work at our London Research Institute in the 1980s – a new molecule called Her2 was discovered to drive breast cancer in some women. This discovery led to the drug trastuzumab (better known as Herceptin).

And again, women can be tested for Her2, and are ‘Her-2 positive’ if their tumour contains high amounts of the protein. These cancers also tended to have worse outlook (at least until the advent of trastuzumab).

But this wasn’t the whole picture. Again researchers found that some ‘Her2-positive’ women responded to Herceptin better than others.

Today, in the NHS, women are routinely given tests for the oestrogen and progesterone receptors, and for Her2 – and their treatment determined by the results.

For some women, this means their cancer is ‘triple-negative’ – their tumours contain low or normal amounts of ER, PR and Her2, and there are no extra treatments available for them. These cancers also tend to be very aggressive.

Genetic insights

Modern genetic technology is increasing our understanding of cancer

All of the tests described above measure the levels of proteins inside tumours. Recently, research has focused on testing which genes are switched on or off inside the cancer cells.

This has led to tests, not yet widely used in the NHS, such as ‘PAM50’. This examines 50 separate genes inside a woman’s tumour, and uses the resulting ‘fingerprint’ to group cancers into four subtypes’:

• Luminal A cancers, which are usually ER+ and/or PR+ – and make up about half of all cases. They tend to have low amounts of Her2. Women with these tumours tend to have the best outlook.
• Luminal B cancers, which again tend to be ER+ and/or PR+, but also Her2+. These have a good outlook (but not as good as luminal A cancers), and account for about 12 per cent of cancers.
• Her2-amplified cancers. About one in ten cancers are ER and PR negative, but have high levels of Her2. These tumours have a poorer outlook than the two types above, but can be treated with trastuzumab (Herceptin).
• Basal-like tumours – these are usually the ‘triple-negative’ cancers mentioned above, and make up about 20 per cent of tumours. They have the least favourable outlook.

There’s a more detailed description of these genetic subtypes here.

Other commercially available gene-based tests are also available, such as Oncotype DX and MammaPrint. There’s more information about these here.

Such gene tests can be used like the protein-based tests – guiding treatment and helping doctors predict how the tumour will behave. But they’re more expensive, and there’s little hard evidence that they outperform the high-quality protein-based tests currently offered by the NHS. Newer is not always better, from a patient perspective.

Overlap and confusion

Researchers following the fates of women diagnosed with different types of breast cancer soon noticed that, occasionally, women with a supposedly ‘poor survival’ form of cancer would respond very well to treatment.

Similarly, some women who ‘should’ respond to drugs like trastuzumab, (because their cancer seemed to contain high levels of Her2 protein), didn’t.

Even the four ‘genetic’ types of cancer can’t reliably predict the best treatment or how a patient’s tumour would behave.

So, as it stands, our current map of breast cancer just isn’t detailed enough. It outlines broad, vague, overlapping continents, rather than showing clear boundaries between countries, counties or cities.

The research published today gives us a newer, better map of breast cancer.

Molecular cartography

The new study has produced a more detailed 'map' of breast cancer

The METABRIC project has produced a “goldmine” of data, according to Professor Caldas.

Over a period of decades, the team has carefully developed a resource of thousands of individual tumours, which can be (and have been) analysed and reanalysed in a number of different ways.

Crucially, each of these tumour samples is linked to detailed information about the subsequent fate of the women they were from. And, just as crucially, a large number of the samples are linked to a ‘matched normal’ sample (in other words, a sample of non-tumour DNA from the same patient).

The METABRIC team used sophisticated DNA hybridisation machines to analyse regions of variation in the DNA of nearly 1000 tumours. These regions, called copy-number variations, occur when a dividing cell makes mistakes, and result in regions of DNA being repeated, or deleted. Both of these alterations can affect gene activity.

