Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated ...sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.
IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.
IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.
IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
BRAF V600 mutation has been reported in more than 50% of melanoma cases and its presence predicts clinical activity of BRAF inhibitors (iBRAF). We evaluated the role of MIA, S100 and LDH to monitor ...iBRAF efficiency in advanced melanoma patients presenting BRAF V600 mutations. This was a prospective study of melanoma patients harboring the BRAF V600 mutation and treated with iBRAF within a clinical trial (dabrafenib) or as part of an expanded access program (vemurafenib). MIA, S100 and LDH were analyzed in serum at baseline, and every 4–6weeks during treatment. Eighteen patients with melanoma stages IIIc–IV were enrolled with 88.8% of response rate to iBRAF. Baseline concentrations of all the tumor markers correlated with tumor burden. MIA and S100 concentrations decreased significantly one month after the beginning of treatment and, upon progression, their concentrations increased significantly above the minimum levels previously achieved. MIA levels lower than 9μg/L one month after the beginning of treatment and S100 concentrations lower than 0.1μg/L at the moment of best response were associated with improved progression-free survival. In conclusion, MIA and S100 are useful to monitor response in melanoma patients treated with iBRAF.
•Basal MIA and S100 levels correlated with tumor burden using the RECIST 1.1 criteria.•MIA and S100 levels decrease significantly one month after beginning of treatment with iBRAF.•MIA and S100 levels increase significantly during progression.•S100 and MIA levels during treatment were of prognostic value.•Low S100 and MIA levels were associated with better progression-free survival.
BACKGROUND: Around 50% of cutaneous melanomas harbor the BRAF.sup.V600E mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as ...(cfBRAF.sup.V600E). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAF.sup.V600E by ddPCR in patients with melanoma during therapy with BRAF inhibitors. METHODS: Plasma concentrations of cfBRAF.sup.V600E were measured in 8 controls and 20 patients with advanced melanoma having the BRAF.sup.V600E mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression. RESULTS: The BRAFv.sup.600E mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAFv.sup.600E and plasma cfBRAF.sup.V600E was 84.3%. Baseline cfBRAF.sup.V600E correlated with tumor burden (r = 0.742, P < 0.001). cfBRAF.sup.V600E concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAF.sup.V600E compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/mL; P = 0.013). Lower concentrations of basal cfBRAF.sup.V600E were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively). CONCLUSIONS: cfBRAF.sup.V600E quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.
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Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% ...of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. Table: see text
Around 50% of cutaneous melanomas harbor the BRAF(V600E) mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free BRAF(V600E) ...(cfBRAF(V600E)). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAF(V600E) by ddPCR in patients with melanoma during therapy with BRAF inhibitors.
Plasma concentrations of cfBRAF(V600E) were measured in 8 controls and 20 patients with advanced melanoma having the BRAF(V600E) mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression.
The BRAF(V600E) mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAF(V600E) and plasma cfBRAF(V600E) was 84.3%. Baseline cfBRAF(V600E) correlated with tumor burden (r = 0.742, P < 0.001). cfBRAF(V600E) concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAF(V600E) compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/mL; P = 0.013). Lower concentrations of basal cfBRAF(V600E) were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively).
cfBRAF(V600E) quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.
Around 50% of cutaneous melanomas harbor the BRAFsupV600E/sup mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free ...BRAFsupV600E/sup (cfBRAFsupV600E/sup). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAFsupV600E/sup by ddPCR in patients with melanoma during therapy with BRAF inhibitors. Plasma concentrations of cfBRAFsupV600E/sup were measured in 8 controls and 20 patients with advanced melanoma having the BRAFsupV600E/sup mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression. The BRAFsupV600E/sup mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAFsupV600E/sup and plasma cfBRAFsupV600E/sup was 84.3%. Baseline cfBRAFsupV600E/sup correlated with tumor burden (r = 0.742, P < 0.001). cfBRAFsupV600E/sup concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAFsupV600E/sup compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/ mL; P = 0.013). Lower concentrations of basal cfBRAFsupV600E/sup were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively). cfBRAFsupV600E/sup quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.
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