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S100-Beta, Melanoma-Inhibiting Activity, and Lactate Dehydrogenase Discriminate Progressive From Nonprogressive American Joint Committee on Cancer Stage IV Melanoma

From the Department of Dermatology, University of Heidelberg, and Central Unit of Biostatistics R0700, German Cancer Research Center, Heidelberg, Germany.

Address reprint requests to Martin Deichmann, MD, Department of Dermatology, University of Heidelberg, Voßstraße 2, 69115 Heidelberg, Germany.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Monitoring advanced malignant melanoma, serum levels of S100-beta (S100ß) and melanoma-inhibiting activity (MIA) were assessed for the ability to discriminate progressive from nonprogressive disease. S100ß and MIA were supposed to be superior to conventional variables, such as lactate dehydrogenase (LDH) level.

PATIENTS AND METHODS: Seventy-one patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer (AJCC) were included in the study. Results of restaging examinations were used as an independent reference standard for diagnosing progressive disease, and S100ß, MIA, LDH level, and erythrocyte sedimentation rate (ESR) were determined in venous blood just before restaging. Sensitivities and specificities of the parameters were calculated by logistic regression analysis. Discrimination ability was assessed by Somers' D_xy rank correlation and the area under the receiver-operating characteristic curve (ROC-AUC).

RESULTS: All tested serum parameters were significantly elevated in patients with progressive disease. The highest sensitivities according to the established thresholds were found for S100ß and MIA (91% and 88%, respectively). LDH had the highest specificity (92%). ESR was dropped from the analysis because of low specificity. In calculating Somers' D_xy and ROC-AUC values, S100ß, MIA, and LDH showed high discrimination ability. By multiple logistic regression, LDH was identified to be the only statistically significant marker for progressive disease. S100ß and MIA did not provide additional significant information because of their high correlation with LDH with respect to clinical outcome.

CONCLUSION: Elevated serum levels of S100ß, MIA, and LDH indicate current disease progression in AJCC stage IV melanoma. LDH was the most relevant overall parameter.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN ADVANCED METASTATIC melanoma, serum markers would be useful for monitoring the course of disease and evaluating the effectiveness of treatment. Recently, the S100-beta (S100ß) protein and melanoma-inhibiting activity (MIA) were suggested as such clinical markers.

S100ß, a 21-kd acidic calcium-binding protein, was first isolated from bovine brain.¹ Consisting of and ß subunits, S100ß was found in melanoma cells² and is widely used today for the immunohistochemical diagnosis of amelanotic melanomas.³ Similarly, MIA was found to be highly expressed and secreted in malignant melanomas.^4,5 This 11-kd protein was first identified within supernatants with growth-inhibitory activities purified from tissue culture supernatant of malignant melanoma cells.⁶

It was suggested that S100ß⁷ and MIA^8,9 were of value in the assessment of advanced melanoma disease after they were detected in patients' serum. Indeed, the proportion of patients with elevated serum levels of S100ß increased from stage I to IV melanoma disease,^10-12 according to the American Joint Committee on Cancer (AJCC).¹³ In AJCC stage IV melanoma, the serum S100ß level was elevated in 74% of 23 patients,¹⁰ 79% of 34 patients,¹¹ 77% of 22 patients,¹⁴ and 49% of 22 patients.¹² MIA was even more frequently detected in the serum of patients with AJCC stage IV melanoma, with elevated levels found in 96% of 27 patients⁹ and all of 44 patients.⁸

With regard to individual patients, response and nonresponse to therapy correlated with changes in serum S100ß^10-12 as well as in serum MIA.^8,9 Both proteins were therefore suggested as serum markers for staging and monitoring therapy of metastatic malignant melanoma.^{8,10,11,15,16} However, prospective studies with statistically assessable cohorts of patients have not yet been conducted.

