The new project, Breast Cancer Now’s LEGACY Study for Secondary Breast Cancer, will analyse tissue samples from secondary breast cancer patients, collected just hours after they pass away.
The study is a collaboration between the ICR and our colleagues at The Royal Marsden Hospital, and is funded by the new charity Breast Cancer Now.
The project is the first of its kind in the UK, and tissue will be taken quickly enough to do highly sophisticated genetic and biological analysis in ICR laboratories. This will allow our researchers to help create an inventory of tumours around the body and to look in the finest detail at the way genetic messages drive the cancer to develop and grow.
Why LEGACY is so important
When breast cancer spreads around the body the cancer evolves and becomes resistant to treatment. Researchers have been trying to understand this process, but access to tumour tissue has been limited.
I spoke to Professor Andrew Tutt, Director of the Breast Cancer Now Research Centre, currently the Breakthrough Toby Robbins Breast Cancer Research Centre, at the ICR and joint lead on the LEGACY study, who explained the challenges: “We are already doing research to work out why breast cancer spreads and becomes resistant to treatment, but it is very difficult to get the depth of understanding we need. Often the cancer spreads to an area of the body like the brain or spinal cord where it may be too difficult to take a sample or the procedure may be too risky.
“Even if we are able to take a sample of the metastatic tumour, it may not provide all the information we need to give the best possible treatments for patients. Unfortunately we see lots of variation within each tumour – different areas of a single tumour or its metastases often have different genetic and biological characteristics and could respond differently to treatments. Simply taking one sample of an individual tumour does not give us enough information.
“LEGACY will give us access to samples from all the breast cancer in the body, and the chance to examine different areas of each tumour. This is unprecedented and will allow us, for the first time, to build up a full picture of what is happening.”
Highlighting the differences in metastatic tumours
The site of the tumour is also very important to the behaviour of the cancer, and tumours in different organs will act in different ways. Professor Tutt told me about these differences: “As cancer cells leave the breast and colonise other areas of the body they learn to survive in their new environment. They do this by building up genetic and biological changes that allow them to exploit the conditions of their new home. A tumour in the brain will be exposed to a very different environment to a tumour in the liver. Secondary cancers in different organs sometimes operate so differently it is hard to believe they originated from the same primary cancer, and this can affect the way they to respond to the same treatments. This makes treating cancer that has spread especially challenging.
“If we can begin to understand how breast cancer tumours behave in different organs around the body, we can start to think about how to tackle them to ensure our therapies attack both variations and similarities in how they have evaded previous treatments.”
Cancer microenvironment
Interestingly, cancer cells also recruit neighbouring healthy cells to act as their accomplices, to provide important factors they need for growth. This cancer ‘microenvironment’ is an increasingly important area of cancer research, and might help us develop treatments to stop cancer growth and spread in future. So as part of the LEGACY study, samples of tissue will be taken both from the tumour and adjacent non-cancerous tissue to allow our researchers to delve further into this relationship.
Tumour profiling and mapping cancer spread
Tissue samples will be analysed in the ICR Tumour Profiling Unit, our specialised facility that is able to pinpoint the tiniest genetic and biological changes in cancer cells and compare them to normal tissue in the body. These cutting edge technologies will allow our researchers to map cancer spread and provide a detailed understanding of how breast cancer develops resistance as it moves round the body. By comparing tumours around the body to the original cancer, they hope to build a cancer cell family tree that shows how the cells change their DNA as they develop and spread around the body.
As Dr Amanda Swain, who heads up our Tumour Profiling Unit told me: “The LEGACY study can provide us with a history trail of breast cancer spread, telling us where the individual tumours came from and when they appeared. For example, we should be able to work out if the metastatic tumours originate from the breast, or if they have been seeded by other metastatic tumours. We need to unravel this hugely complex interplay to become more intelligent about the way we treat breast secondary cancer patients.”
Spotlight on DNA messages
Not only will researchers be looking at changes in the code of DNA that accumulate in cancer cells, they will look at the way messages are transmitted from the DNA into proteins that control the behaviour of the malignant cells. Tissue samples will undergo widespread analysis of the molecules that DNA uses to send messages, messenger RNA, and the resulting proteins that change cell behaviour. Our researchers will be able to do this because tissues will be taken so quickly after the patient has passed away, so the proteins and RNA will still be intact. They will also study proteins that bind to DNA, which change the way DNA makes proteins, and methylation – one of the ways the cell controls whether genes are active or not.
Evolution of drug resistance
These microscopic changes are the key to understanding why cancer cells become resistant to treatments. Cancer cells often switch off proof-reading mechanisms for their DNA and this allows them to build up lots of genetic and biological changes as they develop. This is a speeded up form of evolution, where there can be many different cell types in a population – and those that are the best at adapting to their environment, reproducing and evading treatment are the ones that thrive.
Professor Andrew Tutt told me about the process: “The more genetic and biological changes that occur in cancer cells over time, the more difficult cancer is to treat. If we know precisely what these changes are, we can look through our existing toolbox of treatments to see if we can use what we have already in cleverer ways, or see if we can repurpose or combine drugs used for other types of cancers for use in breast cancer. And, in the longer term, this clearer understanding will help us design new drugs and drug combinations for secondary breast cancer.”
Studying live cells
In order to mimic the metastatic cancer in the laboratory, our scientists will use two approaches. Firstly, they hope to be able to grow some of the cells taken from the tissue in the laboratory to do further research and test treatments. They can also use genetic editing techniques to test the effect of removal of the 'driver' genes of the metastases and to reproduce what they see as 'drivers' in the tissue samples in existing cell lines.
Liquid biopsy
As well as shining a spotlight on cancer cells, our scientists will scrutinise DNA found in the blood plasma of women. Dr Amanda Swain told me why this is important:
“We want to know if DNA found in breast cancer patient’s blood correlates to what is going on in the tumours in the patient’s body. If research shows there is a correlation, blood tests, rather than biopsies, may help inform which treatment a patient receives in future.”
In summary
While there is quite some way to go before this research begins to shape our understanding of secondary breast cancer, the number and scope of research projects that the LEGACY study will fuel is quite remarkable.
As Professor Tutt concludes: “Only with a deep scientific understanding of what happens when breast cancer spreads will we be able to move to an era where we will be able to treat secondary breast cancer with confidence.”
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