It’s time to be positive about triple negative breast cancer

“When I was diagnosed I could not believe it was happening to me. I used to work in a histology lab and my first thought was, ‘They have the wrong results’”.

For self-confessed keep-fit fanatic Michaela, the news that she had cancer came as a shock. But there was an extra kicker when she got back the results of the lab tests on her tumour.

Michaela’s world turned upside down when she was diagnosed with triple negative breast cancer

She says, “My husband and I had been convinced by several medical professionals that my lump was nothing to be concerned about, so I went for the results on my own. That was when my world was turned upside down. The results showed I had in fact got a rarer type of aggressive breast cancer – triple negative.”

There is no ‘good’ type of breast cancer, but to those working in breast cancer treatment and research – and the patients that hear it – the phrase “triple negative” carries a heavy weight. The disease is notorious for having a poorer survival rate and is less well understood than other types of breast cancer.

But research is making a difference.

Last week our scientists made a step forward in understanding the genes driving triple negative breast cancer. So we thought we’d take a closer look at this finding, and at some of the other work going on to beat the disease.

The same but different

The story of progress in beating breast cancer is a testament to decades of painstaking work by researchers around the world. Nearly eight in 10 women diagnosed today will still be going strong ten years later, compared to around half that number back in the 1970s.

But this broadly positive picture of ‘breast cancer’ hides a complex biological tapestry: not all breast cancers are equal.

For starters, around three quarters of all breast tumours are what’s called ‘ER positive’, meaning they carry oestrogen receptors (ER) and so respond to the female sex hormone oestrogen. About two thirds of these are also ‘PR positive’, bearing receptors for another female hormone called progesterone. These types of cancers usually respond well to hormone-blocking treatments, such as tamoxifen, and there is a very good chance of surviving for a decade or more.

Then there are the ‘HER2 positive’ bunch – around one in five breast cancers. These carry multiple copies of a molecule called HER2, and tend to grow more aggressively. But they can be targeted by the drug Herceptin (trastuzumab), which has helped to boost survival.

By a process of elimination, triple negative cancers are those that are left – ER negative, PR negative and HER2 negative, and these make up roughly 15 per cent of all breast cancers – somewhere in the region of 7,500 cases every year in the UK. Younger women under 40 are more likely to have this type, as are black women, and the cancers tend to grow and spread aggressively.

People carrying an inherited fault in one of their BRCA1 genes are also more likely to develop triple negative tumours. This link is something that’s been previously explored by our scientists, providing important information about how these cancers might develop resistance to chemotherapy and radiotherapy.

It’s the ‘negativity’ of triple negative cancers that causes a problem when it comes to treatment. With no oestrogen or progesterone receptors, hormone-blocking therapies are unlikely to work. And tumours without HER2 don’t respond to Herceptin. So the best treatment usually involves a gruelling combination of surgery, radiotherapy and chemotherapy.

But although triple negative breast cancer tends to have poorer survival than other types, this blunt statistic hides a slightly more optimistic situation. Although there’s a higher chance that the cancer will come back within 5 years compared to the ‘positive’ tumours, once that hurdle is cleared then the chances of survival are roughly similar – something that rarely gets mentioned when people talk about the disease.

In addition, researchers are still unsure about exactly what triple negative breast cancer is. In 2012, work by our own scientists revealed at least 10 distinct types of breast cancer, each with their own genetic signature.

And just as the umbrella term ‘breast cancer’ encompasses several different forms of the disease, so triple negative tumours can be divided into smaller specific groups, based on their genetic and molecular makeup. Broadly speaking, many triple negative cancers fall into a category known as “basal-like”, but there are certainly molecular sub-divisions within that group that need to be teased out.

Based on these facts, it’s clear that the key to improving things for people with triple negative breast cancer must involve understanding the disease better on a genetic level – to improve diagnosis and treatment, and reveal new targets for therapies (just as Herceptin targets HER2) – and finding more effective ways to treat it right from the start.

Now another step in the right direction has come from scientists at our Beatson Institute in Glasgow.

Taking a RUN at the problem

The new research, led by Dr Karen Blyth and published in the journal PloS One, focuses on a protein molecule called RUNX1, produced within cancerous as well as healthy cells. It’s something known as a ‘transcription factor’, meaning that it acts as a molecular switch that turns on certain genes.

