Abstract
Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used as a predictive biomarker; however, it lacks specificity. Therefore, it is of utmost importance to identify other novel biomarkers that can predict treatment outcome. Experimental design: We studied a small cohort of 16 patients with advanced-stage melanoma treated with first-line checkpoint inhibitors. Plasma samples were collected prior to treatment initiation and continuously during the first year of treatment. Circulating tumor DNA (ctDNA) level and the expression of ten inflammatory cytokines were analyzed. Results: We found that the ctDNA-level in a blood sample collected after 6–8 weeks of therapy is predictive for response to checkpoint inhibitors. Patients with undetectable ctDNA had significantly longer progression-free survival (PFS) compared with patients with detectable ctDNA (median 26.3 vs. 2.1 months, p = 0.006). In parallel, we identified that high levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α(TNFα) in baseline blood samples were significantly associated with longer PFS compared to low level of these cytokines (median not reached vs. 8.2 months p = 0.0008). Conclusions: These findings suggest that the levels of ctDNA, MCP1, and TNFα in baseline and early follow-up samples can predict disease progression in metastatic melanoma patients treated with checkpoint inhibitors. Potentially, these minimally invasive biomarkers may identify responders from non-responders.
Highlights
Metastatic melanoma is an aggressive cancer for which the incidence rate continues to rise worldwide [1]
The present study investigated the association between progression-free survival (PFS) and the levels of Circulating tumor DNA (ctDNA) and cytokines in baseline and early follow-up samples from melanoma patients treated with first-line checkpoint inhibitors
We demonstrated that high baseline levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α (TNFα) predicted longer PFS
Summary
Metastatic melanoma is an aggressive cancer for which the incidence rate continues to rise worldwide [1]. Treatment options have been limited for metastatic melanoma patients but with the emergence of novel immunotherapeutic approaches over the past several years, the management of this disease has been vastly transformed. 40–60% of patients do not respond to immunotherapy and no clearly defined biomarker is available for predicting if patients will benefit from treatment [3,4,6]. The most widely accepted, clinically used predictive biomarker is the expression of PD-1 ligand (PD-L1) on tumor cells, which has been associated with higher likelihood of response to therapy [7]. Up to 41.3% of melanoma patients with PD-L1 negative tumors respond to immunotherapy [4]
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