By measuring such changes in each of the thousand samples, the team generated a ‘copy-number map’. And because they had the matched normal samples, they could remove any naturally occurring gene variations. As a result, they were able to draw up the first ever map of copy-number alterations specific to breast cancer.

The researchers also looked for other types of ‘single letter’ genetic variation, called SNPs, for each tumour sample.

And to cap it all off, they measured which genes were active in each sample (so-called ‘gene-expression data’), by measuring levels of molecules called RNAs. In all, they measured the levels of more than 30,000 different types of RNA, each corresponding to the activity of a single gene.

Annotating the map

Researchers have classified breast cancer in to ten different types

But a map is useless without directions. The METABRIC data allowed unprecedented comparison of gene data – copy-number, SNPs and gene-expression – with the outlooks of the patients the tumours came from. This was done using specialised computer software to sift gigabytes of data, searching for patterns.

What they found was remarkable. Distinct patterns emerged from the data, with certain copy-number aberrations far more likely in women with certain clinical features (such as high levels of the oestrogen receptor, or of Her2), or with distinct, and shared, clinical outlook.

In all, there were ten clear ‘clusters’ in the data – corresponding to ten entirely new ways to classify breast cancer.

To check this finding was accurate, they then painstakingly repeated the analysis on a second panel of nearly 1000 tumours. Again, the same ten subtypes shone out from the data.

Finding the drivers

One thing immediately became clear from the new map. Different ‘clusters’, or subtypes, seemed to be characterised by genetic variations at certain ‘hotspots’.

These were associated with the activity of large groups of other genes. This is what you’d expect if a single genetic mutation was turning on lots of different cell processes associated with cancer.

The team looked in detail at these genetic hotspots, to see if they could find the gene or genes responsible. This analysis showed up some ‘old friends’ – for example the gene that makes the Her2 protein. But it also revealed some entirely new genes that had never previously been linked to breast cancer.

These are potentially excellent targets to develop the next generation of Herceptin-like drugs.

Intriguingly, one of the clusters (Cluster 4, below) contained both ER+ and a sub-set of triple-negative tumours with – paradoxically – a good prognosis. But these tumours didn’t show any large-scale gene defects. Instead, the team spotted subtle deletions, not in cancer genes, but the genes of the immune system.

Checking the original biopsy revealed what was going on. Looked at down the microscope, these tumours were packed full of white blood cells. It seems that, for some women with a supposedly poor outlook, their own immune system somehow comes to their rescue, holding the tumour at bay. This had been observed before, but never in such detail. And certainly not as a distinct ‘type’ of breast cancer.

The ten ‘clusters’

Here’s an overview of the characteristics of each of the clusters identified:

What next?

It’s important to say that this new way of looking at breast cancer won’t affect the way anyone with breast cancer is currently treated. It advances how scientists approach future research and clinical trials, but there’s not enough information to know how to put this information to use in a way that will benefit patients. The standard tests available on the NHS are sufficient for the drugs currently available, for the time being (although as new treatments emerge, this will change).

And these ten subtypes aren’t the end of the story. Already it looks like ‘cluster 4’ can be further broken down, and Caldas’s team is planning on analysing other aspects of his sample collection to increase the resolution of METABRIC’s map further. He’s currently looking at the levels of tiny molecules called miRNAs in each tumour, adding this data to the computer clusters. This will doubtless yield even more insights.

They also plan to fully sequence 150 genes in each sample, focusing on those most important in breast cancer. Again, this should refine the map even further.

Professor Carlos Caldas, who co-led the METABRIC study

Another priority for the team is to focus on the links between the immune system and cancer. Immunotherapy – treatments that harness the immune system to fight a patient’s cancer – is a hot topic, and has huge potential in breast cancer.

Understanding how some women’s immune systems can fight their own tumour raises the prospects of treatments that can do likewise.

According to Professor Caldas, “the fact that we have collected matched normal blood samples for all the patients is testament to the set-up here in Cambridge – of high-quality, long-term genetic research”.

