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A breast cancer cell Credit: London Research Institute EM Unit

In 2012, our scientists redefined breast cancer.

By analysing samples from nearly 2000 tumours they found that breast cancer was not one, but 10 different diseases, as we explained in our blog post.

Led by Professor Carlos Caldas, based at the Cancer Research UK Cambridge Institute, and Professor Sam Aparicio at the British Columbia Cancer Agency, the team discovered they could tell tumours apart by looking at faults in their DNA. And these differences defined how these breast cancers behaved, from how likely they were to respond to treatment to how likely tumours were to come back after surgery.

Since then the team has tested their rulebook on even more samples collected by labs around the world. And regardless of where the samples came from, the new set of rules held true.

“What we have here is a universal classification of breast cancer,” says Caldas.

And 7 years after the first study was published, the research team have shown that their rulebook stands the test of time. Publishing their latest work in Nature, they’ve found that the group a woman’s breast cancer is initially placed in could predict how they will fare 20 years after diagnosis.

Writing the new genetic rules

Scientists are constantly looking for new ways to tell tumours apart. They’re searching for something that can help them know if a cancer is likely to be aggressive or if it’s likely to come back. Does it need treating? And if so, how?

That something could be a molecule on the surface of cancer cells – like hormone receptors – or a fault nestled in cells’ DNA.

For years doctors have used molecules on the surface of breast cancer cells to reveal what’s buried within. Markers like oestrogen receptors and HER2 have helped patients and doctors to decide what treatment might be best.

Other tests have come in that look at a tumour’s DNA, including one called PAM50. But Caldas and his team began to look for a more accurate way to distinguish between different breast cancers.

“The big thing about our 2012 study was that we were distinguishing between tumours based on their molecular wiring – what’s going on inside the cells – rather than their prognosis,” he recalls.

The team split the cancers into 10 groups – which they call clusters – based on this molecular data.

And Caldas and his team wanted to see if grouping tumours in this way can more accurately predict the future for these patients than current tests.

Using samples from 1,980 women with breast cancer, they plotted the likelihood of the tumour returning (relapse) or spreading (metastasis) based on its molecular information. And then they looked at how well this prediction stacked up against tests like PAM50.

“What we’ve found now is that if you follow patients for up to 20 years after diagnosis, the women have very different propensities to relapse or even for their disease to become metastatic depending on which subtype of breast cancer they have.”

Importantly, separating tumours based on Caldas’s classification was a better predictor of future disease than looking for molecules on the surface of tumours or the PAM50 test.

Refining the rulebook

The long-term data has done more than just confirm the potential value of classifying breast cancer in this way, it’s also refined it.

“We realised that one of the groups, cluster 4, needed to be split,” says Caldas.

Cluster 4 was the largest group in the original study, accounting for around 1 in 5 tumours. Tumours in this cluster don’t have any major damage to their DNA, which Caldas says is why they were originally grouped together.

“The group had breast cancers that were oestrogen receptor positive and some that were triple negative, but they were clustered together based on features in their DNA.”

But over time Caldas and his team realised that despite the genetic similarities, the oestrogen receptor positive and negative tumours had very different clinical outlooks. So, in the latest paper, they’ve split them into 2 different groups – creating 11 different types of breast cancer in total.

Beyond triple negative breast cancer

The team also learned more about triple negative breast cancers. Defined by the lack of hormone receptors or HER2 on the cancer cells’ surface, they’re considered to be one of the most aggressive forms of the disease.

But according to Caldas’s research, not all triple negative breast cancers are the same.

“We can clearly define two groups of triple negative breast cancers. In one group, women have a very good outlook if they haven’t relapsed after 5 years. Unfortunately, women in the other group have a high chance of their cancer returning even after 5 years.”

This was somewhat surprising for Caldas, as in the first study the outlooks were reversed. Women whose cancer was more likely to come back in the long term had a better prognosis in the first 5 years.

The results not only reinforce the importance of following patients up over long periods of time, it also calls into question how trials are run.

“These patients have very different clinical course – but at the moment they’re treated and followed up in the same way. And trials include both groups,” says Caldas.

Caldas believes that these differences should be considered when new treatments are tested.

“We’re already starting to do it,” he adds. Caldas’s colleagues, led by Dr Jean Abraham, are running a clinical trial called PARTNER, where they’re identifying the type of triple negative breast cancer each women has before they enter the study.

“They’re aiming to get equal proportions of women with the two types of triple negative in each arm of the trial,” says Caldas

The trial is testing if adding a targeted drug called olaparib (Lynparza) to standard chemotherapy is better for women with triple negative breast cancer. The trial is also open to women whose tumours have a faulty BRCA gene. And by taking the different types of triple negative cancer into consideration at the start of the trial, Caldas hopes it will tell researchers if there are differences in how the groups should be treated.

