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

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.

Changes in circulating tumor DNA and outcomes in solid tumors treated with immune checkpoint inhibitors: a systematic review

“…Also, patients with continued elevation of ctDNA levels, while receiving ICIs, had worse outcomes even the setting of detecting high TMB levels. In Marsavela et al , 18 there was no statistically significant difference in clinical benefit between patients with high TMB versus patients with low TMB and no reported association between TMB and ctDNA clearance.…”

“…Data suggest that TMB alone might not be able to identify the group of patients who might benefit from ICIs. 18 Therefore, there is a need to validate dynamic markers that can provide clinicians with early and reliable insights about disease response in patient with advanced malignancies.…”

Molecular Profile of Skin Cancer

“…The predominance of either GLI1 or GLI2 in relation to the development of BCC is still unclear; however, there seems to be a positive feedback loop in which GLI2 directly activates the expression of GLI1. Moreover, there is a small number of sporadic BCCs where SMO mutations are found, also resulting in the up-regulation of this pathway [42,[56][57][58][59][60][61].…”

Identification of a Gene Prognostic Model of Gastric Cancer Based on Analysis of Tumor Mutation Burden

“…On the one hand, mutations in driver genes are detrimental to drive tumorigenesis in humans, but on the other a large number of somatic mutations may generate many new antigens, which could be recognized and attacked by immune cells (14)(15)(16). In multiple cancers, high TMB had shown a close association with outcomes in patients using ICIs, such as non-small cell lung cancer (NSCLC) (17)(18)(19), breast cancer (20,21), and melanoma (22).…”