Dr Matthew Lam discusses how genetics shine a light on how breast cancer occurs and can help us select the right treatment for individuals.

With astronomy, looking into the past is easy.  Stare at the North Star - which is around 430 light years away from Earth - and it’ll be showing you what it looked like 430 years ago.  This is the time it has taken for that star light to cross space and hit the retina in your eye.

With genetics, you can also look back in time – all the way back to the origins of a disease in a single person.  A new study published this week in Cancer Discovery and funded by Breakthrough reveals how the genetic history of individual breast cancers has helped shine a light on how these cancers occurred. It’s also shown us a new way to select the right treatment for each patient.

Unstable

Triple negative breast cancer (TNBC) is an aggressive form of the disease and one we’ve written about previously on the blog.  A key feature of TNBC is that the tumour cells tend to have highly unstable genomes – that is the cells lack the proper defence mechanisms to look after their DNA and so are more susceptible to genetic changes that can cause the disease to progress.

The BRCA genes are one of these defence mechanisms – so faults in these genes can cause TNBC to grow.  But although faults in the BRCA genes are common, they’re not present in every case of TNBC so there must be other underlying problems responsible for the instability of these genomes.

Genomic scarring

Researchers recently found in a landmark study that particular activities, such as smoking, produce characteristic genetic patterns in cancer that leave behind a historical record in a cancer’s genome.  These genetic patterns are caused by DNA damage, and in the same way that cutting your skin with a knife leaves a scar, so does this DNA damage.  The more unstable a genome is, the more ‘scarring’ occurs.

The great thing is that this genomic scarring leaves marks on the DNA that can be detected in the laboratory.  By analysing the genetics of tumour samples donated from TNBC patients treated with carboplatin (a chemotherapy drug), the research team at Kings College London, led by Professor Andrew Tutt and Dr Anita Grigoriadis, were able to give each patient a ‘genomic scarring’ score.  A higher score means more scarring, which means a more unstable genome.  With this information in hand they were able to show that patients whose tumours had a higher score, and so a more unstable genome, were more responsive to carboplatin.

On a knife’s edge

A high response to carboplatin is likely to be a consequence of the increased genomic instability in these tumours.  Carboplatin causes massive amounts of DNA damage to cells, and cells that are already genetically unstable are particularly bad at defending against this damage.  These cells spend their time on a knife’s edge between life and death and all they need is a nudge in the right (or wrong, depending on how you look at it) direction to send them careering out of existence.

We know that faulty BRCA genes could be responsible for this instability, but when the team found that many of the tumours that responded well to carboplatin and had high scores of genomic instability didn’t have faults to either BRCA1 or BRCA2, they had to ask - what is causing these unstable genomes?

HORMAD1

To get to the bottom of this question, the researchers had to get deep into the genetics of these tumours.  Scanning for individual genes common across these tumours revealed that a gene called HORMAD1 was switched on at an abnormally high level.  Tumours that had too much HORMAD1 also had more molecular markers associated with unstable genomes.  But why was this? What does HORMAD1 do in these cells that causes unstable genomes?

It turns out that the protein that HORMAD1 produces is able to recognise damage to DNA and quickly sticks to damaged areas to kick off a process to repair the damage.  There are several different repair mechanisms but it turns out that an over active HORMAD1 gene pushes cells towards favouring a particular repair mechanism over another.  This makes it difficult for the cells to repair certain types of damage to DNA, making them more genetically unstable.  Here’s the killer part – the defunct repair mechanism in these cells is also the one that should repair the type of DNA damage caused by carboplatin.

So, TNBC tumours that have high levels of HORMAD1 are more genetically unstable because one of the repair mechanisms for DNA damage doesn’t work properly.  This in turn makes them more susceptible to chemotherapy drugs such as carboplatin, and as also shown in this study, more targeted treatments that exploit this weakness such as PARP inhibitors.

What does this all mean?

That’s a lot of science.  But it’s a great study that doesn’t just answer one question, but pushes to understand exactly how things are working.  The final thing the team looked at was how relevant all this was to the clinic and to patients.  Using tumour samples donated from patients before they started treatment, they found that HORMAD1 or their ‘scarring’ scores could both be used as biomarkers to predict a patient’s response to treatment, highlighting its value as a test to select the most appropriate treatment.

Looking for faults in the BRCA genes is already used in some cases to help choose which patients will respond best to certain treatments.  Combining these new biomarkers with BRCA means we can make more accurate predictions - adding more evidence to the benefit this research could have on clinical practice.

TNBC is a type of breast cancer with no targeted treatments.  Identifying biomarkers which help detect who will respond best to what treatment has the capacity to drastically improve how women with this type of breast cancer are treated.  Although some verification of this study’s results is needed, it is encouraging to know that research is starting to find positives about triple negative breast cancer.

Dr Matthew Lam is Breakthrough Breast Cancer's Senior Research Officer