“That in turn is testament to the investment Cancer Research UK has put in here, to build and nurture an environment where this sort of discovery is possible”.

Other researchers are similarly excited by the new results. Professor Charles Swanton is the Cancer Research UK-funded researcher who discovered variegation in kidney cancer (as mentioned earlier). He called the new results an “extraordinary” finding that took our understanding of breast cancer “to the next level”.

“We’re increasingly seeing that what was previously thought to be a single ‘type’ of cancer can be subdivided into smaller clinically relevant groups through cancer genomics analysis.

“Breast cancer is perhaps the stand-out example of this, and analyses of gene expression over the years have revealed a hidden complexity in this disease,” he added.

He was also quick to point out the international nature of the work: “METABRIC also illustrates the importance of large international collaborations, and the need to include sufficient numbers of patients to be able to work out what’s going on in smaller and smaller patient groups.

“This extraordinary effort is likely to have important implications for clinical trial design in breast cancer and will prime researchers worldwide to define new approaches to treat each subgroup,” he confirmed. His hope, like Professor Caldas’, is that the ultimate end will be improved outcomes for patients.

And speaking of patients, Professor Caldas had this to say:

“I want to stress, this study wouldn’t have been possible without the breast cancer patients who donated their samples and agreed to take part in the study. None of this would have happened without them, and I’m so grateful for their participation.”

METABRIC is a landmark study, and a shift in how we view breast cancer. It will shape future research, including the search for newer, better treatments – particularly for those with the worst outlook. It could also lead to women with the best prognosis being spared the side effects of chemotherapy they don’t need. And the classification system it sketches out will likely form the basis for newer, better ways to diagnose and manage the disease.

Thanks to the generosity of two thousand breast cancer patients who took part, things look more hopeful for their daughters, grand-daughters and great-grand-daughters.

Henry

Find out more:

• This week’s headlines: Why a breast cancer ‘blood test’ is still a work in progress.
• For more information about breast cancer, please visit our CancerHelp UK website
• Help support our work to beat cancer

Reference

Curtis, C. et al. (2012). The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups Nature DOI: 10.1038/nature10983

Alcohol is linked to an increased risk of breast cancer

For regular readers, alcohol and breast cancer may seem like old news, and you might wonder why it’s hit the headlines again.

But solid new data from a team of international researchers gives a new, more accurate estimate of how much one small drink a day can increase a woman’s risk of breast cancer.

The study – which reviews all the available evidence – helps settle the question of how big the risk is for women who only drink lightly, as we’ll see below.

The research also increases the overall strength of the evidence for a link between alcohol and breast cancer.

And given the recent news on minimum alcohol pricing, it’s worth bearing in mind the impact that small changes can make.

Why is this new?

Research has already established beyond doubt that breast cancer is more common in women who regularly drink alcohol. And we also know that the more alcohol a woman drinks, the greater her chances of developing the disease.

But there’s still been a question about the size of the risk for women drinking smaller amounts of alcohol – and different studies have given slightly different answers.

Intricate calculations

Until now, the best evidence available for the risk in light drinkers has come from doing ‘dose-risk analyses’.

In these, researchers plot all the results from a study on a graph – in this case for women drinking a certain amount of alcohol (dose), what proportion developed breast cancer (risk) – and find an equation that best describes how the two things are related.

The results from this type of analysis have shown an increase in risk of breast cancer of around 7 – 12 per cent for each extra drink a day.

But this isn’t the same as actually measuring that change in risk in women who drink lightly.

And because the change in risk is quite small, studies that set out to directly measure this risk couldn’t be sure their results weren’t down to chance, whether they showed an increase in risk or not.

Meta-analysis

This new study is what’s known as a meta-analysis. It looked at all the available results of research that directly measured the effect of light drinking on breast cancer – a total of 113 academic papers – and used statistical analysis to reveal the pattern behind all the data.

