Blood-based biomarker could advance melanoma treatment
Circulating tumour DNA (ctDNA) is emerging as a blood-based biomarker for many solid tumour types, including melanoma. Researchers at The University of Queensland (UQ) have now assessed ctDNA in the blood of patients with BRAF wild-type (BRAF WT) stage III and IV melanoma, finding that measuring ctDNA may lead to alternative treatment options and better outcomes.
Approximately 40–50% of all patients with late-stage cutaneous melanoma have a BRAF p.V600 mutation; in these patients, treatment with selective BRAF and MEK inhibitors significantly prolongs both progression-free survival and overall survival. Immune checkpoint inhibitor (ICI) therapy shows promising results when combined with targeted therapies in patients with BRAF p.V600-positive tumours; longer overall survival is observed when ICI therapies are combined. However, BRAF WT patients or patients harbouring an alternative BRAF variant do not benefit from these combinatorial ICI therapies.
“Current clinical practice means both BRAF WT and BRAF p.V600 positive patients receive ICI therapy; however, they do not all benefit,” said lead investigators Dr Vanessa F Bonazzi and Dr Lauren G Aoude, from UQ’s Frazer Institute. “We urgently need to identify biomarkers predictive of disease recurrence and response to alternative therapies after ICI failure.
“Patients could be better matched to specific therapies that target genomic alterations in their tumours using biomarkers that identify specific tumour targets and guide patient management. The aim of this study was to identify targetable variants present in the blood that may lead to alternative treatment options and better outcomes for BRAF WT patients.”
Investigators assessed ctDNA from the plasma samples of 106 patients; they also included serial blood collections for a subset of 16 patients to perform a longitudinal study. Variants were detected in 85% of patients, all in targetable pathways. The results were published in The Journal of Molecular Diagnostics.
Interestingly, in melanoma, the concentration of ctDNA had prognostic value. Patients with stage IV melanoma with low ctDNA concentrations (less than 10 ng/mL) had significantly better disease-specific survival and progression-free survival. Patients with both a high concentration of ctDNA and any detectable ctDNA variants had the worst prognosis. In addition, these results indicated that longitudinal changes in ctDNA correlated with treatment response and disease progression determined by radiology.
“Our results showed that changes in ctDNA over time correlated with response to treatment and progression of the disease as assessed by radiology,” Bonazzi said. “Measuring patients’ ctDNA throughout their treatment would help follow their potential response and adapt the treatment regimen accordingly.
“While patients can have a PET/CT scan every six months, a blood test could be performed monthly and provide an accurate answer followed by immediate actions. If, for example, the patient ctDNA profile shows a PIK3CA mutation from baseline, you could follow it in different blood samples from this patient over time, and down the track, you could use a PIK3CA inhibitor and hopefully be able to prevent potential recurrence of disease.”
Aoude added, “The sequencing of the ctDNA provides information for potential drug targets. Furthermore, the quantification could provide additional information regarding disease-specific survival and progression-free survival.”
The investigators concluded that ctDNA is highly attractive as a clinical tool because it offers a non-invasive, repeatable test that can provide additional clinical information regarding treatment response and tumour recurrence in patients with late-stage melanoma. It is particularly valuable as a tool to detect somatic variants with clinically targetable mutations, as a prognostic indicator in patients with stage IV melanoma and for tracking treatment response to ICI therapy.
In a separate study, published in the British Journal of Dermatology, researchers from UQ and The Alfred hospital identified gene variants which may contribute to people being at higher risk for nodular melanoma. The Frazer Institute’s Dr Mitchell Stark said nodular melanoma is the largest contributor to melanoma deaths, due to its rapid growth rate and short window of opportunity for detection and diagnosis.
“Up to 27% of nodular melanoma cases appear as a skin-coloured tumour, as opposed to other more pigmented melanomas, adding an additional challenge to early diagnosis,” Stark said.
“We hope that by identifying these rare variants, it could help establish screening programs to determine the people most at risk.”
The UQ research project analysed 500 genes already associated with melanoma and cancer risk. According to Stark, “We identified 39 genes that had the greatest frequency of DNA variants in nodular melanoma compared to other melanoma subtypes. Of those, four genes with rare DNA variants had the greatest frequency in nodular melanoma patients.”
Associate Professor Victoria Mar, Director of the Victorian Melanoma Service at The Alfred, said the information would enable clinicians to more effectively identify individuals at high risk of nodular melanoma for targeted screening.
“We previously did not have a common genetic risk factor specific to the disease,” Mar said.
“Once we know someone has these gene variants, it’s then possible to offer education and more appropriate screening to hopefully catch it earlier and improve patient outcomes.”
Moderate-intensity exercise can improve cognitive function in people who are sleep deprived and...
US scientists have developed an ingestible device that can safely monitor vital signs like...
With Australia officially in its eight wave of COVID-19, the time is ripe to look back at the...