This week’s publication in Nature is another major step towards the promise of the liquid biopsy. The study shows that the residual DNA fragments from cancer cells which are found in a patient’s blood could really have a role in real-time monitoring of a patient’s cancer in the future. These fragments were used to track the progress of 100 patients with non-small cell lung cancer from diagnosis, surgery to treatments, with regular blood tests every few weeks. Particularly impressive was that early recurrence of cancer following surgery could be predicted.
Furthermore, a related study in NEJM made some insights into intra-tumour heterogeneity – the phenomenon by which a tumour contains several very different cells, expressing different genes. Every time a cancer cell divides, it acquires further mutations. As in evolution, specific mutations lead to a selective advantage which means that the cells will divide and grow faster than other cells.
The study shows that many of the mutations which happen early on in the development of a cancer are within the well-known genes which can be targeted by the specific targeted therapies, like EGFR and MET. As the cancer develops, the cells within the tumour have a broad range of other mutations. Some of the later mutations lead to the cells developing chromosome instability, which the study associates with an increased risk of cancer recurrence and a poorer overall prognosis for the patient. The underlying promise from both of these intriguing papers is that monitoring genetic changes via regular liquid biopsies will allow us to make clear conclusions about how to treat a patient and their inherent prognosis.
To understand what a breakthrough this could be, it would be good to think about potential use in the clinic. A major drug treatment today is called erlotinib, which was first approved to treat non-small-cell lung carcinoma in 2004. It has become a popular treatment as, unlike many other therapies, it does not have significant side effects – especially compared with the more established chemotherapies. Erlotinib works in tumour cells which have activating mutations in the EGFR gene – a gene which encodes for a protein receptor with importance in maintaining cellular stability. There are a number of tests available for EGFR mutations, which means the drug is only given to those patients who will be effectively treated by the drug.
However, approximately a year after the treatment is given, these people will start to become resistant to the drug. This resistance can lead to the recurrence of lung cancer, as the resistant cells may have a specific mutation called T790M which can make the cells grow and divide faster. Another drug, called osimertinib, exists for non-small cell lung cancer patients carrying this mutation.
There are very new diagnostic tests for the T790M mutation – and this is a significant area of commercial interest amongst diagnostics companies. Patients can then be tested again for this mutation. However, the cancers can then become resistant to osimertinib by a variety of mechanisms, sadly within months. The cells may develop repeated copies of the MET gene – which means that they could respond to a drug called crizotinib. Or it may contain a new mutation in the EGFR gene, called C797S. Recent studies show that a drug called brigatinib may be effective in these circumstances, in combination with a standard anti-EGFR therapy such as erlotinib.
So the cancer evolves resistance to multiple drugs quickly. In order to treat the patient effectively, the tumour’s genetic profile needs to be tracked regularly. The invasive biopsy does not allow this to happen but the liquid biopsy could deliver this promise – as illustrated by the latest studies in Nature and NEJM. Both papers originate from the TRACERx study, which will eventually analyse another 742 patients. I keenly look forward to hearing more – as I’m sure do the large number of market-leading companies and innovative start-ups who have been developing technologies to isolate circulating tumor DNA fragments and cells from blood. It is vitally important to make therapy decisions quickly in this disease area as resistances develop within months, and so these technologies could really improve patient outcomes.