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Annals of Surgical Oncology 9:120-126 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Serum TA90 Immune Complex Assay Can Predict Outcome After Resection of Thick (>=4 mm) Primary Melanoma and Sentinel Lymphadenectomy

Mathew H. Chung, MD, Rishab K. Gupta, PhD, Richard Essner, MD, Wei Ye, MS, Reynold Yee, BS and Donald L. Morton, MD, FACS

From the Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint John’s Health Center, Santa Monica, California.

Correspondence: Address correspondence and reprint requests to: Donald Morton, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404; Fax: 310-582-7185; E-mail: mortond{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: We hypothesized that the postoperative serum level of TA90-IC, an immune complex of a 90-kDa tumor-associated antigen and its antibody, might have a significant correlation with recurrence and survival in patients with thick primary melanomas.

Methods: We used our prospective melanoma database to identify all patients who underwent wide local excision and sentinel lymphadenectomy for primary melanomas >=4 mm and from whom sera had been collected and cryopreserved within 6 months after surgery. These sera were analyzed in a blinded fashion for TA90-IC status by using our double-determinant enzyme-linked immunosorbent assay. Results were correlated with disease-free survival (DFS) and overall survival (OS). Standard prognostic factors for melanoma were then compared with TA90-IC status for the prediction of DFS and OS.

Results: The sensitivity and specificity of the TA90-IC assay for predicting recurrence were 70% and 85%, respectively. Five-year DFS and OS rates were higher for the TA90-IC-negative group than the positive group. The differences in DFS and OS between the TA90-IC-negative and -positive groups were significant. At a median follow-up of 25 months, multivariate analysis identified postoperative TA90-IC status and sex as significant predictors of DFS. TA90-IC status was the only independent prognostic factor with multivariate analysis.

Conclusions: TA90-IC status after resection of thick primary melanoma accurately predicts outcome. A positive postoperative TA90-IC level might affect a decision regarding adjuvant therapy, regardless of regional nodal status.

Key Words: TA90 immune complex • Tumor-associated antigen • Immune assay • Primary melanoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Because patients with thick cutaneous melanoma (>=4 mm) have a high risk of distant recurrence,1 many surgeons do not routinely undertake aggressive clearance of clinically negative regional nodes. Their reasoning is that delayed lymph node dissection of a clinically involved regional basin is more cost-effective and may spare many patients the potential morbidity of elective lymph-node dissection (ELND).2 However, contemporary studies show that nodal positivity correlates significantly with outcome in patients with thick cutaneous melanomas.3,4 In one series, 5-year survival rates were 71% with tumor-negative nodes and 28% with tumor-positive nodes.3 Therefore, regional nodal staging seems worthwhile because it could stratify those patients more likely to benefit from adjuvant therapy.

During the last decade, the risk of overtreatment and understaging on the basis of inaccurate assessment of regional nodal basins has been reduced by intraoperative lymphatic mapping/sentinel lymphadenectomy (LM/SL). This is a minimally invasive technique to identify and excise the regional lymph nodes most likely to harbor metastasis from a primary melanoma.5 Because step-sectioning and multilevel examination of this sentinel node (SN) is far more sensitive than conventional histological examination of an ELND specimen, the tumor status of the SN is reportedly the most powerful predictor of outcome for patients with thick melanomas.4

Even with the more accurate and less morbid nodal assessment offered by focused examination of the SN, the prognosis of patients with thick melanomas remains highly variable. The poor survival rates of node-positive and node-negative patients who have thicker versus thinner melanomas have been attributed to the high incidence of occult systemic metastases at the time of presentation.3 The high incidence of recurrent disease after surgical resection may reflect these occult metastases.6 Postoperative adjuvant therapy therefore must be given to these high-risk patients when the goal is cure. Because all therapies for melanoma are most effective when the tumor burden is low,7 a serum tumor marker that could detect occult micrometastasis might improve the selection of patients for postoperative high-dose interferon alfa-2b. This toxic agent is the only approved, standard adjuvant therapy for high-risk melanoma. Alternatively, patients can be entered onto clinical trials of nontoxic therapies such as cancer vaccines.8

