Abstract 1135P
Background
Targeted therapy have significantly improved the outcome in BRAFV600-mutated metastatic cutaneous melanoma (CM). These therapies induce rapid therapy response in BRAFV600E/K disease and can be used alone or in combination (i.e. MEK- and/or BRAF-inhibitors). Although the 5-year overall survival and progression free survival (PFS) are comparable to the results from anti-PD-1 therapy for metastatic CM, resistance often occurs within 6-12 months. Clinically useful treatment predictive biomarkers are lacking. Previously, we have demonstrated that unbiased mass-spectrometry-based in-depth proteomics with high resolution isolelectric focusing, liquid chromatography, mass spectrometry (HiRIEF LC-MS/MS) is able to quantify over 1,000 proteins, including circulating and tissue-derived proteins. Recently, we have reported that HiRIEF LC-MS/MS, with adjuvant targeted proteomic analyses, provided us with a unique and previously unexplored view into the dynamic changes of the proteins present in plasma of metastatic melanoma patients receiving immune checkpoint blockade (ICB), and the ability to detect peptide-coding variants in plasma. Moreover, we showed that the major plasma proteome changes in patients treated with ICB were not detectable in patients treated with targeted therapy, which we analysed for comparison.
Methods
Serial plasma samples from 24 patients with metastatic CM patients receiving targeted therapy were analyzed with a mass-spectrometry proteomics method (HiRIEF LC-MS/MS) and proximity extension assays (PEA). The aim was to investigate systemic biological processes and we estimate the predictive relation between protein plasma levels and PFS as well as tracing numerous proteins back to metastatic CM tissue using TCGA transcriptomics data.
Results
Unbiased MS proteome analysis indicated plasma levels alterations related to treatment in 84 out of 1,160 proteins. In total, 38 proteins were associated with PFS. EPHA1, CPB1, and ICAM3 detected in the analysis of responders were associated with longer PFS. CTSB and SNCA.were associated with shorter PFS. SFTPA and ADGRL4 correlated with PFS.
Conclusions
Several protein signatures linked to melanoma or biological processes during targeted therapy were detected.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Swedish Medical Society, Swedish Cancer Society, Radiumhemmet Research Funds, Swedish Society for Medical Research.
Disclosure
All authors have declared no conflicts of interest.