Implications and future of targeted methylation analysis of cfDNA and its role in the early detection of tumours.

Commenting on the paper Professor Joan Seoane from Vall d’Hebron Institute of Oncology (VHIO), Spain, shares his perspectives on the potential of the test for the early detection of tumours.

In what way does this technique differ from the methods already used for liquid biopsies?

The technique described in the Annals of Oncology paper is different from the common liquid biopsy methods currently used, because it analyses the state of methylation of DNA. One of the mechanisms of regulation of gene expression is through the epigenetic silencing mediated by DNA methylation. The rationale behind the new technology is that the methylation pattern that is found in a tumour cell is different from the one in a healthy cell. The analysis of the methylation pattern in cfDNA allows the detection of fragments of DNA released by the tumour cells. This provides high sensitivity and specificity because there are many regions in the DNA that are methylated, which means that there are many possibilities to detect those different DNA methylated regions present in cancer.

The method that is commonly used today consists in the genomic sequencing of cfDNA in the blood. This technology detects genomic alterations that are found in the molecules of DNA released by the tumour cell.  This technique does not only detect and monitor the presence, progression or response a tumour may have to treatment, but it also gives information about the specific mutations that a tumour has. In some cases, unfortunately still not too many, this can dictate the treatment: if for example a lung cancer patient has an EGFR mutation, that can be detected in the blood by sequencing the DNA, doctors will be able to determine the best treatment approach (a specific EGFR inhibitor). 

Does this new technology have the potential to unlock blood-based screening in the future?

Yes, it is one of the great potentials of this work. With the type of specificity and sensitivity of the test, one can consider doing a massive screening in the population in order to achieve early detection of cancer. The earlier we detect the cancer the better survival and less morbidity.

It can be particularly useful to target some populations that have high chances of developing cancer, presenting syndromes like Li-Fraumeni syndrome, or those with particular status such as very heavy smokers.

The results shown are already a breakthrough. Still, in order to translate them into the clinical practice more studies with even larger populations should be performed.

In addition to the important role for the early detection, what other clinical applications can you see?

The application of this technique may facilitate the answer to one unmet need which is the identification of the site of origin of the cancers of unknown origin, so-called CUP. These metastatic lesions cannot at present be properly diagnosed and treated because their origin is not found. If the new technology works, it will help to diagnose the patients with this type of lesions and determine the right treatment options.

Additionally, in the future it will be interesting to address how the technology may monitor tumour progression and response to treatment in tumours that are not easily detected by imaging. It will be interesting to collect a cohort of patients where analyses are made prior and after treatment to see if the pattern and amount of methylation found in the blood correlates with the tumour burden.

What limitations remain?

The first limitation I can see is linked to its application. It is true that this technique may be applied by healthcare systems in their national screening programmes; however, the economic aspect cannot be ignored. The sequencing and manipulation of the blood needed to perform the test is an expensive procedure and unfortunately, I don’t see that its implementation is feasible at a large scale in the near future.

There are other limitations linked to the detection at various stages of cancer. In the paper it is very well described how the efficacy of the test improves with the stage of the cancer; the more aggressive ones are more easily detected. This means that maybe in the early stages, where detection is really relevant, the technology is not very powerful.

Despite that the study has analysed many types of cancer, still some, that in my opinion are particularly relevant, are missing. For instance, results on brain cancer (primary and metastasis) would be really interesting to see, because these are very aggressive tumours and early detection would definitely make the difference in patients' outcome.

Last but not least, this type of test is based on DNA methylation in contrast with the other type of methods that are based on genomic alterations. With the genomic alterations you have an extra information, which is about targetable alterations, for example EGFR or BRAF mutations, that with this technology cannot be detected.

We have seen that both procedures have limitations, do you think the key for the future will be to combine the commonly used liquid biopsy methods and this new technique to have a full picture at a detection stage?

Definitively. It will be very interesting to combine both techniques and take advantage of the good parts of both. With the new technique you can have much sensitivity by identifying the tumour early and with genomic sequencing you can understand if there are additional targetable genomic alterations and see how the tumour evolves with time. The combination of information will help doctors to precisely detect and characterise the tumour and adapt the treatment to each patient at a specific time.

References

1. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV on behalf of the Circulating Cell-free Genome Atlas Consortium (CCGA), et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Annals of Oncology DOI