We have developed an assay to detect immune complexes (ICs) containing a 90-kDa tumor-associated antigen (TA90). This antigen was first discovered in the urine and sera of metastatic melanoma patients and was subsequently found to be expressed by >70% of human melanomas.9,10 TA90 occurs as free antigen and as immunoglobulin G (IgG)-bound IC in the sera of melanoma patients.11 Our group developed an enzyme-linked immunosorbent assay (ELISA) to detect TA90-IC in the sera of melanoma patients.9 In an earlier article,12 we showed that the preoperative TA90-IC status (positive or negative) was significantly correlated with outcome after surgical treatment of early-stage melanoma. A similar correlation was observed between outcome and postoperative TA90-IC status in patients who had undergone resection of American Joint Committee on Cancer stage I to III melanoma.13 Although that study population included 20 patients whose primary melanomas were thicker than 4 mm, this subgroup was too small for meaningful analysis. This study was undertaken to determine whether the serum TA90-IC status after wide local excision (WLE) and LM/SL is an important risk factor for recurrence or survival. If so, then TA90-IC might serve as a marker for the detection of subclinical metastasis and potentially aid in decisions regarding adjuvant therapy.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
The prospective melanoma database at the John Wayne Cancer Institute was used to identify all patients who underwent WLE of primary cutaneous melanomas >=4 mm and complete resection of any regional nodal disease from August 1, 1985, to October 30, 1999. The extent of nodal resection was guided by LM/SL, which in all cases was undertaken after preoperative lymphoscintigraphy to identify nodal drainage basins. Excluded from the analysis were patients with clinical or radiological evidence of metastatic melanoma in regional lymph nodes, distant sites, or both.

A total of 70 patients met the selection criteria and had cryopreserved sera collected postoperatively in our specimen bank. The first 22 patients underwent ELND regardless of SN status, because at that time the LM/SL procedure was still in developmental stages at our institution; the remaining patients underwent complete nodal dissection only if the SN contained tumor. Forty-four patients (63%) received postoperative immunotherapy with an irradiated polyvalent vaccine (CanvaxinTM vaccine; CancerVax Corporation, Carlsbad, CA) containing the TA90 antigen; in these cases, only the sera collected before initiation of vaccine therapy were correlated with outcome.

Prognostic variables analyzed included patient age and sex, the primary tumor’s Breslow thickness, Clark level, anatomical site, presence of ulceration, and the tumor status of the regional lymph nodes. Disease-free survival (DFS) was the interval between the primary surgery and first recurrence or last follow-up. Overall survival (OS) was the interval between the primary surgery and the last follow-up or death from disease.

Sentinel Lymph Node Mapping Technique
LM/SL was performed as previously described.5,14,15 Briefly, all patients underwent preoperative lymphoscintigraphy with an intradermally injected radioisotope (.5–1.0 mCi of filtered technetium [99mTc] sulfur colloid, injected 1–4 hours before surgery) to identify lymphatic drainage patterns and establish those basins at risk for metastasis. Intraoperative lymphatic mapping was then performed with intradermal injection of 1 to 3 ml of 1% isosulfan blue dye (LymphazurinTM; USSC, Norwalk, CT) around the intact tumor or biopsy site. Beginning in 1994, a handheld gamma counter (Neoprobe 1000, 1500, or 2000; Neoprobe Corporation, Dublin, OH) was used during LM/SL to facilitate the location and verification of SNs.

Each SN was excised and submitted for pathologic analysis. All patients underwent WLE of the primary melanoma with a margin >=2 cm. Serial sections of each SN were stained with hematoxylin and eosin. Immunohistochemical staining with antisera to the S-100 protein and the melanoma antigen HMB-45 was used to clarify equivocal findings. Patients with a tumor-positive SN underwent complete lymph node dissection.

TA90-IC Assay
Sera were drawn 1, 2, 4, and/or 6 months after surgery and collected as part of the protocol approved by our institutional review board. All prospectively collected serum samples were then stored in liquid nitrogen. Coded serum samples from each patient were aliquoted in a blinded fashion, and TA90-IC assay was performed as described previously.9 Briefly, an antigen-specific ELISA that uses murine monoclonal antibody AD1-40F4 against TA90 was used. Patient sera were diluted 1/60 in .025 M of phosphate-buffered saline and .5% TritonTM X-100 (Rohm & Haas Company, Philadelphia, PA), pH 7.2. Diluted sera were placed in ELISA plates containing wells coated with AD1-40F4, incubated for 45 minutes, and washed to remove unbound proteins. Goat anti-human IgG F(ab)2 conjugated to alkaline phosphatase was added; the plates were incubated for 45 minutes and then washed to remove unbound IgG F(ab)2. The substrate addition of 1 mM of p-nitrophenyl phosphate in 10% diethanolamine produced a yellow color in the presence of the bound alkaline phosphatase conjugate. After incubation at room temperature for an hour, absorbance was measured at 405 nm. Samples were assayed in duplicate, corrected for nonspecific binding, and compared with standard positive and negative controls.