The PARTNER trial is a start, but Caldas thinks it needs to go much further.

“We need to take this into account in more clinical trials. To continue to recruit women based on their hormone receptor status is really nonsensical to me.”

Getting personal

What the team discovered is intimately linked with other projects in Cambridge, including the Personalised Breast Cancer Programme. The project aims to tailor treatment to individuals by mapping their DNA.

So far, they’ve recruited 400 women with breast cancer to the programme, all of whom have had their tumours classified into 1 of the 11 subtypes.

“We’re going to be following these women knowing which cluster they’re in from the word go,” says Caldas.

And with 85% of women in the programme enrolled into a clinical trial or a monitoring study, Caldas says they’ll be learning a lot about the best way to treat these women.

The team are also looking to go one step further. The plan is not just to see which treatments work for which group – but to develop drugs specifically for them.

“We’re creating models of as many of the women’s tumours as possible. And we’re going to use this to try and get to the next step, which is identifying therapies that are tailored to each of the clusters.”

What’s next?

While the rulebook Caldas and his team are writing has proved essential reading so far, they’re not done revising it just yet.

“We’re planning to do an even bigger validation in the next few years, looking at the 11 subtypes in around 10,000 cases of breast cancer,” he says.

They’re also looking to develop a test that can be more easily used on the NHS.

So far, samples have been analysed using expensive equipment that isn’t widely available. And they’ve been done using samples collected during surgery and preserved for this research, which isn’t feasible in an NHS setting. To get a test that could be used in the clinic, Caldas says that it must work on tissue samples that are preserved by locking them in paraffin wax.

“We’ve got a Cancer Research UK-funded pathologist in my lab who is trying to develop a test that can be done on paraffin-embedded material affordably. And by that, I mean a test that wouldn’t cost more than £500.”

From research tool to patient benefits

It’s hard not to feel optimistic when hearing Caldas talk about the potential of the new breast cancer rulebook. Defining breast cancer in this way could change how women are treated and followed up in the future. But we’re not there yet.

“What we have at the moment is a research tool, it’s not useful in the clinic yet.”

The most important aim for Caldas and his team now is to figure out if using the test can change the outlook for women with breast cancer for the better.

“What we need to do now is demonstrate that by using the test we can improve a patient’s outcome. And that’s quite a high bar to reach.”

Caldas and his team are planning to implement the test through a programme that’s already used in the UK to help make treatment decisions for breast cancer, called PREDICT. This tool, developed by Professor Paul Pharoah’s team, already uses a variety of information to make treatment recommendations – including the size and grade of the tumour and if it’s positive or negative for HER or oestrogen receptors.

“What we’d essentially be creating is a PREDICT plus,” says Caldas. “We’d add our test on top of what PREDICT already offers and see if it’s better at individualising recommendations for treatment and follow-up.”

They’re not ready to launch PREDICT plus just yet, but it’s a goal they hope to move towards in the coming years.

Caldas and his team have big ambitions – to turn what they’ve learnt into a test that could help give women diagnosed with breast cancer more certainty about their future and treatment options that are right for them.

And while they’ve still got a long way to go, the latest findings prove they’re moving in the right direction.

Katie 

  • If you have questions about breast cancer you can speak to our nurses on freephone 0808 800 4040.

Reference

Rueda, O et al. (2019) Dynamics of breast cancer relapse reveal late recurring ER-positive genomic subgroups. Nature. DOI: 10.17863/CAM.37037

Comments

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Margaret Barr May 3, 2019

Really interested as I have had. Breast Cancer four times. Both breasts. now removed and I have the faulty gene

Sue May 3, 2019

Diagnosed Her2+,11 years ago, mastectomy, chemo, radio, herceptin. NHS support the best. Research like this is amazing! Thankyou! The future will be so much better.

Rama Payel May 2, 2019

Hi my mom died with thyroid cancer I seen her suffer for only 3weeks but that was enough what ever you guys doing best for people I really Appreciated Thank you

Veronica Goddard April 13, 2019

I had a mastectomy and chemotherapy in 1998, followed by 10 years on Tamoxifen. I had mammograms every 2 years for the first ten years and have now reverted to every three years with the regular breast screening service. This research and the article is fantastic, the more we know the better. Is there any research being done or planned on the DNA of women like me who had oestrogen positive tumours in the past. They would be very welcome to my DNA if it could contribute in any way to further research.

Ann Thorley April 13, 2019

I am coming up to my 5 years post op. My tumour was only diagnosed by mammogram as it was deep. I am concerned that future mammograms will revert to every 4/5 years.

