What's new in cancer?: cell free DNA

Back in 2022, I wrote about some of the promises of cell free DNA.

Since then it has become a routine technique for selecting precision therapies for cancer especially lung and breast cancer.

In the last year there have been trials which are helping us better understand how cell free DNA may be best used.

Early detection of cancer

Modern medical imaging can detect abnormalities as small as 1mm, but a 1mm³ speck of cancer may contain as many as 100 million cells. To find cancer earlier than approaches that detect disease at cellular level are necessary. This was tested in the NHS-GALLERI trial, the world’s largest study of Multi-Cancer Early Detection tests (MCEDs).

With a massive effort from English Cancer Alliances 142,000 people agreed to take part in a trial where a blood sample was analysed for detectable DNA changes associated with 50 types of cancer. When launched in 2020 by the Matt Hancock, former Secretary of State for Health and Social Care, it was described as “ground breaking” and a “potential game changer”.

Earlier this year we saw results, which were sadly disappointing. The trial failed to meet its target of showing a statistically significant reduction in the numbers of cancers detected at Stage 3 and 4. The numbers of late stage cancers detected did fall with each of the three years of testing but using what is currently a very expensive test.

This does not mean that MCEDs won’t be used, but that we need testing protocols that permit clinically useful detection in a cost-effective way. The future will need trials in targeted populations and refinements in MCED technology. Trials will be difficult to do but the National Screening Committee has now helpfully issued a position statement on how those trials should be designed and reported.

MCEDs look for traces of any cancer in a person with no cancer diagnosis. A more specific task is to use ctDNA to track a known cancer. Two recent trials have shown how this can help avoid therapy or perhaps change it.

Adjuvant therapies are treatments that are given after cancer surgery with aim of ‘mopping up’ any microscopic cells of cancer left behind. It would spare many people unnecessary therapy if testing could reliably tell whether any cells were there to treat.

Muscle-invasive bladder cancer is usually treated with initial chemotherapy and then surgery. If the cancer returns after the surgery, then often the prognosis is poor. The UK-led IMvigor-011 study looked at 761 people who had had their bladders surgically removed for cancer.

250 of these were found to have ctDNA for bladder cancer cells in the blood after the operation and these people were then allocated to further treatment with immunotherapy or a placebo. The immunotherapy extended survival (overall survival in people having immunotherapy was 9.9 months compared to 4.8 months in those who received placebo), but the therapy is toxic and 2% people had fatal side effects.

The really intriguing part of the trial was in those who tested negative for ctDNA, 357 remained persistently ctDNA negative and 88% were disease free at two years. This result suggests that in the future we may be able to use ctDNA to target toxic adjuvant therapies more selectively, rather than treating everyone ‘just in case’.

In advanced disease cancer cells often become resistant to therapy. It is this resistance that leads to cancer escaping control and the need for new treatments. In breast cancer the emergence of a ESR1 mutation in cancer DNA predicts resistance to standard therapies. It is a provocative idea that detecting the mutations that lead to treatment failure before any resistance becomes a clinical issue might allow for better outcomes – using ctDNA as the genetic equivalent of Tom Cruise in ‘Minority Report’.

This was the theory tested in the SERENA-6 study led by Professor Nick Turner from the UK and conducted in 264 hospitals in 23 countries. 3,256 people had at least one ctDNA test looking for ESR1 mutations whilst on therapy for secondary breast cancer. 315 with a positive test were randomly allocated to continue their current therapy or to switch to the drug Camizestrant (predicted to be effective even with a ESR1 mutation). From the point of switching people on the new drug waited an average of 16.8 months before their disease progressed compared to only 9.8 months in those who carried on their original treatment.

We don’t yet know if this benefit translates into patients living longer, and this combined with the fact that a huge number of expensive tests were required to find a relatively small number of positive tests mean that this process isn’t ready for routine use.

The technology continues to refine and show some tantalising glimpses of ways in which we might be able to get one step ahead of cancer.