Sera were considered positive if the absorbance was >=.410 optical density (OD) at 405 nm. This value had been generated previously by testing 59 normal volunteers: an OD of .410 was at least 3 SDs above the group mean. A TA90-IC value with an OD of .410 has since been confirmed as a significant prognostic factor in various high-risk melanoma populations.9,12,13,16,17

Statistical Analysis
The results of the TA90-IC analyses (positive or negative) were coded, recorded separately, and submitted to the Statistical Coordinating Unit at the John Wayne Cancer Institute for analysis. The most recent TA90-IC value, obtained before initiation of vaccine therapy if applicable, was used for correlation with clinical outcome. Sensitivity, specificity, and predictive values of the TA90-IC assay for recurrence were calculated. Survival curves for TA90-IC-positive and -negative patients were constructed with the method of Kaplan and Meier. Univariate and multivariate analyses were performed with the Cox regression proportional hazards model, by using TA90-IC status and the following prognostic variables: age, sex (male vs. female), site of primary tumor (extremity vs. nonextremity), Breslow thickness, Clark level (III or IV vs. V), ulceration (yes vs. no), and nodal metastasis (yes vs. no). Age and tumor thickness were treated as continuous variables for our analysis. The significance of the association between TA90-IC status and other significant prognostic variables was determined with {chi}2 tests. Results were considered significant if the P value was <.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Tumor Characteristics
The characteristics of the study population are listed in Table 1. Almost half of the patients had ulcerated lesions, and the median thickness of all primary melanomas was 5.5 mm (range, 4–15 mm). Thirty (43%) patients had SN metastasis. SN status accurately predicted regional nodal status in all 22 patients who underwent LM/SL followed routinely by ELND. Of the 70 patients, 44 (63%) elected therapy with a polyvalent vaccine (Canvaxin); these patients entered the vaccine protocol/trial within 3 months after surgical resection. Twenty-four (34%) patients refused any adjuvant therapy, and two (3%) elected standard treatment with high-dose interferon. The median follow-up time was 25 months from the primary surgery.


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  		TABLE 1. Patient demographics and pathologic data
 
TA90-IC Level: Correlation With Recurrence and Survival
By using the ELISA cutoff level of .410, 27 (39%) patients had positive TA90-IC values. Of the 30 (43%) patients who developed disease recurrence during follow-up, 21 had positive TA90-IC values; of the remaining 9 patients with negative values, 3 had a DFS exceeding 51 months before recurrence. The pattern of disease recurrence was variable. Only four patients had local recurrence, and two of these cases were associated with simultaneous distant metastasis. Of the 10 patients with regional nodal recurrence, 5 had recurrence in the SN basin. All 10 patients with regional nodal recurrence had concurrent distant metastasis. The remaining 16 patients had systemic metastasis. The median times to recurrence for TA90-IC-positive and -negative patients were 8 and 113 months, respectively (P = .0001). The sensitivity and specificity of TA90-IC for predicting disease recurrence were 70% and 85%, respectively; the corresponding positive and negative predictive values were 78% and 79%, respectively. It is interesting to note that of the 40 patients who did not develop recurrence, only 6 had positive TA90-IC values, and 1 of the 6 had undiagnosed bladder cancer, which probably increased the TA90-IC.

The 43 patients with negative TA90-IC levels had a significantly higher 5-year DFS rate (73% vs. 10%) than patients with positive TA90-IC levels (Fig. 1). Likewise, 5-year OS rates were higher for patients with negative TA90-IC levels (84% vs. 26%) than those with positive levels (Fig. 2). Differences in both DFS and OS between the two groups were significant (P = .0001) by the log-rank test. The 5-year OS rate for the entire group was 62%.