It showed that the risk of breast cancer in women drinking one small drink (about 1 ½ units) a day increased by 5 per cent. This figure was widely reported by the media.

But what does this figure mean? 5 per cent of what? To really understand what the research is saying, we need to turn this into an ‘absolute risk’ figure.

Here comes a tiny bit of maths

To convert a relative risk into an absolute risk figure, we need to know the overall risk of women who don’t drink (since this is the figure that increases by 5 per cent).

Unfortunately, this paper doesn’t contain that statistic. However, we can make an educated estimate:

As we blogged about last year, the lifetime risk of breast cancer for all women is 1 in 8, or 12.5 per cent. This means that 12-and-a-half women in every hundred (or, better, 125 out of 1000, since you can’t have half a woman) develop breast cancer at some stage in their lives.

But this figure includes all women, from non-drinkers to those who drink very heavily. So let’s make an assumption* that the lifetime risk of non-drinkers is lower – 1 in 9, or 11.1 per cent.

If we multiply this figure by 5 per cent (the increase due to low level drinking), we get 11.7 per cent.

Now let’s convert these numbers to actual people

In a thousand non-drinkers, we can expect 11.1 per cent of them to develop breast cancer – that’s 111 women.

And using our new figure, in a thousand women who have one alcoholic drink a day, we can expect 117 to develop cancer.

That’s six additional women, out of a thousand.

This is a slightly lower figure than previous estimates, but because of the weight of data behind the new 5 per cent statistic, the researchers are confident that it is a much more accurate picture of reality, rather than a statistical fluke.

What does that mean for the woman at the bar?

A 5 per cent increase in risk isn’t huge. But it’s worth remembering that this is just for one drink a day, and it all adds up – the more people drink, the higher the risk of cancer.

Other studies have found that drinking more heavily, like four small drinks (about 6 units) a day, increases breast cancer risk by 55 per cent.

Repeating our calculation above, this translates into 172 women per thousand – an extra 61 women compared to 1000 non-drinkers.

And overall, in the whole population, all these risks can add up to a lot of people. For example, our recent study on lifestyle and cancer estimated that 3,000 cases of breast cancer a year are related to alcohol.

On balance

We often write about the overall balance of evidence. And that’s exactly what this study is about. It’s a way of putting all the evidence on the scales and seeing where the needle points.

And taken together with what research has already shown about alcohol and the risk of breast cancer, this new evidence means we can be more certain that there is a risk associated with low-level drinking, but it is a fairly small one.

Our overall message remains the same – the more you cut down on alcohol, the more you can reduce the risk of cancer. And for women making choices about their lifestyle, that’s worth knowing.

Sarah

Sarah Williams is a health information officer at Cancer Research UK

*Whether this assumption is valid depends on the proportion of women who drink heavily in the general population. We actually looked a range of situations using figures in between 1 in 8 and 1 in 9 for the risk of non-drinkers – the absolute figures still came out at around 6 extra women per 1000 in all cases.

Reference

• Seitz, H., Pelucchi, C., Bagnardi, V., & Vecchia, C. (2012). Epidemiology and Pathophysiology of Alcohol and Breast Cancer: Update 2012 Alcohol and Alcoholism DOI: 10.1093/alcalc/ags011

The UK population has traditionally had a close relationship with alcohol

Alcohol has been a well-loved but problematic part of British life for centuries, as immortalised in 18^th century artist Hogarth’s depictions of “Gin Lane” and “Beer Street”.

In its latest steps to try to tackle England’s long-standing and complex relationship with booze, the Government has just announced its alcohol strategy.

As you probably spotted last Friday, one of its headline-grabbing – and welcome – measures will be the introduction of a minimum price of 40p per unit of alcohol sold.

While the strategy’s main aim is to reduce binge drinking, its impact will be seen far beyond our city centres after closing time.

Because it would be a mistake to look at modern-day footage of drunken young people falling over in the streets and assume that alcohol is a purely social problem – the hidden damage to the nation’s health from excessive alcohol consumption is just as serious.

