Could a cancer comeback be written in your blood? A new approach tracks genetic traces left behind by dying tumour cells – revealing who is at real risk of relapse. By bypassing tissue biopsies and focusing on what is floating in the bloodstream, scientists hope to guide smarter treatment decisions and reduce unnecessary chemotherapy. Early results suggest that this works surprisingly well.
The standard treatment for many people with cancer is a one-two punch: surgery to remove as much tumour tissue as possible followed by chemotherapy to kill any remaining cancer cells and reduce the likelihood the cancer will recur.
But chemotherapy can be gruelling, with difficult-to-manage side-effects ranging from appetite loss to a weakened immune system. Some people with certain types of cancer with a low rate of recurrence may not have much to gain from chemotherapy, explains Claus Lindbjerg Andersen, a molecular biologist and cancer researcher at Aarhus University and Aarhus University Hospital, Denmark and Director of the Danish National Center for Circulating Tumor DNA Guided Cancer Treatment.
“We are overtreating many people with this follow-up chemotherapy,” Claus Lindbjerg Andersen says, adding that an estimated 60–70% of people with colon cancer may receive little benefit.
A new technique could help doctors to identify who really needs chemotherapy – and who might be able to do without – based on a blood test that predicts the likelihood that the cancer will recur.
These next-generation blood tests could help to “de-escalate cancer treatment when it is not necessary,” says co-author Francisco Gimeno Valiente, a postdoctoral biology researcher at University College London Cancer Institute.
What blood reveals after surgery
Tumours form when mutations in DNA cause the rhythms of cell death and cell birth to go haywire. Alterations to cell birth lead to the out-of-control proliferation of cancer cells, and some tumours also become necrotic – cells dying massively before their time.
When a cell dies, the cell wall pops like a bubble, jettisoning its contents. The defective DNA from these dead cancer cells makes its way into the bloodstream as circulating tumour DNA. Previous research suggests that the more of this ends up in the blood after surgery to remove a tumour, the more likely the cancer will eventually recur.
There are currently about 30 tests on the market in Europe that measure circulating tumour DNA in the bloodstream after surgery, but none have been approved by the European Medicines Agency to guide cancer treatment, Claus Lindbjerg Andersen says. “Evidence indicates that the tests are accurate but does not indicate any good use for the knowledge the tests provide,” he explains. “However, some oncologists in the United States already use these circulating tumour DNA tests to inform treatment decisions.”
These existing tests rely on tumour tissue biopsies to determine which mutations to detect in the blood – but tissue biopsies are often very small, perhaps a few millimetres in diameter. “When you send a tissue biopsy to the pathologist, they check just that one specific region of the tumour,” Francisco Gimeno Valiente says. This risks missing the complexity contained in a single tumour, which can comprise regions with different mutations, he explains. As such, it is not surprising that these existing tests have limited accuracy – one on the market today only predicts about 55% of recurrences, he says.
Skipping the tumour for better data
Francisco Gimeno Valiente and his team suspected that they could beat those odds – by ignoring the tumour itself and concentrating on the blood.
The researchers followed 320 people treated for colon cancer at a hospital in Valencia, Spain between 2015 and 2019. Instead of relying on a tissue biopsy to identify what circulating tumour DNA mutations to track, they took blood samples before surgery – when the whole tumour was still present and dumping its defective DNA into the bloodstream – to capture every mutation present in the tumour and not just whatever happened to be present in a 4-millimetre tissue biopsy. “You can detect many types of alterations at once,” Francisco Gimeno Valiente adds.
But using the pre-surgery blood samples to identify target mutations has its own set of hurdles. The advantage of using a tissue biopsy is that researchers are certain that whatever DNA they find inside a tumour is from the cancer. To use the liquid biopsy, Francisco Gimeno Valiente and his team would have to figure out how to distinguish between tumour DNA and all the normal DNA also circulating in the blood.
A one-size-fits-all human reference genome would not do the trick. “There is too much individual variation,” Francisco Gimeno Valiente explains. So the researchers sequenced DNA from each person’s white blood cells to set an individual baseline for their DNA unaffected by cancer.
By comparing circulating DNA in the blood with each patient’s “normal” DNA, the researchers compiled a list of mutations present in the tumour before surgery and ranked them by prevalence. For the new technique, Francisco Gimeno Valiente and his team decided to make each person’s top 16 variants with the highest variant allele frequency (TAV16) the target for the search after surgery.
They found that TAV16 predicted cancer recurrence in the cohort in Spain with remarkable accuracy: it correctly flagged 95% of those who eventually relapsed. Of those TAV16 flagged as having higher risk, 87% experienced recurrence. “TAV16 is a lot more sensitive than previous tests,” Francisco Gimeno Valiente notes.
Validating the test and expanding its scope
To validate the test’s accuracy, the researchers needed to put it through its paces with another cohort. “It was very complicated to find another cohort with the same very, very specific profile”, Francisco Gimeno Valiente says. Eventually, the researchers reached out to Claus Lindbjerg Andersen.
Fortunately, he had collected blood and tumour samples from 15 people treated for recurring colon cancer in Denmark between 2015 and 2022 as part of another study. TAV16 performed even better with this cohort, correctly flagging 100% of those whose cancer recurred.
For patients like those in the cohort in Spain, that kind of accuracy could mean skipping chemotherapy – and months of side-effects – without increasing their risk.
Clinical trials are required before TAV16 makes its way into oncology clinics in the European Union, but its creators hope that it will one day guide treatment decisions – and not just for colon cancer.
Francisco Gimeno Valiente says that he and his team have patented TAV16 and are currently working to validate TAV16 for lung, kidney and pancreatic cancer. The search is on for more cohorts with cancer around the world that have taken liquid biopsies both before and after surgery.
The early results are promising, Francisco Gimeno Valiente says. Their unpublished data suggest that TAV16 predicts recurrence in pancreatic cancer about as accurately as for colon cancer. “Its sensitivity is quite high. We believe that this could change how relapse risk is assessed – not just for colon cancer but across oncology.”
