Under the Skin

Even the first time around, melanoma is a frightening diagnosis. But for patients who experience a recurrence or metastasis, the outlook is much worse and the options far fewer. In cases like these, the sooner the relapse is discovered, the better the chance of treating the disease and extending patients’ survival times. To that end, scientists from the Cancer Research UK Manchester Institute have developed a blood test that may not only detect the first signs of returning cancer, but also yield information on mutations that can lead to treatment resistance.

The study examined blood samples from seven patients with advanced melanoma, tracking both levels of circulating tumor DNA (ctDNA) and the mutations present (1). Richard Marais, senior author and Cancer Research UK’s skin cancer expert, explains, “We monitor levels of mutated DNA in the blood of melanoma patients using an assay that allows us to simultaneously trace 10 genomic loci associated with resistance to targeted therapy. When following patients on BRAF-targeted therapy, we look for increasing levels of the BRAF mutation that the patient was originally diagnosed with, and at the same time, we try to pick up new mutations that may be the cause of resistance.”

The analysis of ctDNA is thought to offer a number of advantages over tissue biopsies: convenience to the patient, cost-effectiveness to the healthcare provider, and the detection of mutations from multiple metastatic sites while avoiding the selection bias associated with tissue biopsies. “Overall,” says Marais, “the analysis of ctDNA represents an ideal tool for the implementation of personalized medicine, and to complement standard imaging procedures to monitor disease progression.”

What might this research mean for the clinic? Marais anticipates the development of molecular profiling kits for ctDNA analysis to complement tissue profiling. “The analysis could easily be performed by pathologists,” he says, “and the results interpreted by the multidisciplinary teams treating the patient.” He and his colleagues hope that the analysis of ctDNA will help tailor the clinical management of patients to their needs, supplementing current disease-monitoring practices. “Blood can be collected on a regular basis at clinic visits by a local general practitioner, or even in the comfort of a patient’s home. Fixed intervals between scans could be replaced by a flexible schedule, giving priority to patients showing early signs of disease progression in the blood, or even delaying scans for patients whose blood indicates a good response to treatment.” He emphasizes that the technique would not replace current approaches, but rather would be used to refine patient care.

At the moment, the approach is ideal for the longitudinal follow-up of patients with pre-described mutations, but the team are aiming to determine the capability and applicability of their test for patients at risk of developing stage IV melanoma. In the meantime, they’re busy establishing ctDNA analysis as a clinical tool, testing the application of different technologies to prospectively monitor a larger cohort of patients, and incorporating their protocols into new clinical trials.