But while most people know that drinking excessively over time can cause liver damage, fewer know that it also increases the risk of cancer.

Alcohol and cancer – the facts

Drinking alcohol is associated with increased risks of mouth, food pipe, breast, bowel and liver cancers. The evidence shows the more you drink, the greater your risk. And as far as we know, it doesn’t seem to matter whether you have a couple of drinks every night, or save it up for one night a week.

Overall, research shows that over 12,500 cases of cancer are caused by drinking – that’s one in every 25 cancers in the UK. The only way to address the problem is to reassess our relationship with alcohol, and consider ways to reduce consumption.

But that doesn’t mean you have to be teetotal. You can minimise your risk by drinking less than 3 units a day if you’re a man, or less than two units a day if you’re a woman.

Minimum pricing – our view

We believe that minimum pricing for alcohol is a positive step in addressing our consumption as a nation. A recent paper by researchers from the University of Sheffield shows that the proposed minimum price of 40p per unit, together with a ban on discount sales, will lead to a nationwide reduction in consumption of 4.6 per cent.

This may not sound like much, but the authors think it would reduce the number of alcohol-related hospital admissions by 5,100 a year. And an overall reduction in consumption would also reduce the number of alcohol-related cancers in England.

Naturally, most people wonder what minimum pricing will mean for them. The simple answer is ‘not much’. According to the Sheffield study, the impact of minimum pricing on moderate drinkers (defined as no more than 14 units per week for women and 21 units for men) will be £5-6 per year, equivalent to a couple pints down the pub.

But for harmful drinkers, the estimated cost is an estimated additional £100-135 a year.

The reason for the difference lies in how minimum pricing works: it increases the price of cheap, high-strength drinks, like white ciders, that are typically consumed by harmful drinkers. Minimum pricing could also be a lifeline for the local pub, by stopping the use of alcohol as a loss leader by supermarkets and helping to even the playing field between the two.

Added benefits

While the spotlight is on minimum pricing, there are other positive measures in the Government’s strategy. For example, the Government recognises that a lot people still don’t understand the health risks of excessive drinking, so they’re expanding the Change4Life programme to include alcohol. We’ve worked recently with Change4Life on their recent adverts which highlighted how one drink can easily turn into a few.

In addition, we’re optimistic about the plans to include tools for health professionals to spot hazardous drinkers and help them reassess their drinking patterns. The development of a new approach to help under-18s who arrive at A&E with alcohol-related problems is also an encouraging step.

But despite these positive steps, we think the Government needs to balance these health messages with greater restrictions on alcohol marketing, particularly when it comes to protecting children. It is worrying that recent research has shown that more children recognise major alcohol brands than popular cake and sweet brands.

Overall, this strategy represents a big step forward in Government action on alcohol. It’s needed because the harms of excessive alcohol consumption extend much further than drunken chaos on a Saturday night.

Helping people to make healthy choices about alcohol consumption will help to reduce the toll of cancer on our nation.

Chit Selvarajah is a policy adviser at Cancer Research UK

Click on the logo to download the podcast

In this month’s podcast a landmark cancer study sheds light on tumour genes, and experts suggest that more breast cancer patients should have genetic tests.

New figures reveal worrying numbers of schoolchildren taking up smoking, and leading model agencies sign up to a no-sunbed policy.

Meanwhile, a new drug combo destroys pancreatic cancer in the lab, and our Delay Kills report shows that ignorance and fear are behind thousands of avoidable cancer deaths.

Listen now through the audio player below:

Or click here to download the podcast as an mp3.

Also, the podcast is available on iTunes to subscribe and download for free.

Alternatively, go to the podcast page on our website, where you can hear the show directly through our own Flash player and explore previous shows in the archive. And there’s also a full transcript of the podcast available here.

We hope you enjoy it – please do let us know what you think of the podcast in the comments below, or email us at podcast@cancer.org.uk.