In the present study, S100ß and MIA were assessed for indication of current disease progression in a consecutive series of 71 patients with AJCC stage IV malignant melanoma after treatment. Sensitivities, specificities, and coefficients of discrimination ability were calculated. Using multiple logistic regression, S100ß and MIA were compared with conventional parameters such as lactate dehydrogenase (LDH) level and erythrocyte sedimentation rate (ESR).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Between April 1997 and July 1998, 71 consecutive patients with metastatic malignant melanoma were entered onto the study. All patients had histologically confirmed malignant melanoma (15 nodular, 11 superficial spreading, four acral lentiginous, 19 not classified cutaneous, six uveal melanoma, three extracutaneous primary tumor, and 13 no primary tumor). All patients had clinical stage IV disease according to the AJCC criteria¹³ and were treated with chemotherapy (28 patients), immunochemotherapy (12 patients), immunotherapy (seven patients), radiotherapy (eight patients), and surgery (16 patients), depending on the clinical situation. The time span between treatment and restaging was at least 3 weeks. Blood was drawn directly before re-evaluation for progression versus nonprogression of the disease. Course of the disease and response to therapy were determined by clinical examination, routine laboratory tests, and chest radiographs. Tumor size measurements were taken by ultrasound, computed tomography scans, and nuclear magnetic resonance imaging. Complete, partial, and mixed response, stable disease, and no evidence of disease were considered as nonprogressive disease. Thirty-eight healthy adult men and women were included in the study to establish an independent reference interval for S100ß and MIA proteins.

Laboratory Analysis
Serum concentrations of S100ß were measured by a two-site immunoluminometric assay according to the manufacturer's instructions (LIA-MAT; Sangtech Medical, Bromma, Sweden). This test is based on three monoclonal antibodies (mAbs) that specifically bind to the beta subunit of the S100 protein. Briefly, S100ß of the sample was bound by the coated antibody during the first incubation. Unbound material was then removed by washing, and the tracer antibody was bound to S100ß at the tube wall during the second incubation. After the unreacted tracer antibody was washed off, peroxide solution was added and the light signal was measured in a luminometer. The S100ß concentration of the sample was calculated using the provided internal standard reagents. Samples were analyzed at a dilution that resulted in measured concentrations within the range of the standard curves.

MIA was measured by a one-step enzyme-linked immunosorbent assay according to the manufacturer's instructions (Boehringer Mannheim, Mannheim, Germany). Two mAbs directed against 14-meric NH₂-terminal and COOH-terminal peptides were then raised and conjugated to horseradish peroxidase and biotin, respectively. Ten microliters of serum or standard were incubated with 200 µL of reagent containing mAb-biotin and mAb-horseradish peroxidase in streptavidin-coated 96-well plates for 45 minutes with shaking. After being washed three times with phosphate-buffered saline, 200 µL of 2.2'-azino-di-3-ethylbenz-thiazoline sulfonate was incubated in the wells for 30 minutes and measured colorimetrically at 405 nm. Using the provided standard concentrations of recombinant MIA, linear signals were measured at MIA concentrations of 0.1 to 50 ng/mL. Reproducibility of test results was confirmed by repeatedly measuring eight standard sera using different enzyme-linked immorsorbent assay lots. The standard curve was calculated in a linear fashion.

LDH and ESR were determined by routine analysis, and cutoff values were 240 U/L and 8 mm/1 hour, respectively.

Statistical Analysis
Sensitivities and specificities of the serum parameters were calculated by a logistic regression model in which the gold standard is one of the covariates.¹⁷ Confidence intervals (CIs) for sensitivity and specificity were then computed using the estimates from this model. Global error rates were computed as the proportion of false-positive plus false-negative results. Two-dimensional scatterplots of the serum markers were drawn, including cutoff values recommended by the manufacturer (S100ß) or previously reported (MIA),⁸ as well as those resulting from computing the maximum selected ² statistics.¹⁸ The pairwise correlations between two markers were described by Spearman's correlation coefficient, where approximate 95% confidence limits were computed using Fisher's z transformation.

Possible diagnostic markers indicating progressive disease were analyzed by logistic regression. The model included age and sex along with log10-transformed values of S100ß, MIA, LDH, and ESR as possible prognostic factors. A backward selection procedure using Akaikes information criterion as a stopping rule was used to find relevant factors in the multivariate analysis.¹⁹ Model validation was performed upon bootstrap resampling.¹⁹ The model fit was measured by the R² index reported by Nagelkerke.²⁰

Discrimination ability of the serum parameters was assessed by the standardized Mann-Whitney (MW) statistic or Somers' D_xy rank correlation. Somers' D_xy measures the correlation between a continuous variable X and a binary (0-1) variable Y. Somer's D_xy is related to the standardized MW statistic by D_xy = 2 MW - 1. The standardized MW statistic is given by MW = U/(nm), where m and n describe the sizes of the two groups of X defined by the dichotomous variable Y. U is the test statistic of the MW test. MW provides an estimate of the probability that a realization of X given Y = 1 is larger than a realization of X given Y = 0 by the frequency of correctly sorted pairs. MW is equal to the area under the receiver-operating characteristic (ROC) curve, which is a graphical representation of the pairs of false-positive test results (specificity) and true-positive test results (sensitivity) for the realizations of a quantitative test.

