Abstract
Simple SummaryMalignant melanoma is one of the most aggressive cancer types among the solid tumors; therefore, more clinically applicable protein biomarkers predicting survival and therapy response have mandatory importance, impacting patient treatment. The aim of the study was to discover new proteins in biobanked FFPE samples that relate to progression-free survival and response to targeted- and immuno-therapies in patients with melanoma. Protein expressions were detected and quantified by high-resolution mass spectrometry and were integrated with the clinical data and in-depth histopathology characterization. Sample groups with distinct protein expression profiles were connected to longer and shorter survival as well as other clinicopathologic features. In addition, key regulating proteins were assigned, as predictive of progression-free survival in immuno- and/or targeted therapy. Some of the proteins exhibited functionally important correlations to progression and therapy response, which ultimately contributes to a better understanding of melanoma pathology.The discovery of novel protein biomarkers in melanoma is crucial. Our introduction of formalin-fixed paraffin-embedded (FFPE) tumor protocol provides new opportunities to understand the progression of melanoma and open the possibility to screen thousands of FFPE samples deposited in tumor biobanks and available at hospital pathology departments. In our retrospective biobank pilot study, 90 FFPE samples from 77 patients were processed. Protein quantitation was performed by high-resolution mass spectrometry and validated by histopathologic analysis. The global protein expression formed six sample clusters. Proteins such as TRAF6 and ARMC10 were upregulated in clusters with enrichment for shorter survival, and proteins such as AIFI1 were upregulated in clusters with enrichment for longer survival. The cohort’s heterogeneity was addressed by comparing primary and metastasis samples, as well comparing clinical stages. Within immunotherapy and targeted therapy subgroups, the upregulation of the VEGFA-VEGFR2 pathway, RNA splicing, increased activity of immune cells, extracellular matrix, and metabolic pathways were positively associated with patient outcome. To summarize, we were able to (i) link global protein expression profiles to survival, and they proved to be an independent prognostic indicator, as well as (ii) identify proteins that are potential predictors of a patient’s response to immunotherapy and targeted therapy, suggesting new opportunities for precision medicine developments.
Highlights
Malignant melanoma is the most metastatic human cancer among all tumor types [1,2]and was responsible for more than 50,000 deaths worldwide in 2020 [3].The incidence of melanoma is anticipated to increase 3% annually at least until 2022 in Norway, Sweden, the UK and the US [4].While the primary prevention and patient education are better than they were decades ago, the unpredictable behavior of the disease and the maintenance of a proper therapy regimen is still a struggle of the healthcare systems.Nowadays, the first- and second-line therapy of disseminated melanoma is based on the kinase and immune checkpoint inhibitor approaches
The applied retrospective cohort is composed of 90 melanoma samples from 77 patients with mainly progressed melanoma
The melanomas were stratified according to the 8th edition of the American Joint Committee on Cancer (AJCC8) staging system [30] and the 3rd edition of the WHO classification [31]
Summary
The first- and second-line therapy of disseminated melanoma is based on the kinase and immune checkpoint inhibitor approaches. The kinase inhibitor therapies, such as BRAF inhibitors, combined with MEK inhibitors, achieve a dramatic tumor response rate in a short period with the prolongation of the progression-free survival (PFS) and the overall survival (OS). The immune checkpoint inhibitors, such as anti-PD-1, PD-L1 and CTLA4 agents, have a prolonged effect both on the melanoma niche and on the innocent immune cells [5]. Even though the effect of targeted and immunotherapy extend the objective response rate of metastatic melanoma patients to approximately 50–70% [4,6], there are no proper predictive biomarkers or tools with high sensitivity and specificity values to predict ad hoc therapy response and distinguish among biological therapies
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