Whether we are off sick, on holiday, in a relationship or in a meeting, we are constantly updating our status to the world. Using various apps, people can communicate what they are up to and where – if only to inspire envy – by producing a timeline of these activities.
But while we use social media or a messaging app, cancer tumours send updates to their surroundings – they just do it through our blood.
As tumour cells grow and die, they release their DNA as tiny fragments into our bloodstream – known as circulating tumour DNA or ctDNA. For researchers and clinicians, ctDNA is effectively a genetic status update that the tumour has unwittingly released.
Although our healthy cells also release DNA into our blood as they die and are replaced, ctDNA can be distinguished from our normal cell DNA by encoding cancer-specific genetic mutations or by their unusual fragment sizes.
READING A GENETIC UPDATE
These DNA sequences produce specific genetic signatures that can be ‘read’ by genomic sequencing. This technique provides the entire genetic makeup of an organism, cell or tumour type.
ILLUMINA STORY LINK
The DNA changes are unique to each person and their cancer, but there are distinctive patterns seen in certain cancer types, even when they occur in different organs or tissues, or have already spread in the body.
“Every cancer is a result of DNA damage over time,” says Professor Sean Grimmond, director of the University of Melbourne Centre for Cancer Research, and lead at The Advanced Genomics Collaboration Clinical Genomics Platform.
“For every cancer to develop it needs approximately five genetic changes that allow it to grow and spread, overcoming the normal cell controls and enabling the tumour to increase its growth rate, move into nearby tissues and evade our immune system,” he says.
“We want to use ctDNA to identify these changes and reveal whether or not the tumour encodes an Achilles heel. This would be an opportunity to personalise treatment against that specific DNA change for the best outcome for the patient.”
FASTER DIAGNOSIS AND PERSONALISED TREATMENT
For some years now, researchers including Professor Grimmond’s team have been extracting and analysing DNA taken directly from cancer tissue. Once sequenced, the cancer DNA can then be assembled into a reference database to compare against patient samples.
This work identified the 40 genes that promote pancreatic cancer growth. Pancreatic cancer is particularly deadly – only five per cent of patients will still be alive within five years of their diagnosis. The study also looked for similar mutation profiles between different types of cancer, in the hope of identify similar root causes.
In the case of pancreatic cancer, these efforts identified a subtype of pancreatic cancer that had similar genetic changes to bladder and lung cancers, where treatments were already being developed.
“Finding similarities allows us to draw on prior expertise and therapies designed for specific cancer types and test them in cancers from different tissues but having the same mutation-type,” says Professor Grimmond.
Now researchers are looking beyond surgical biopsies and focusing on blood tests or ‘liquid biopsies’ to access more genetic information using ctDNA.
A blood test can be especially beneficial when tissue biopsies are difficult or sometimes impossible to take surgically – for example, biopsies from the lungs and brain, or once a cancer has spread. They are also useful when the patient has multiple tumours.
Unfortunately, chemotherapy itself can induce genetic changes. In the same way that DNA changes are needed to start cancer’s uncontrolled growth, there are also specific changes that help it overcome drug treatment. That means some proportion of the tumour cells may be drug-resistant, and others not.
“Now, ctDNA offers a way to understand the entire cancer genome, through a less invasive test,” says Professor Grimmond.
“To treat cancer, we need to know what kind of cancer it is, whether it has spread and if it’s resistant to certain types of treatment. That’s at least three genetic status updates right there.”
Professor Grimmonds’ group are currently undertaking clinical studies in partnership with Illumina, one of the world’s leading biotechnology companies, with the aim of bringing liquid biopsies into routine healthcare.
Some of these studies aim to enhance the detection of tiny amounts of tumour DNA. In the case of ctDNA, it comprises only around 0.5 per cent of our total circulating free DNA (cfDNA), so together with Professor Oliver Hofmann’s bioinformatics team and Illumina, Professor Grimmond’s group are working to standardise and enhance ctDNA extraction, processing and analysis.
Previous studies show ctDNA detection sensitivity varies from 40 per cent in Stage I cancers to 80 per cent in Stage III disease, where the level of ctDNA in the blood is usually higher.
The goal is to raise this detection sensitivity because diagnosis even one stage of cancer earlier can reduce cancer-related deaths and more invasive treatment.
One way to do this could be a ‘lab on a chip‘ which means that any researcher or clinician using this technology, anywhere in the world, has the same methods, reagents and processes. The team also hope this will also make genomic testing more cost-effective.
“By achieving economies of scale, we can ensure everyone can benefit from genomic medicine, not just the one per cent who can afford it now,” Professor Grimmond says.
“As well as the type of mutation a cancer has, we can also detect the amount of ctDNA in the bloodstream. This gives an idea of ‘tumour burden’ – how big and how many tumours there may be.”
REAL-TIME CANCER TESTING
Clinicians could then use the concentration of ctDNA to measure a tumour’s response to treatment in real-time.
“Sampling ctDNA before and after surgery or chemotherapy could indicate if the tumour burden hasn’t decreased, so a clinician can quickly switch to a different treatment regime,” he says.
But before genomics can become part of routine cancer care, a large study supported by the University’s partnership with Illumina focusing on the practical aspects of bringing genetic testing into the health system needs to be completed.
The Cancer of Low Survival and Unmet Need (COLUMN) Initiative is piloting real-time genomic testing for patients with cancers that are challenging to treat – including rare or aggressive tumours, those that are resistant to treatment and are prone to recur – by both tissue-based and ctDNA genomic testing.
“Ultimately, we’d like to move beyond using liquid biopsies for more than just cancer diagnostics.
“We aim to test its value in early detection of cancer recurrence for patients in remission and even screening high-risk patient groups – just like we use mammograms and colorectal screens now – but without the need for a surgical biopsy or imaging equipment,” Professor Grimmond says.
“Apart from a being a less invasive technique, this approach has the potential to benefit remote communities who may have limited access to advanced imaging and surgical biopsies, further delaying initial diagnosis.”
“Instead, interpreting a cancer’s status using a blood test, and in real-time, offers many ways to improve cancer care.”
This research is part of The Advanced Genomics Collaboration (TAGC), a partnership between Illumina and the University of Melbourne to increase genomics innovation, its translation and adoption into the healthcare system and improve patient outcomes.
TAGC has three core platforms that enable research, analysis, trials and commercialisation: Clinical Genomics Platform, led by Professor Sean Grimmond; Bioinformatics Platform, led by Associate Professor Oliver Hofmann; Health Economics Platform, led by Professor Maarten IJzerman.