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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Several therapeutic options exist for patients with advanced BRAF-mutant melanoma. Biomarkers able to identify patients with refractory disease or with poor progression-free survival (PFS) and overall survival (OS) expectancy with respect to specific treatments might allow a more personalized therapeutic approach. Here, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR. Receiver Operating Characteristics (ROC), Kaplan–Meier and univariate and multivariate Cox regression analyses were performed on miR-1246 and miR-485-3p baseline levels to assess their ability to discriminate between responding and non-responding patients and to determine their prognostic value for PFS and OS. Globally, our results suggest that circulating miR-1246 and miR-485-3p could be valuable biomarkers for identifying patients most likely to be resistant to targeted therapy or with a poor expectancy of PFS and OS. Prospective studies in a larger cohort of patients are warranted.

Abstract

Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients treated with targeted therapy. Using next-generation sequencing, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR. Receiver Operating Characteristics (ROC), Kaplan–Meier and univariate and multivariate Cox regression analyses were performed on the validated miR-1246 and miR-485-3p baseline levels. The median baseline levels of miR-1246 and miR-485-3p were significantly higher and lower, respectively, in the group of patients not responding to therapy (NRs) as compared with the group of responding patients (Rs). In Rs, a trend toward an increase in miR-1246 and a decrease in miR-485-3p was observed at progression. Baseline miR-1246 level and the miR-1246/miR-485-3p ratio showed a good ability to discriminate between Rs and NRs. Poorer PFS and OS were observed in patients with unfavorable levels of at least one miRNA. In multivariate analysis, a low level of miR-485-3p and a high miR-1246/miR-485-3p ratio remained independent negative prognostic factors for PFS, while a high miR-1246/miR-485-3p ratio was associated with an increased risk of mortality, although statistical significance was not reached. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify melanoma patients most likely to be unresponsive to targeted therapy or at higher risk for short-term PFS and mortality, thus improving their management.

Details

Title
Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy
Author
Levati, Lauretta 1 ; Bassi, Cristian 2   VIAFID ORCID Logo  ; Mastroeni, Simona 3 ; Lupini, Laura 4 ; Gian Carlo Antonini Cappellini 5 ; Bonmassar, Laura 1   VIAFID ORCID Logo  ; Alvino, Ester 6 ; Caporali, Simona 1 ; Pedro Miguel Lacal 1   VIAFID ORCID Logo  ; Narducci, Maria Grazia 1 ; Molineris, Ivan 7   VIAFID ORCID Logo  ; De Galitiis, Federica 5 ; Negrini, Massimo 2 ; Russo, Giandomenico 1   VIAFID ORCID Logo  ; Stefania D’Atri 1 

 Laboratory of Molecular Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; [email protected] (L.L.); [email protected] (L.B.); [email protected] (S.C.); [email protected] (P.M.L.); [email protected] (M.G.N.); [email protected] (G.R.) 
 Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy; [email protected] (C.B.); [email protected] (L.L.); [email protected] (M.N.); LTTA Center, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy 
 Clinical Epidemiology Unit, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; [email protected] 
 Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy; [email protected] (C.B.); [email protected] (L.L.); [email protected] (M.N.) 
 Department of Oncology and Dermatological Oncology, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; [email protected] (G.C.A.C.); [email protected] (F.D.G.) 
 Institute of Translational Pharmacology, National Council of Research, Via Fosso del Cavaliere 100, 00133 Rome, Italy; [email protected] 
 Department of Life Science and System Biology, University of Turin, Via Accademia Albertina 13, 10123 Turin, Italy; [email protected] 
First page
3706
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2700530762
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.