Genetic clues help predict lung cancer's next move
14 April 2023
Scientists at UCL and the Francis Crick Institute have uncovered early genetic clues that could indicate where and when cancer cells might spread next.
The research, which is funded by Cancer Research UK and published across seven papers in Nature and Nature Medicine, could pave the way for doctors to use blood tests to predict cancer’s future, monitor it in real-time and adapt treatments accordingly.
It also offers the possibility of clinicians being able to analyse the disease’s risk of returning following surgery.
The discoveries were made through the TRACERx study, which analysed the tumours of 421 patients with non-small cell lung cancer - the most common form of the disease – from when they were diagnosed to monitor how the tumours changed over time.
In the papers, the researchers describe how changes to cancer cells’ DNA are enabling them to anticipate how those cells will behave in the future. This includes where and when cancer will spread to other parts of the body in a process known as metastasis, which is responsible for most cancer deaths worldwide.
While the research was carried out on patients with lung cancer, the findings can be applied to other cancer types, such as skin cancer or kidney cancer.
Lead researcher Professor Charles Swanton (UCL Cancer Institute, the Francis Crick Institute and Cancer Research UK), said: “TRACERx recognises that cancer is not static and the way we treat patients shouldn’t be either.
“What makes the TRACERx project particularly powerful is that it treats tumours as ever-changing ‘ecosystems’ made up of diverse cancer cell populations.
“By looking at the tumour in its entirety, we can observe how these cell populations interact and even compete with one another, which is helping us to glean valuable insights into the likelihood that a tumour will return and when this might happen. We can also observe how the tumour is likely to evolve over time, spread and respond to treatment, offering hope to millions of patients in the future.”
Among the major findings in the seven papers are:
- Tumours can be made up of many different populations of cancer cells which carry sets of genes that are constantly changing. The more diverse these tumours are, the more likely the patient’s cancer will return within one year of treatment.
- Some patterns of DNA changes when observed in a patient’s tumour indicate what their cancer might do next.
- These patterns could indicate to doctors which parts of a tumour might leave the primary lung cancer and spread to other parts of the body in the future.
- Blood tests could be used to monitor these changes to tumour DNA in real time, helping doctors pick up on early signs that cancer is returning or not responding to treatment.
These studies are the culmination of nine years of research from Cancer Research UK’s £14 million TRACERx study – the first long-term study of how lung cancer evolves. TRACERx is a nation-wide research effort, involving more than 800 participants in clinical trials and a community of 250 investigators who are based at 13 hospital sites across the UK.
The latest research has revealed three main areas of interest:
Constant changes to cells allow tumours to thrive
Tumours are made up of different “populations” of cancer cells which all carry different genetic mutations. The more diverse these mutations are, the more that tumours can evolve and gain resistance to treatments.
The researchers found the specific patterns of genetic mutations in cell populations enable cancer to return in a patient quicker – within one year of surgery.
These patterns of mutations also indicate whether a tumour is more likely to spread to other areas of the body beyond the lungs and chest.
In the future, this information could help doctors to predict whether someone with early-stage cancer, who should be treated successfully with surgery, may end up seeing their cancer return.
Additionally, researchers also found that the genetic diversity of cell populations within a tumour not only stems from genetic changes, but also from the way that genes are expressed.
Changes in gene expression can affect important aspects of cancer biology, including whether a tumour will return after surgery.
In this instance, the researchers suggest that doctors treating lung cancer patients could intervene early by identifying those whose cancer is most at risk of returning after surgery and following up with further treatment, to help prevent the cancer from coming back.
Identifying what leads cancer to spread
Researchers also looked more closely at how cancer had spread in the TRACERx participants.
They identified which cells in a tumour were most likely to be responsible for cancer spreading (metastasis) in future because these cells were more likely to harbour certain changes in their genes. These indicate that a cell has a higher chance of leaving the tumour and moving to other parts of the body, where it then grows into a new tumour.
Metastasis is estimated to cause 90% of cancer deaths, so understanding which parts of the tumour are responsible for triggering this process could allow researcher to target specific treatments to prevent cancer from spreading.
Transforming how we track people’s cancers
The TRACERx scientists investigated whether they could track changes in the tumour and features of its genetic diversity without the need for surgery or biopsies – a type of medical procedure that involves taking a small sample of tissue and examining it in a lab.
By analysing DNA released into the bloodstream from tumour cells, known as circulating tumour DNA (ctDNA), researchers found that the presence of ctDNA in the blood before or after surgery suggested that the patient’s cancer was highly likely to return in the future.
The presence of tumour DNA in the blood isn’t the only indicator that cancer might spread or come back. Researchers found the microscopic patterns created by the arrangement of tumour cells are linked with the risk of cancer returning.
Executive Director of Research at Cancer Research UK, Dr Iain Foulkes, said: “A blood test that reads ctDNA could let doctors track someone’s cancer in real time, allowing them to personalise treatments to that patient.
“Currently, the best option we have to monitor a patient’s tumour is to extract tissue either through a biopsy or during surgery. Both are invasive and time-consuming options which give us a limited snapshot of how that tumour is behaving at a given point in time.
“Analysis of ctDNA would give us a fuller picture of how the tumour is changing over the course of the patient’s disease using minimally invasive blood tests. It would allow doctors to treat people more proactively, taking swift action to change a treatment plan that’s not working.”
TRACERx has now entered its next phase, known as TRACERx EVO, which will receive just under £15million in additional funding over the next seven years to further our understanding of tumour evolution and use that knowledge to change how patients with cancer are treated.
- The evolution of lung cancer and impact of subclonal selection in TRACERx
- Professor Charles Swanton’s academic profile
- UCL Cancer Institute
- UCL Medical Sciences
- The Francis Crick Institute
- Dividing cancer cell metastasis division as a disease anatomy concept as a growing malignant tumor on an organ inside the human body as a 3D illustration. Credit: wildpixel on iStock