Two (S100ß, MIA), four (LDH), and 17 (ESR) missing values were assumed to be "missing at random."²¹ All original variables were transformed to have maximum correlation with the best linear combination of the other variables, resulting in canonical variates. Missing values were replaced by the predicted values from this model.

Both the correlation between the markers and the discrimination of patients with progressive disease from those with nonprogressive disease by the markers were displayed two-dimensionally with a biplot. Originally developed by Gabriel,²² the biplot graphically describes the result of a principal component analysis of the markers by displaying the first two principal axes in a point-and-arrow form. Arrows from the origin show the positive direction of the marker axes. The correlation between two markers is approximated by the angle between the two corresponding arrows.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
To assess manufacturers' reference values, we measured S100ß and MIA in healthy volunteers. Thirty-eight serum samples were evaluated and 95th percentiles were found, with S100ß 0.11 µg/L and MIA 7.9 ng/mL. S100ß and MIA levels were not increased above the manufacturer's upper normal limits in any of the controls. Because the cutoff values were similar to the limits proposed by the manufacturer (S100ß) or those previously reported (MIA),⁸ namely, S100ß 0.12 µg/L and MIA 6.50 ng/mL, we decided to use the latter in our analysis.

Seventy-one patients with AJCC stage IV melanoma were considered for analysis. Staging examinations showed progressive disease in 34 patients and nonprogressive disease in 37 patients (Table 1). In both groups, sex and age did not differ significantly. All tested serum markers were markedly elevated in patients with progression of melanoma disease.

First, the serum parameters were investigated for sensitivity and specificity. With regard to sensitivity, S100ß (0.91) and MIA (0.88) were superior to LDH (0.79; Table 2). In contrast, LDH had the highest specificity (92%). ESR was dropped from the analysis because specificity was only 27%. Computed error rates were all less than 0.20 except ESR. The S100ß, MIA, and LDH levels in individual patients are compared in Fig 1.

View larger version (13K): [in this window] [in a new window]   Fig 1. Scatterplot of LDH v S100ß (A) and LDH v MIA (B) for patients with progressive (•) and nonprogressive () metastasized melanoma. The cutoff values obtained from computing the maximum selected 2 statistics (– – –) as well as those previously reported () are shown.

Estimates for both sensitivity and specificity in separating patients with progressive disease from those with nonprogressive disease were obtained using ROC analysis (Fig 2). S100ß and MIA achieved higher sensitivity than LDH but lower specificity (Table 3).

View larger version (17K): [in this window] [in a new window]   Fig 2. Area under the ROC curves of LDH (•) v S100ß (; A) and v MIA (; B).

Somers' D_xy and the R² index were used to describe the discrimination ability of the serum markers. All parameters except ESR were highly positively associated with current progressive disease (Table 3). LDH was the serum parameter with the highest value to predict restaging results after therapy, closely followed by S100ß. A combination of LDH with either S100ß or MIA only slightly improved Somers' D_xy to greater than 0.85.

Next, an attempt was made to identify significant serum markers for progressive disease using a logistic regression model. By backward selection, LDH remained as the most relevant factor. Validation with 100 bootstrap samples resulted in 50% selection of LDH and only 12% and 8% selection of S100ß and MIA, respectively. The fact that S100ß and MIA did not provide additional significant information to LDH may have resulted from their high correlation with LDH: The Spearman correlation coefficients were calculated as 0.73 (approximate 95% CI, 0.59 to 0.82) for S100ß and LDH, 0.65 (95% CI, 0.48 to 0.77) for MIA and LDH, and 0.78 (95% CI, 0.67 to 0.86) for S100ß and MIA.

Finally, a biplot was drawn to display the serum parameters and their individual values together in two-dimensional space (Fig 3). S100ß, MIA, and LDH clearly corresponded to a separation of melanoma patients with progressive disease from those with nonprogressive disease in a comparable way, whereas ESR did not. The larger the distance between the data points of two patients in the biplot was, the higher the difference in the values of combination of the serum parameters. The small angle between the arrows of LDH and S100ß represents a high correlation of these two parameters.

View larger version (13K): [in this window] [in a new window]   Fig 3. Biplot showing the ability of the parameters to discriminate progressive (•) from nonprogressive () AJCC stage IV melanoma.

