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Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma.

ABSTRACT: PURPOSE:Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues. EXPERIMENTAL DESIGN:Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray (TMA; n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. RESULTS:Expression of CD74 on melanoma cells was unique, and in the discovery TMA, it associated with favorable patient outcome (OS: HR, 0.53; P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation data set confirmed the CD74 prognostic significance and revealed that the absence of macrophage migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (P = 0.003) with OS in the melanoma TCGA data set. CONCLUSIONS:Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue. Clin Cancer Res; 22(12); 3016-24. ©2016 AACR.

SUBMITTER: Ekmekcioglu S

PROVIDER: S-EPMC4911309 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma.

Ekmekcioglu Suhendan S Davies Michael A MA Tanese Keiji K Roszik Jason J Shin-Sim Myung M Bassett Roland L RL Milton Denái R DR Woodman Scott E SE Prieto Victor G VG Gershenwald Jeffrey E JE Morton Donald L DL Hoon Dave S DS Grimm Elizabeth A EA

Clinical cancer research : an official journal of the American Association for Cancer Research 20160118 12

<h4>Purpose</h4>Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues.<h4>Experimental design</h4>Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray ( ...[more]

PMID: 26783288

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Project description:ImportanceAlthough regression is commonly observed in cutaneous melanoma, it is uncertain whether it is associated with patient prognosis.ObjectiveTo determine whether histologically confirmed regression was associated with better or worse survival in patients with primary cutaneous melanoma.Design, setting, and participantsThis cohort study analyzed data from 2 large cohorts of adults (one in the Netherlands and the other in Australia) with histologically proven, stage 1 and 2 primary, invasive cutaneous melanoma with known regression status treated between 2000 and 2014, with median follow-up times of 4.5 and 11.1 years for the Dutch and Australian cohorts, respectively. For the Dutch patients, population-based data from PALGA, the Dutch Pathology Registry, were used, and follow-up data were retrieved from the Netherlands Cancer Registry. For the Australian patients, data from the database of a large, specialized melanoma treatment center were used.Main outcomes and measuresMultivariable Cox proportional hazards analyses were performed per cohort to assess recurrence-free survival (RFS) and overall survival (OS), and subgroup analyses according to Breslow thickness category and melanoma subtype were performed.ResultsA total of 17 271 Dutch patients and 4980 Australian patients were included. In both cohorts, survival outcomes were better for patients with disease regression. For Dutch patients, the hazard ratio (HR) for those with disease regression was 0.55 (95% CI, 0.48-0.63; P < .001) for RFS and 0.87 (95% CI, 0.79-0.96; P = .004) for OS; for the Australian patients, the HR was 0.61 (95% CI, 0.52-0.72; P < .001) for RFS and 0.73 (95% CI, 0.64-0.84; P < .001) for OS. Subgroup analyses showed that the presence of regression improved RFS within thin and intermediate Breslow thickness melanomas in both cohorts. For patients with superficial spreading melanoma (SSM) subtype, regression improved RFS and OS in both cohorts. For Dutch patients with SSM, the HR for those with disease regression was 0.54 (95% CI, 0.46-0.63; P < .001) for RFS and 0.86 (95% CI, 0.76-0.96; P = .009) for OS; for the Australian patients with SSM, the HR was 0.67 (95% CI, 0.52-0.85; P = .001) for RFS and 0.72 (95% CI, 0.59-0.88; P = .001) for OS.Conclusions and relevanceIn 2 large patient cohorts from 2 different continents, regression was a favorable prognostic factor for patients with stage 1 and 2 melanomas, especially in those with thin and intermediate thickness tumors and those with SSM subtype.

Project description:BackgroundOn the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.MethodsAfter patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety.ResultsAt a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.ConclusionsAs adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

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Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma.

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Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma.

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