Use of ctDNA in identifying an actionable BRAF mutation in stage 4 metastatic melanoma

Discussion

Those who present with aggressive, quickly progressing melanoma can rapidly respond to BRAF and MEK inhibitors within a few days, meaning that commencing this treatment promptly can be a lifesaving intervention. However, completion of the diagnostic pathway can take up to 2 weeks; from tissue sampling, to the pathologist retrieving the formalin-fixed, paraffin-embedded (FFPE) block, to receiving the BRAF result. This is a relatively long time for patients who have a heavy burden of metastatic disease as this cohort can significantly deteriorate while awaiting the test result. These patients may suffer poorer outcomes due to the current standard of testing. Furthermore, current guidance suggests that we should not perform BRAF analysis for any patient with a lower stage than stage 2a.6 For the cohort of patients who later relapse, this guidance means those with an early stage at their original presentation will not have a BRAF result to action when required.

Liquid biopsies are an emerging tool in oncological practice to guide treatment decisions, monitor disease status and prognosticate.7 Through venepuncture, a blood sample can be collected and analysed for the presence of circulating tumour cells or ctDNA. The volume of ctDNA identified generally correlates with overall disease burden.8 In non-small cell lung cancer, there is already some movement towards using NHS commissioned hotspot ctDNA prior to attempting biopsy, in order to identify actionable epidermal growth factor receptor (EGFR) variants quickly.9 There has, however, been little or no use of this in melanoma patients and NICE does not currently recommend the use of hotspot ctDNA biomarkers as routine practice in the diagnostic pathway for melanoma.6 Despite this, there is a growing body of evidence for ctDNA use to guide treatment decisions. Recent European Society for Medical Oncology (ESMO) recommendations acknowledge the value of this sample type in the time critical setting, or when tissue diagnosis is unsuccessful or unattainable.7 Increasingly, it is being explored as an alternative method for analysing BRAF status in melanoma. Although the time required to process a result for IHC can be comparable to ctDNA, ctDNA analysis can demonstrate numerous V600 variants in contrast to IHC assessing for V600E alone.10 Further benefits of ctDNA include the representation of tumour heterogeneity,11 a limitation of tissue biopsy, and the minimally invasive nature of the investigation. Advanced malignancy in situ is often unresectable and can be in a technically challenging location for tissue biopsy; sampling for a blood biomarker is technically easier. In addition, there is potential benefit for patients where BRAF was not performed on the original tissue, or in cases like ours, where issues later arise during tissue analysis. Sacco et al 8 recently reviewed the diagnostic performance of 14 trials and reported sensitivity to be variable, though generally acceptable; overall specificity was good.8 As always, limitations in a diagnostic technique must be appreciated by the decision-making clinician, in order to ensure safe and robust decision making in the best interests of the patient.7

As a single case, there are limitations to be recognised. Prior to implementation in routine NHS diagnostic practice for melanoma, further refinement of methods is required to ensure valid, reliable and standardised testing technologies across laboratories are adopted and formal assessment of cost-effectiveness considered. In a recent study, results were obtained within 120 min of venepuncture; the time from collection to centrifugation of the samples was less than 1 hour.12 Rapid turnaround of results would be resource intensive, and review of local pathways would be necessary to consider if this could be consistently achieved.

In this article, we describe the use of hotspot ctDNA analysis, where tissue BRAF analysis initially failed. This directly influenced early treatment of a patient clinically deteriorating from the burden of their progressing malignancy. We believe the use of this approach requires further consideration to see if it could provide an alternative within the diagnostic cancer pathway for hotspot BRAF testing in patients where treatment is time critical.