The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies-Beyond BRAF Mutant Detection.

Gabriela Marsavela,Michelle R Pereira,Ashleigh C Mcevoy,Peter A Johansson,Michael Millward,Cleo Robinson,Anna L Reid,Benhur Amanuel,Tarek M Meniawy,Leslie Calapre,Lydia Warburton,Melanie R Ziman,Muhammad A Khattak,Elin S Gray,Nicholas K Hayward

doi:10.3390/cancers12123793

Abstract

In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen's k = 0.798, p < 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.

Highlights

In recent years, improved knowledge of melanoma pathogenesis has led to the development of BRAF and MEK inhibitors that target tumours carrying BRAF oncogenic mutations, accounting for40–50% of all melanoma cases
We first evaluated the rate of circulating tumour DNA (ctDNA) detection in 142 plasma samples collected prior to treatment initiation (Figure 1)
The 41 patients were treated with anti-PD1 inhibitors, 12 patients were treated with anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and 19 patients with a combination of both (26%)

Summary

Introduction

In recent years, improved knowledge of melanoma pathogenesis has led to the development of BRAF and MEK inhibitors that target tumours carrying BRAF oncogenic mutations, accounting for40–50% of all melanoma cases. A significant number of patients do not achieve sustained benefit from either targeted therapy or immunotherapy [2,3,4,5,6]. Predictive biomarkers of therapy response that can be assessed prior to initiation of treatment and early during therapy are critical to guide clinical management of metastatic melanoma. Baseline ctDNA levels and subsequent decline with treatment have been indicated as an early predictor of tumour response and clinical benefit [13,15,24,25]. To confirm the utility of ctDNA as a clinical biomarker, its ability to monitor and/or predict treatment response and clinical outcome requires further validation in a large cohort of melanoma patients, especially in those treated with immunotherapy

Objectives

Methods

Results