Kat

Read our weekly summary below

Some weeks are busier than others, and the past seven days have been a whirlwind. Lots of fascinating cancer research has been covered in the media, including some important work by our own scientists.

We’ve summarised the week for you below. Click on the links for further information on any of the stories that catch your eye.

If you want to share anything on Twitter or Facebook, then hover over the right hand portion of each section for share options.

Diagnosing cancer early saves lives

If cancer is diagnosed early, it’s nearly always easier to treat successfully. But too many cancers are still diagnosed at a late stage – thousands of lives could be saved in the UK if more cancers were spotted early.

We’re working hard to solve this problem, and we’re excited to announce a major new partnership with Tesco. By working together we will find ways to close the gap between survival rates in the UK and the best countries in Europe so that thousands more will survive cancer in the future.

Tesco will raise £10 million to fund 32 early diagnosis research projects across the UK, as well as displaying our leaflets on the signs and symptoms of cancer to the millions of customers who go through their stores’ checkouts each week.

But what exactly will this research involve? Read on for just a few highlights of the work that this valuable partnership is supporting.

Testing for prostate cancer

Men who inherit faults in their BRCA genes (which are normally thought of as ‘breast cancer’ genes) have a higher risk of prostate cancer. But could they benefit from regular tests to help diagnose the disease early? Professor Ros Eeles at The Institute of Cancer Research in Sutton is investigating targeted PSA testing for men with faulty BRCA1 and BRCA2 genes. Men are taking part in towns across the UK including Liverpool, Aberdeen and Newcastle.

Faster chest X-rays to detect lung cancer early

Could more lives be saved if all patients with possible lung cancer symptoms were sent for an urgent chest X-ray? Professor Richard Neal in Bangor is investigating. Initially, he’s running a small trial, with the aim of planning a larger study testing this approach. The disease is one of the most common cancers in the UK and it’s often diagnosed late, so in the long-term, this research could make a real difference to thousands of people.

Improving cervical screening

Based in London, Professor Peter Sasieni is investigating whether testing women aged 25-65 for the human papillomavirus (HPV) as part of the cervical screening programme could save even more lives than the smear test alone. All cervical cancers are linked to HPV, and it’s hoped that HPV testing could make the screening programme more accurate and more effective at preventing the disease and diagnosing it early.

A new test to help diagnose oesophageal cancer

In Cambridge, Dr Rebecca Fitzgerald is trialling a simple new screening test to detect changes in the oesophagus (foodpipe) that can develop into cancer. The test could identify people who need early treatment, helping to prevent the disease from developing. If successful, Dr Fitzgerald’s study could save more people from this hard-to-treat cancer.

Recognising skin cancer symptoms

Researchers in Edinburgh are finding out whether people can learn how to recognise the signs of melanoma skin cancer by looking at images online. Melanoma is becoming more common and it’s important that people are aware of the symptoms so they can visit their doctor as early as possible.

Improving bowel cancer screening

In London, Professor Wendy Atkin is finding better ways to prevent bowel cancer and detect the disease early through her research testing new screening and diagnosis techniques. Her work has already proved the benefits of a new test called flexible sigmoidoscopy, which can detect and remove bowel polyps before they develop into cancer. This test will soon become part of the national screening programme in England.

Better tools for diagnosing breast cancer

In Guildford, Professor Kenneth Young is finding out if new digital X-ray technology could improve breast screening. He believes this technology could be more efficient than the current method, particularly in women who are younger or have denser breast tissue.

These are just a handful of the potentially life-saving projects Tesco is supporting across the UK. To find out more about the many other projects that are part of this exciting partnership, explore our interactive map and find out about research happening near you.

You can find out more about our work into early diagnosis on our website, and there is information about how to spot cancer early, including signs and symptoms to look out for, on our Healthy Living pages.