Faults in RUNX1 are important in leukaemia, but there’s been growing evidence, including from large cancer gene studies, that RUNX1 might be involved in breast cancer too. But so far there’s no conclusive evidence.

Dr Blyth and her team decided to scan through tumour samples from nearly 500 breast cancer patients, searching for associations between RUNX1 and particular tumour types.

A tissue microarray

They did this using tissue microarrays, where hundreds of tiny slices from different tumour samples are stuck onto glass slides and then simultaneously tested for the presence or absence of various molecules – such as oestrogen or progesterone receptors, HER2 or RUNX1.

After careful analysis, the scientists found high levels of RUNX1 in triple negative breast tumours from patients with the poorest survival. This is an important observation, as at the moment there are no reliable biological markers for these tumours. Being able to spot these people would help doctors decide on the best approach for treatment for each individual.

But perhaps most importantly, this discovery points towards potential new treatments for triple negative breast cancer. For technical reasons it’s difficult to develop drugs that directly target RUNX1 itself, but researchers in other labs are trying to unpick the complex biological chain of events that leads to RUNX1 being activated, as well as how it works with other molecules to switch on genes. The hope is that some of these other players might prove to be good targets for new therapies.

While there’s still a lot more work to do to nail down exactly what RUNX1 is up to in breast cancer – and to turn that information into viable treatments for patients – it’s an urgently-needed step forward.

Into the future

But to make significant progress in boosting survival from triple negative breast cancer, we urgently need to fight the disease on multiple fronts – and RUNX1 is just one part of the story. So we’re also supporting several other projects around the UK to try to speed up progress.

For example, Dr Walid Khaled at Cambridge University is about to start work on an exciting new project aimed at understanding exactly which cells in the breast spawn triple negative cancers. By analysing the genetic faults in these cells, he hopes to pinpoint potential targets for future tests and treatments.

And as well as lab work, we’re funding clinical trials too, such as a major study called TNT. The trial is testing adding carboplatin – a platinum based drug – to a combination of chemotherapy drugs for the disease. Hundreds of women have been recruited, and the researchers are following them up, gathering and analysing data, and we’re waiting for the results.

International researchers are working on triple negative cancers too. One particularly interesting avenue is the potential of PARP inhibitors – drugs designed to specifically target cells with faulty BRCA genes, which we’ve written about before. Because BRCA1 gene faults are strongly implicated in triple negative breast cancer, there is hope that these might prove effective.

So far small trials – such as this US-led one – have been promising,  and, here in the UK, we’re currently supporting a trial of a new PARP inhibitor for people with advanced cancers (including triple negative breast tumours) through our national Experimental Cancer Medicine Centre network.

And in another exciting approach, researchers have found that some triple negative breast cancers are positive for receptors for male sex hormones (androgens), which are also produced in small amounts in women. This opens up the possibility that male hormone-blocking drugs, some of which are already used to treat prostate cancer, might have potential for improving survival. Trials, such as these two US studies, are currently under way.

But while the researchers are working away, for Michaela – now four years clear – life goes on. She says, “I remember looking at my husband and two boys and thinking ‘Bring it on!’ I really believed that although I had cancer, it wasn’t going to have me.”

She managed to keep going to the gym all the way through her treatment, and is still as crazy about fitness as ever. This proved useful in 2012 when she was chosen as one of the Olympic torchbearers, which was a truly emotional moment. “One of the best days of my life was when I visited the local hospice with the torch – I cannot put into words how special that day was for me. That was something positive that came out of me having cancer and I truly hope I have many, many more days like that ahead.”

For Michaela and her family, and for everyone touched by cancer, we won’t stop working as hard as we can to make sure those hopes become reality.

Kat

Reference:

Ferrari N., et al. (2014). Expression of RUNX1 Correlates with Poor Patient Prognosis in Triple Negative Breast Cancer., PloS one, PMID: http://www.ncbi.nlm.nih.gov/pubmed/24967588

• Pink ribbon photo by wishuponacupcake from Wikimedia Commons, Microarray image from Johns Hopkins