Background Despite impressive response rates, most patients with advanced melanoma ultimately progress following therapy with B-Raf proto-oncogene (BRAF) inhibitors (BRAFi). Therefore, frequent radiologic assessments are necessary, and reliable serum biomarkers would be beneficial for disease monitoring. Objective This study investigated the ability of lactate dehydrogenase (LDH) and S100 calcium-binding protein B (S100B) to detect response and disease progression during treatment with BRAFi. Patients and Methods Baseline levels of LDH and S100B and repeated measurements during therapy were recorded retrospectively in 191 patients with metastatic melanoma. LDH and S100B levels were compared between distinct time points (baseline, first follow-up visit [FV], best objective response [BR], and progressive disease [PD]). The prognostic ability of the serum biomarkers in relation to disease-specific survival (DSS) was assessed with univariable and multivariable Cox regression analysis. Results Elevated baseline LDH and S100B correlated with impaired DSS. In contrast with LDH (P = 0.12), S100B levels at FV correlated with response (P = 0.0030). Both markers significantly decreased during the first weeks of BRAFi treatment (LDH, P = 0.00034; S100B, P < 0.0001) and increased between BR and PD (LDH, P = 0.016; S100B, P < 0.0001). Patients with elevated S100B (P = 0.00062) but not with elevated LDH (P = 0.067) at the time point of radiologically confirmed PD showed significantly impaired DSS after PD. Interestingly, DSS after PD differed significantly according to S100B levels determined as early as 8 weeks (median) before PD (P = 0.0024). Conclusions LDH and S100B are suitable serum biomarkers during therapy with BRAFi. S100B shows stronger correlation with response and exhibits more accuracy in predicting PD. Close biomarker monitoring with S100B is recommended during treatment with BRAFi to detect PD early.
BackgroundCheckpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.MethodsMGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB–IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.ResultsPretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036).ConclusionsHigh pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.
The incidence of malignant melanoma is steadily rising. Resistance to therapy in malignant melanoma is linked to an increase of melanoma cell heterogeneity especially in regard to the response to pro-inflammatory signals from the tumor microenvironment (TME). For different tumor entities an infiltration of mast cells (MCs) into the TME has been reported, but their impact on tumor progression has been discussed controversially. We recently demonstrated that in melanoma MCs accumulate, especially in areas of immune regression. Since MCs are very plastic and can secrete various mediators, we are currently investigating how different stimuli activate MCs and how this affects the immune control of melanoma. MC precursors were isolated from murine femur and matured in medium containing IL-3 and stem cell factor. Mature bone-marrow derived MCs (BMMCs) were then stimulated with a variety of stimuli, including IL-33 and TLR-ligands. Changes in cytokine production was analyzed by ELISA. Through stimulation with IL-33, BMMCs were activated to produce a wide range of cytokines, as detected in the supernatant. This activation also impacted the transcription of genes, as shown by RNA-Sequencing. This effect can be intercepted through the application of resveratrol. In combinations with other stimuli both antagonistic and synergistic effects could be identified, indicating a directed development of MCs upon intervention. Among the highest concentrations of cytokines detected in the supernatant were chemokines that play a crucial role in the recruitment of immune cells, such as CCL3 and CCL22. In vivo experiments of wild type mice show that IL-33 does not impact tumor size, however, alters the immune cell recruitment to the tumor and the infiltration into the tumor. To investigate the impact of stimulated MCs on tumor progression and immune cell recruitment, in vivo studies with mastcell deficient Mctp5-Cre RDTA mice are performed.
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