Nell

Professor Mike Stratton led the team that tracked down BRCA2

In part one, we told the story of Cancer Research UK’s involvement in the race to identify BRCA1 – the first known breast cancer gene.

Although this was a very important discovery, it wasn’t the end of the story. Along the way, researchers had discovered evidence suggesting that there had to be at least one more gene out there.

Here we look at how our scientists revealed the identity of the second breast cancer gene, BRCA2, and what the discovery of both these genes means for cancer patients and their families.

Tackling the next hurdle

As we mentioned in part one, although BRCA1’s discovery was incredibly exciting at the time, researchers found that it wasn’t responsible for every case of inherited breast and ovarian cancers.

Research showed that faults in BRCA1 accounted for most families with many cases of both breast and ovarian cancer that set in at an early age, and just under half of all families affected by multiple breast cancer cases. But the gene wasn’t implicated in any families affected by both male and female breast cancer.  The hunt was now on for the next breast cancer gene – “Breast Cancer 2”, or BRCA2.

The main hurdle in the search for this gene was cleared in 1994 by an international team led by Professor Mike Stratton at The Institute of Cancer Research. With funding from The Cancer Research Campaign (Cancer Research UK’s predecessor), the Medical Research Council and others, the researchers analysed DNA from 15 families from around the world affected by early-onset breast cancer that wasn’t related to BRCA1.

Using painstaking genetic techniques, the researchers pinpointed the location of BRCA2 to a region on one end of human chromosome 13 – a region known to contain a number of different genes. As with BRCA1, scientists around the world then raced to pin down which one of these was BRCA2.

Professor Stratton – along with a team that included several other Cancer Research Campaign-funded scientists, was the ultimate winner. They revealed the identity of BRCA2 in a paper published in the journal Nature at the end of 1995.

Using DNA samples from a set of Icelandic families affected by multiple cases of breast cancer, Stratton and his team had narrowed down the possible location of BRCA2 to a relatively small region of DNA within chromosome 13. Next, they figured out which bits of this region were likely to be genes, and set about reading the DNA sequence of these potential genes in members of 46 families affected by breast cancer unrelated to BRCA1.

In particular, the researchers were hunting for mistakes in the DNA sequence that would stop a gene from being ‘read’ by a cell (genes are instructions that tell a cell to make a particular protein).  After poring over thousands of DNA ‘letters’, the researchers spotted ‘stop signals’ in the same gene in three people from different families.

Could this be the elusive BRCA2?

To confirm BRCA2’s identity, the scientists pulled together the full DNA sequence of their prime suspect. Luckily, this task was made easier by the Human Genome Project – an international consortium of researchers sequencing the entire human genome – who had just published a draft version of the DNA sequence from the end of chromosome 13.

The researchers patched together the sequence of the entire gene and compared it to the DNA of people from families affected by breast cancer.  They found mistakes in the gene in members of several different families, including those affected by male breast cancer. But they didn’t see any faults when they looked at DNA from over 500 healthy women.

This was enough evidence to confirm the identity of the mystery gene as BRCA2.

Moving forward

Since the BRCA genes were identified, they have come under intense scientific scrutiny. We now know that around 1 in 1,000 people carry a fault in one of the genes, and that around 2 in every 100 women with breast cancer have a faulty version of either BRCA1 or BRCA2.

Carrying a faulty version of a BRCA gene means a woman has a roughly 80 per cent chance of developing breast cancer in her lifetime – as opposed to around a 12 per cent chance in the general population, roughly one woman in eight -  and more than a fifty-fifty chance of getting ovarian cancer.

In 1995, our funding allowed scientists at The Institute of Cancer Research to show that BRCA1 faults were more common in younger women who develop breast and ovarian cancer. We now know that faulty BRCA2 is also linked to male breast cancer as well as prostate and pancreatic cancers, and in 2008 our scientists revealed how specific faults in BRCA2 can affect how a patient’s cancer responds to treatment.