When type of melanoma and treatment were included as covariates in the logistic regression model, neither clinical outcome of the patients nor sensitivities and specificities of the serum parameters were related to these parameters.

In a second analysis that included a subset of 21 patients with progressive disease and 22 with nonprogressive disease, blood was drawn, and the patients were staged, treated, and then re-evaluated for progression versus nonprogression. Here, serum parameters were evaluated for the ability to predict clinical outcome at the next staging, an average of 3 months later. Sensitivities of S100ß and MIA (0.74 [95% CI, 0.50 to 0.89] and 0.84 [95% CI, 0.61 to 0.95], respectively) were superior to that of LDH (0.52 [95% CI, 0.32 to 0.71]). Similar to the results of the actual serum markers, preceding LDH values showed a higher specificity (0.82 [95% CI, 0.60 to 0.93]) compared with S100ß and MIA (0.64 [95% CI, 0.42 to 0.81] and 0.59 [95% CI, 0.38 to 0.77], respectively). Area under the ROC curve values were 0.77 (S100ß), 0.75 (MIA), 0.73 (LDH), and 0.64 (ESR).

By univariate analysis, pretreatment levels of S100ß had the highest discrimination ability (Somers' D_xy = 0.511) compared with MIA (0.464), LDH (0.426), and ESR (0.208). Addition of any other marker in multivariate analysis did not increase the result of S100ß alone.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
S100ß^2,3 and MIA^4,5,23 proteins are expressed in melanoma tumor cells and were found in sera of melanoma patients.^8-11 In metastatic disease, S100ß^10-12,14 and MIA^8,9 were frequently detected in patients' sera, and changes correlated with response and nonresponse to therapy in individual patients.^8,10,11 As a result, both proteins were suggested as serum markers for staging and monitoring therapy of metastatic malignant melanoma.^8-11,15,16 Therefore, we assessed S100ß and MIA in a representative number of patients with AJCC stage IV melanoma for the ability to discriminate progressive from nonprogressive disease.

Elevated S100ß and MIA serum levels correlated strongly with current disease progression. Unexpectedly, S100ß and MIA were not superior to LDH upon logistic regression analysis. Neither S100ß nor MIA added relevant information to conventional LDH, which was described previously as the most powerful prognostic variable for survival in metastatic malignant melanoma.^24,25 Similar to our results, S100ß was recently reported to correlate with shorter survival duration in patients with metastatic melanoma but added no information to LDH alone.²⁶ Clinical outcome of the patients and sensitivity and specificity of the serum parameters were not related to the histologic type of melanoma or type of treatment.

LDH was reported to have prognostic value for several tumors (eg, small-cell and non–small-cell lung cancer, Hodgkin's and non-Hodgkin's lymphoma, and prostate cancer).²⁵ An elevated serum LDH level does not necessarily indicate liver involvement with tumor, as has been suggested previously. Because LDH is metabolized at a fairly constant rate, elevated levels are believed to represent tumor cell turnover and tumor burden. In our study, 43% of patients had an elevated serum level of LDH, but only 21% had liver involvement by radiographic criteria. Moreover, elevated levels of LDH were uncommon in patients with less advanced disease, supporting its correlation with tumor burden.

In contrast to LDH, ESR, as the second prognostic parameter for survival in metastatic malignant melanoma,²⁴ resulted in low specificity and low discrimination ability in our study. Unspecific elevations cause the low specificity and are unfavorable for ESR's value as a tumor marker.

With regard to specificity, LDH level is known to be elevated after a variety of tissue-damaging conditions, eg, hepatitis, hemolysis, or myocardial infarction. Unspecific increases are also known for S100ß and MIA: in addition to malignant melanoma cells, S100ß and MIA were also found in chondrocytes.^7,27 In patients with malignancies or strokes of the brain, S100ß was detected in serum in 90% and 40%, respectively.⁷ Similarly, MIA values were elevated in up to 17% of patients with epithelial neoplasms,⁸ ruling out the hope that S100ß or MIA might be highly specific melanoma markers.

In conclusion, serum S100ß, MIA, and LDH are good "stand-alone" markers for progressive disease of metastatic melanoma. Sensitivities, specificities, and discrimination values of these parameters were higher in the assessment of current course of disease than in the prediction of response to subsequent treatment. Unfortunately, because of their high correlation with LDH, S100ß and MIA did not provide additional information to LDH alone upon multiple logistic regression analysis.

	ACKNOWLEDGMENTS

 
The authors thank Stefan Meisel for technical assistance.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 8, 1998; accepted January 25, 1999.

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