Abstract

Background

Immunotherapy and targeted therapy have revolutionised outcomes for patients with metastatic melanoma, however there remain patients who are refractory to treatment or who develop resistance. Tools are therefore required to identify patients at high risk of progression and to detect emerging resistance early so personalised treatment options can be explored. Circulating tumour DNA (ctDNA) can be used to monitor response to therapy, identify mechanisms of resistance and be used as a prognostic biomarker. We aimed to understand how ctDNA could be used to inform clinical decision making for patients with melanoma.

Method

Patients treated at The Christie hospital underwent longitudinal blood sampling for ctDNA. Following extraction of cell free DNA from plasma, we performed whole exome and targeted sequencing to identify mutations. Furthermore, we carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial.

Results

Levels of circulating tumour DNA mirrored response in patients undergoing treatment for melanoma. We identified mutations associated with resistance to therapy in patients with disease progression on targeted therapy. Detectable ctDNA within 12 weeks of surgery for stage II/III melanoma was associated with inferior disease-free, distant-metastatic free and overall survival. Based on these results we have designed two trials; CirculAting Tumour DNA gUided therapy Switch (CAcTUS) and Circulating tumour DNA guidEd Therapy for stage IIB/C BRAF or NRAS mutant- positive mElanoma after surgiCal resecTION (DETECTION).

Conclusion

CtDNA is a useful tool to monitor treatment response and to characterise mechanisms of resistance to therapies for melanoma. Furthermore it can be used to predict relapse and survival of patients at high risk of disease progression following curative intent surgery. Clinical trials are ongoing to assess the impact of ctDNA-guided decision-making on patient outcomes.