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  		FIG. 1. Disease-free survival according to TA90-immune complex (IC) status for all patients (n = 70). The estimated 5-year disease-free survival rates were 10% and 73% for TA90-IC-positive and -negative patients, respectively (P = .0001).

 


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  		FIG. 2. Overall survival according to TA90-immune complex (IC) status for all patients (n = 70). The estimated 5-year overall survival rates were 26% and 84% for TA90-IC-positive and -negative patients, respectively (P = .0001).

 
Among the patients with tumor-positive SNs, survival was significantly worse for the TA90-IC-positive group than the TA90-IC-negative group (Fig. 3). Likewise, OS seemed to be improved when TA90-IC was negative rather than positive for patients with tumor-negative SNs (Fig. 4).



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  		FIG. 3. Overall survival according to TA90-immune complex (IC) status for patients with a positive sentinel node (n = 30). The estimated 5-year overall survival rates were 18% and 92% for TA90-IC-positive and -negative patients, respectively (P = .001).

 


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  		FIG. 4. Overall survival according to TA90-immune complex (IC) status for patients with negative sentinel nodes (n = 40). The estimated 5-year overall survival rates were <=65% and 82% for TA90-IC-positive and -negative patients, respectively (P = .203).

 
Analysis of TA90-IC Status as a Prognostic Factor for Survival
Standard prognostic factors for melanoma (age, sex, extremity vs. nonextremity site of primary tumor, Breslow thickness, Clark level of invasion, ulceration, and SN status) were compared with TA90-IC status (Table 2). By using the univariate analysis of the Cox proportional hazards regression model, only the TA90-IC status was a significant (P = .0001) predictor of DFS. However, both sex (P = .0175) and TA90-IC status (P = .0001) became significant on multivariate analysis for DFS. Although ulceration (P = .047), SN positivity (P = .027), and TA90-IC positivity (P = .0001) were significant negative predictors of OS by univariate analysis, only TA90-IC remained significant (P = .0001) when the stepwise procedure was used to select a multivariate model. Prognostic factors found to be significant for DFS, OS, or both in our analysis (sex, ulceration, and SN positivity) were then grouped by status of the TA90-IC assay (Table 3). Patients with a positive TA90-IC assay were statistically more likely to have primary tumors associated with SN metastasis (P = .03, {chi}2 test). Patient sex and tumor ulceration were not significantly different between TA90-IC groups.


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  		TABLE 2. Prognostic factors influencing survival
 

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  		TABLE 3. Distribution of significant prognostic factors according to status of TA90-IC assay
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although recent advances in immunotherapy and chemotherapy offer hope of improving survival, the prognosis for the majority of patients with advanced melanoma has not changed significantly over the past several decades.18 Therefore, contemporary investigators have focused on diagnosing subclinical metastatic disease to identify patients who would be best served by adjuvant therapy trials begun when therapeutic regimens may be more effective.19–21 Unfortunately, serum assays based on 5-S-cysteinyldopa, S-100 protein, and lipid-associated sialic acid are not yet sensitive enough for reliable detection of subclinical metastasis.22,23 Reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of the SN is a sensitive method for detecting submicrometastatic disease. In the study of Li et al.,21 which focused primarily on patients with intermediate-thickness (1–4 mm) melanomas, the rate of regional nodal metastasis was 69% with RT-PCR versus only 31% with hematoxylin and eosin and immunohistochemical staining. However, at a mean follow-up of 20 months, their RT-PCR results had not yet produced an apparent improvement in the prediction of survival (P = .06). Although RT-PCR analysis of the SN is promising, further refinements in techniques and longer follow-up are needed before molecular staging techniques can be recommended for routine use.

