Skin deep: Rethinking liquid biopsy for skin cancer

The concept of liquid biopsies – searching for cancer specific markers in fluids rather than tissues – has opened new opportunities for improving the way cancers are diagnosed in primary care.

And with good reason. 60% of the human body consists of fluids that are contained within cells, are surrounding cells (interstitial fluid) or make up the fluid component of blood. However, whilst blood and urine are by far the most interrogated fluids for liquid biopsies, are they necessarily the best source of information?

The main role of extracellular fluid is to enable cellular communication and to remove waste products. Molecules secreted by cancer cells, like those secreted by healthy cells, will begin their journey through interstitial fluid before entering blood, in systemic circulation throughout the human body. Once in the systemic circulation, cancer-derived molecules are heavily diluted and the challenge of detecting them is huge. It really does become like looking for the proverbial needle in a haystack.

A different approach

Back in 2019, we decided to approach the problem from a different angle. We wanted to ask: what is the journey of the needle before it ends up in a haystack? Can we catch it in the early stages of its journey when it is still part of a smaller bunch of hay?

In the context of liquid biopsies, this meant searching for molecules secreted by cancer cells in the extracellular fluid surrounding the tumour rather than in a fluid freely circulating across the body.

We decided to apply this concept to skin cancer diagnosis, by developing a new technology that could collect, in a totally painless manner, interstitial fluid and substances within it. Applied in close proximity of a suspicious skin lesion, our patch could capture molecules secreted by cancer cells before they reached the blood, providing unprecedented spatial resolution. With support from a CRUK Cancer Technology acceleration award, we were able to develop a medical device comprising of a small patch of tiny needles (less than 1 millimetre long) made of a highly absorbent material that could collect enough fluid to enable the detection of specific RNA molecules secreted by cancer cells.

Now, with our latest CRUK funded award, we are exploring whether small changes in the pH of skin interstitial fluid – rather than RNA molecules within it – can be exploited as a universal biomarker for skin cancer.

Although it is already well known that metabolic changes during the formation of solid tumours causes the extracellular pH to drop, how much this is reflected in skin interstitial fluid is yet to be demonstrated. The aim of our research is now to develop our second generation of skin patches to demonstrate that localised deregulation of pH in interstitial skin fluid sampled from – or in proximity to – suspicious skin lesions can provide a sensitive window to diagnose skin cancers.

long-term vision

The aim here is to improve patient stratification and diagnosis accuracy of skin cancers in primary care.

Cancers of the skin are the most common of all cancers and affect almost equally women and men. The number of cases is increasing rapidly, including for melanoma, one of the deadliest forms. Other skin cancer types such as basal cell carcinoma and cutaneous squamous cell carcinoma are thankfully less deadly but much more common. They too require fast intervention and are notoriously very hard to diagnose, especially at an early stage, without the help of a biopsy.

The way skin cancers are diagnosed in primary care has barely evolved in decades despite being highly subjective and inaccurate. Whilst primary care clinicians are generally accurate at recognising suspicious skin lesions only 6-15% of patients referred in secondary care via the urgent suspected cancer ‘2-week-wait’ (2WW) pathway in England end up being diagnosed with skin cancer. This results in many unnecessary skin biopsies performed every year in the UK, which is both distressing to patients and costly to the NHS (around £35million is spent each year on unnecessary diagnostic procedures for skin cancer).

The ever-increasing pressure on NHS practitioners to diagnose skin cancer in both primary and secondary care is reflected by the recent replacement of the 2WW pathway with the Faster Diagnosis Standard (FDS) pathway, which streamlines referral to diagnosis to occur within 28 days. Improving patient stratification and the quality of referral in primary care settings is becoming increasingly critical. Therefore, providing GPs with additional tools that are affordable and can be easily inserted in the current diagnostic pathways, has the potential to reduce the number of patients sent unnecessarily to secondary care.

We believe that the solution is not only to improve visual analysis of skin lesions (with AI playing a significant role) but to combine those with a streamlined approach for rapid and cost-effective analysis of molecular biomarkers.