Mrs Dawn Asplen April 12, 2019

I have breast I have had a mastectomy and radiotherapy I did have asthma but now after having radiotherapy it has left me with emphysema and lymphoedema I also am a coeliac I’m allergic to gluten and wheat that started when I was a child but didn’t get diagnosed till I was 49 that has given me loads of illnesses, osteoporosis arthritis, angina,hypertension PTSD low moods and anxiety I had to have all my teeth extracted by operation as they were crumbling ,also I was suffering with brittle bones ,anaemia, migraines, also I was anorexic I just wonder if my breast cancer could be because of being a coeliac and not being diagnosed early enough I also am on the border of being a diabetic I am deaf in both ears and aso have glaucoma I know I have liver disease because of being a coeliac but can coeliac disease be connected to all these other illnesses I have been told it can cause bowel cancer but can it be connected to other cancers as coeliac disease is hereditary my mum died of lung cancer ,my daughter has had skin cancer twice and had a thyroid in her neck removed and she has just gone through a hysterectomy and also had a blood transfusion is that also connected being a coeliac as it gets really worrying

Jane Waddington April 12, 2019

As a HER2 positive survivor for 8 years so far, having received excellent NHS support and treatment, fantastic to see the progress being made by scientists. The fear of a recurrence never goes away, but the more that is understood about the numerous variations is the key to the future of so many BC patients’ survival and quality of life.. HOPE.

Joanne April 12, 2019

It is a complex disease and everyone is different. Correct diet may help, but it is not the whole solution. Epigenetic has a lot to do with it too. Everyone’s DNA,is different, thus response unique too. Lifestyle adjustments can help. In addition, their are too many endocrine disruptors and chemical pollutants corrupting our environment.

As we age the immune system becomes less able to repair itself properly. Cancer may have begun in your body 40 years earlier and you or others would have no way of knowing.

Research is imperative and Science and empirical evidence has made enormous progress. May they continue to do so, but we as patients must learn too and educate ourselves as best we can and raise people’s awareness too.
Remain open minded about solutions and enjoy your life as you progress.

Life and time is so precious. Take care and never give up. xx

Elaine (Joanne) Bowen April 12, 2019

Please put me on the mailing list for updates. I have Secondary Breast Cancer, Metastes in lungs now, being treated with Palbociclib & Letrozole. I like to keep up to date and informed. Thank you.

Maureen April 12, 2019

This is fantastic work and a great breakthrough, but we should still be looking at our diets, at what we eat, this disease could be preventable and reversible by eating a plant based diet.

Hilsry Oag April 12, 2019

Fantastic work really good article
Our daughter is fighting oestrogen feed cancer with brilliant support from the NHS
We just pray for the future
Keep up the good work

Kaz April 11, 2019

My sister in law is currently fighting stage 4 breast cancer. Lets hope they find an amazing break through in time for her. Keep up the amazing work xx

Georgina Brooks April 11, 2019

I think it’s amazing how much more is known now about diagnosis and treatment of breast cancer. A close friend died twenty years ago from breast cancer. I’m sure she would have had a better chance of surviving today. The research is fantastic and power to the scientists behind it!

Julie Frankland April 11, 2019

Very interesting. But why is the article written as if only women get breast cancer?

jane April 11, 2019

this is good. so people like me thats had breast cancer only half a boob gone my aunt 10 years after I had it had 1 removed then 1 year later the other. how do we know if its going to return. plus i had lung cancer being on the right side as the breast cancer 12 years later. is it all connected? why was i the first the aunty then cousins… could it be our food too with ll the chemicals in them …pollution etc…

Elizabeth Budh April 11, 2019

My mother survived breast cancer but was upset when women she knew did not. This could explain why?

Rob Partington April 10, 2019

Fantastic article and insight as to the meticulous work that goes on in the labs and data analysis. Good effort CR 👍

Yme April 10, 2019

Great news! Look forward to hearing more about this,

Mick April 10, 2019

Is there any thing being done for stage 4 breast cancer

Meenakshi Bhatnagar April 8, 2019

Any research that helps the breast cancer patients is most welcome. It just seems like there is no family who have not been touched by this horrible disease. I was diagnosed with Triple negative BC last year in February and I am still getting treatment though there is no guarantee that it has been destroyed. I wish you all the best for this research and I contribute to charity as much as I can.

Dawn Asplen April 7, 2019

I have breast cancer I have had a masectomy and radiotherapy also I am taking lexatrole for 10 years but I also have many other illnesses on top

Karen milton March 14, 2019

I hope this horrible diease comes to a end having tripple breast cancer myself is awful i am recovering now after a third diagnoses i wish ya good luck in ya further research