We previously demonstrated the utility of TA90-IC assay, a double-determinant ELISA technique, in predicting clinical outcome for different stages of melanoma in both preoperative and postoperative settings.9,11–13,16,17 In a recent study of 166 patients with stage I to III melanoma, postoperative serum TA90-IC status correlated significantly with recurrence and survival.13 Five-year OS rates were 84% for TA90-IC-negative patients and 36% for TA90-IC-positive patients (P = .0001). Multivariate analysis with standard prognostic variables identified TA90-IC status as the strongest independent prognostic factor for both DFS and OS. In addition, the assay detected recurrence with a sensitivity of 78% and specificity of 77%. It is interesting to note that the TA90-IC assay detected recurrence on an average of 19 months sooner than did routine clinical and radiographical evaluation. This is not surprising because routine clinical and radiographical surveillance rarely detects metastatic deposits smaller than 1 cm in diameter.24

In this study, we have shown that postoperative serum TA90-IC level correlates significantly with the clinical outcome of patients with thick cutaneous melanoma (Table 2). It is interesting that rates of recurrence and death were higher in TA90-IC-positive patients than in SN-positive patients (78% vs. 50% and 59% vs. 47%, respectively; Table 4), but they were lower in TA90-IC-negative patients than in SN-negative patients (21% vs. 38% and 14% vs. 20%, respectively). These differences might be used to stratify patients for adjuvant therapy on the basis of SN status and TA90-IC assay results. Patients with estimated 5-year OS rates of 82% and 92% (groups 1 and 3 in Table 5) may not want adjuvant therapy, whereas patients with estimated 5-year OS rates of <=65% and 18% (groups 2 and 4) might be very enthusiastic about the potential survival benefit of adjuvant therapy, regardless of its toxicity.


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  		TABLE 4. Comparison of sentinel node and TA90-IC status with recurrence, death, and survival
 

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  		TABLE 5. Recurrence and death for patient groups stratified by sentinel node status and TA90-IC status
 
It is unclear why patients with tumor-negative SNs and negative TA90-IC levels (group 1 in Table 5) did not have the best clinical outcome. The most likely explanation is our small sample size. It is also possible that not all of these patients had tumors that expressed TA90 antigen; however, we have shown that this antigen is expressed in at least 72% of human melanoma cells.9 It is also remotely possible that LM/SL identified a nonsentinel lymph node in a small portion of our patients. Alternatively, the assay might not have been sensitive enough to detect very low levels of TA90-IC in certain patients with extremely small micrometastases. Of the nine patients with false-negative TA90-IC assay results, three patients developed recurrence after a DFS exceeding 51 months. Larger sample size and longer follow-up may confirm our suspicion that a combination of tumor-negative SN and negative TA90-IC value is associated with the best long-term prognosis.

Our 5-year OS rate of 62% is in accordance with those of other published series.3,4,6 Although previous studies have shown that the tumor status of the regional node basin is the most accurate prognostic indicator for OS, our data suggest the addition of a new prognosticator (TA90-IC). In our multivariate analysis, both SN status and TA90-IC status correlated significantly with OS (P = .0272 and P = .0001, respectively). Furthermore, among the patients with tumor-positive SNs, survival was significantly worse for the TA90-IC-positive group than the TA90-IC-negative group (P = .001). Therefore, we believe that the results of the TA90-IC assay can complement the information gained from LM/SL and better identify those patients in clear need of adjuvant therapy. Among the patients with tumor-negative SNs, OS seemed better when TA90-IC was negative rather than positive. However, the small sample size and relatively short follow-up probably combined to mask a significant difference between the two groups (P = .203).

In conclusion, we have demonstrated that the postoperative serum TA90-IC assay is a powerful tool that can aid a clinician in managing patients with thick primary melanomas. The TA90-IC assay is now available through Specialty Laboratories (Santa Monica, CA) as Melanoma MonitRTM test code 3925. In our study it was more powerful than standard prognostic variables for melanoma, including SN status. We believe that the serum TA90-IC assay alone or in combination with focused analysis of the SN can yield data that better define a patient’s clinical outcome and thereby guide decisions regarding postoperative adjuvant therapy. Patients whose TA90-IC level is positive might be entered onto an adjuvant therapy trial, even if their SN specimens have no evidence of tumor. We are currently conducting an international multicenter trial to test the validity of the TA90-IC assay in a prospective manner. Results of that trial would be used to better define prognosis and identify those individuals who would be the best candidates for adjuvant therapy trials.


   Acknowledgments
 
Supported by grants CA 12582 and CA 29605 from the National Cancer Institute, by grant DAMD 17-94-J-4459 from the United States Army, and by funding from the Wayne and Gladys Valley Foundation, Oakland, CA, and the Harold McAlister Charitable Foundation, Los Angeles, CA.


   Footnotes
 
Presented at the Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Received for publication March 15, 2001. Accepted for publication September 7, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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