One of the most exciting applications of cancer genomics is the development of liquid biopsies. By measuring circulating tumour cells or cell-free DNA in bodily fluid, liquid biopsies can be used to detect cancer, monitor treatment response, and help map tumour evolution. Arming the clinician with in-depth molecular information in a non-invasive manner can influence clinical decision making. As a result, immense efforts have been underway over the past few years to develop reliable liquid biopsy assays.
At the Festival of Genomics and Biodata 2022, we hosted a liquid biopsy workshop with a host of experts from the space. Below, we share some of the key insights learned from this session.
Different application
Our panel began by highlighting the wide array of applications for liquid biopsy technology, and how there cannot be a “one size fits all” approach. Applications range from early detection and late-stage treatment guidance to identifying high risk populations. Another really interesting application that will be touched on later is confidence in negative results, which is important for deescalating treatment.
Perhaps expectedly, it is easier to detect large tumours than smaller ones, as the amount of ctDNA shedding tends to be higher. As such, the real challenge comes with early detection of small tumours. It was noted that the most advanced application currently is testing for drug resistant mutations, or equally, a druggable mutation, in late-stage tumours. That said, even the more challenging small tumour screenings post-treatment are sometimes able to detect the molecular signal of a relapse years before imaging can.
Liquid biopsy pioneer Klaus Pantel, Chairman of the Institute of Tumour Biology at the University Medical Centre Hamburg-Eppendorf, was quick to point out that for early-stage detection, we are peering into the dark. Although clinicians won’t know the molecular makeup of the tumour, all tumours are heterogenous, and therefore one analyte will not be suitable for all tumour types.
Meanwhile, Dominic Rothwell, Nucleic Acid Biomarker Team Lead, CR-UK Manchester, discussed his multi-omic approach to assay development, incorporating ctDNA, methylation, and fragmentomics. Fragmentomics looks to encompass the study of the structural characteristics and sequence composition of plasma cfDNA to provide further information about the tumour from which they originate.
Sensitivity and specificity
A lot of what was discussed in the workshop focussed on sensitivity and specificity. If a test is likely to correctly identify people with the disease, it is sensitive (high sensitivity = low false positive). If a test is good at correctly identifying those who do not have the disease, it is specific (high specificity = low false negative).
Mike Hubank, Head of Clinical Genomics at The Royal Marsden NHS Foundation Trust, discussed how there is a huge investment into making background error models using tens of thousands of datasets but posed the question: how sensitive do we need these assays to be? As Dominic put, it doesn’t matter how sensitive your assay is if the molecule you’re looking for isn’t there.
Sensitivity is less important for high shedding late-stage tumours but is much more important for early detection. Klaus commented on how there are so many other applications in which high sensitivity is very important, such as minimal residual disease (MRD) and screening elderly people with high levels of mosaic pre-cancer somatic mutations. Asking for ‘too much’ sensitivity may not be unfavourable.
Sensitivity and specificity are inversely proportional, and while generally sensitivity is the goal, it’s also important to have tests with high specificity. As mentioned earlier, an overlooked area is having confidence in a negative result. A negative result in a patient can be the signal to start deescalating their treatment. Not only will this have cost benefits, but it can also reduce patient exposure to severe side effects from treatment. However, this is a delicate area, as patients will want to be as close to certain as possible, and high specificity tests for treatment de-escalation will likely have to be based on several different analytes.
Global standards and integration within healthcare
During the workshop, Lauren Leiman, Executive Director at BloodPAC, talked about BloodPAC’s efforts to create standards. Lauren felt that the technology is moving so fast that everyone needs to “take a breather” and try and work out a set of standards and guidance. She made reference to the surprising fact that there isn’t even a universally accepted lexicon for liquid biopsy, or a definition of what a ‘high risk patient’ is.
Reliable control materials were said to be at the top of the FDA’s list for priorities when trying to create standardisation within the field. Lauren emphasised how important a strong, stable standardisation foundation is for start-ups and emerging research in the field of liquid biopsy, and how translation into clinical settings will rely on this foundation.
The final point raised was how liquid biopsy will be integrated into the various global health systems. Clearly, the NHS is very different from healthcare in the US, and also from in the EU. The workshop questioned whether liquid biopsy would replace current biopsy tests, and whether it would be a supplementary test, or a mixed model.
In the EU, new systems implemented must be subject to a socio-economic assessment. There was agreement here on the wider potential efficacy of liquid biopsy. Mike mentioned a small study during the pandemic in which liquid biopsy was used for patients that couldn’t or didn’t want to come in for tests. In this small study, liquid biopsy proved popular and successful. Equally, Dominic said how the technology has the potential to provide far greater access for people, and that earlier pilot studies using liquid biopsy have boosted patient accessibility in socially deprived areas.
It’s an exciting time to be following developments in liquid biopsy, and it will be extremely interesting to see how the insights in this workshop take shape in real world examples as the technology develops and matures.
Image Credit: Canva