Life-saving knowledge

People with a strong family history of breast and ovarian cancer are now able to have genetic testing to find out whether they carry a faulty version of BRCA1 or BRCA2. If they do, then they may wish to take steps such as regular breast screening, surgery to remove their breasts or ovaries, or preventative drugs to help reduce their chances of getting cancer.

And in 2009, a baby girl was born as a result of an IVF procedure that ensured she would be free of the hereditary BRCA1 fault that had led to her father’s family being haunted by breast cancer for generations.

We also now know that BRCA1 and BRCA2 aren’t the complete story when it comes to breast cancer genes. Although these two genes have the strongest effect on breast cancer risk, researchers have since discovered many more genes that can influence the chances of getting the disease – and our scientists have been at the forefront of this work.

For example, in 2002, Cancer Research UK-funded scientists in Cambridge and at The Institute of Cancer Research led a team that discovered a new breast cancer gene called Chek2.  And in 2003, a different team of Cancer Research UK-funded scientists in the city tracked down EMSY – a gene that proved to be the missing link between BRCA2 faults (which are only found in hereditary cancers) and randomly-occurring (sporadic) breast cancers.

Cancer Research UK scientists are also leading the way in discovering the more subtle variations in our DNA that have a smaller impact on individual cancer risk.  They were part of a groundbreaking 2007 study that found five new gene regions linked to breast cancer, and in 2010 they found five more. And earlier this year, scientists at our Cambridge Research Institute found the first new ‘cancer accelerator’ oncogene in five years, which is also implicated in up to 4,000 cases of breast cancer every year in the UK

This genetic knowledge is starting to work its way into clinical reality. Our researchers are developing sophisticated computer models – such as a programme called BOADICEA – that can help to predict an individual woman’s risk of breast cancer based on her genetic heritage and family history.

And they’re also calculating how genetic information could help to make breast screening more effective by focusing particular attention on women at highest risk of the disease.

From the lab to the clinic

Hundreds of detailed lab studies have revealed what BRCA1 and BRCA2 look like, what they do in cells, how they work, and the other genes and molecules they interact with.  We now know that they help cells repair damage to their DNA, helping to protect us from cancer. If either BRCA gene is damaged or faulty, then the cell can’t repair this damage, increasing the chances of cancer developing.

This finding led to the development of exciting new experimental cancer drugs known as PARP inhibitors, which exploit this genetic ‘Achilles’ heel’ in cancer cells lacking BRCA.  Our scientists, and other groups around the world, are now testing PARP inhibitors in clinical trials with promising early results.  We’ll be covering the development of PARP inhibitors in a future High-Impact Science post, so watch this space.

Across the globe, scientists continue to pore over BRCA1 and BRCA2, trying to understand what makes them tick and how we can use this knowledge to beat cancer.

Just in the past year or so Cancer Research UK scientists have discovered how BRCA1 may be linked to so-called ‘triple negative’ breast cancer, unravelled the complex three-dimensional structure of BRCA2 on an atomic scale, and figured out a molecular ‘volume control’ that helps to determine whether a woman carrying a faulty version of BRCA1 will go on to develop breast cancer.

But there are still plenty of mysteries that need to be solved. For example, it’s still not clear exactly why BRCA1 and 2 faults only cause a relatively small range of different types of cancer – breast, ovarian, prostate and pancreatic – when the faulty genes are found in every cell of the body.  And although the results from the PARP inhibitor trials look good so far, the drugs don’t work for everyone.

Discovering the BRCA genes was just the start. Cancers caused by BRCA faults tend to occur in younger people, and are harder to treat. We urgently need to continue to turn the knowledge gained through research into more and better ways to treat people with cancer. Our researchers have made great strides in the past and – with the help of our supporters – we can make even more progress in the future.

Kat

References

Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, & Averill D (1994). Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science (New York, N.Y.), 265 (5181), 2088-90 PMID: 8091231

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, & Micklem G (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature, 378 (6559), 789-92 PMID: 8524414