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Tumor-Associated Antigen TA90 Immune Complex Assay Predicts Recurrence and Survival After Surgical Treatment of Stage I-III Melanoma

From the Sonya Valley Ghidossi Vaccine Laboratory and the Roy E. Coats Research Laboratories of the John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA.

Address reprint requests to Donald L. Morton, MD, FACS, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; email: mortond{at}jwci.org

	ABSTRACT

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PURPOSE: Immune complexes (IC) containing the tumor-associated antigen TA90 can be identified in the sera of melanoma patients. We have shown that an enzyme-linked immunosorbent assay for TA90-IC can detect subclinical metastasis before surgical treatment of early-stage melanoma. We assayed the TA90-IC levels of postoperative sera from patients with melanoma and evaluated their relationship to recurrence and survival.

PATIENTS AND METHODS: Multiple archival serum samples prospectively collected during postoperative surveillance of 166 patients with American Joint Committee on Cancer stage I, II, or III melanoma were analyzed for TA90-IC in a blinded fashion. Results were correlated with disease recurrence and survival determined by database and chart review.

RESULTS: TA90-IC status in the early postoperative period was strongly correlated with survival. Five-year overall survival rates were 84% for TA90-IC–negative patients and 36% for TA90-IC–positive patients (P = .0001). Respective 5-year disease-free survival rates were 74% and 24% (P = .0001). The TA90-IC assay was a significant predictor of survival for both stage II and III patients. Multivariate analysis identified TA90-IC status as the strongest independent prognostic factor for both overall and disease-free survival. The TA90-IC assay was elevated in 54 (77%) of 78 patients who developed recurrent disease, becoming positive 19 ± 7 months before clinical evidence of recurrence. Overall, the assay detected recurrence with a sensitivity of 78% and specificity of 77%. Exclusion of patients receiving postoperative immunotherapy with a polyvalent melanoma cell vaccine increased sensitivity and specificity to 92% and 86%, respectively.

CONCLUSION: The TA90-IC assay can accurately predict survival and detect the presence of subclinical disease after surgery for melanoma, which should be useful in selecting patients for adjuvant therapy. Because the TA90-IC assay detected recurrence on an average of 19 months sooner than did routine clinical and radiographic evaluation, it may allow more timely therapeutic interventions.

	INTRODUCTION

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SURGICAL RESECTION remains the primary treatment modality for melanoma confined to the skin or regional lymph nodes (American Joint Committee on Cancer [AJCC] stages I-III).^1,2 Surgery is usually curative in patients with low-risk (AJCC stage I or IIa) disease, but those at high-risk (stage IIb or III) often develop a recurrence that is eventually fatal.^1,2 There is no accurate method to identify patients who have occult metastatic disease and are therefore more likely to develop recurrence. The availability of such a test could be particularly useful for determining prognosis and selecting candidates for adjuvant therapy.

Our laboratory has developed an assay to detect immune complexes (IC) containing a 90-kd tumor-associated antigen (TA90).³ This antigen is a highly immunogenic subunit of a urinary tumor-associated antigen, which is found in the urine and sera of metastatic melanoma patients.⁴ TA90 is expressed by more than 70% of melanomas, soft tissue sarcomas, and carcinomas of the breast, colon, and lung.^3,5 Immunochemical analysis and lack of cross-reactivity in antibody blocking studies show that TA90 is distinct from other tumor markers such as carcinoembryonic antigen, prostate-specific antigen, CA-15-3, alpha fetoprotein, and other oncofetal antigens (unpublished data).

TA90 occurs as free antigen and as IgG-bound IC in the sera of melanoma patients.⁶ Patients with distant metastatic melanoma (AJCC stage IV) and extensive tumor burden express high levels of free TA90 and low levels of circulating TA90-IC, whereas patients with early-stage disease and low tumor burden rarely have detectable free antigen but often have elevated levels of circulating TA90-IC.⁶ An enzyme-linked immunosorbent assay (ELISA) was therefore developed to detect TA90-IC in the sera of cancer patients.³ This assay does not require pretreatment of the test samples.

We previously examined the ability of a single preoperative TA90-IC measurement to identify the presence of occult metastasis in patients with clinically local melanoma.⁷ The TA90-IC assay detected occult metastasis with a sensitivity and specificity of 77% and 76%, respectively, and was an independent prognostic factor for survival. However, there was only a 25% to 30% survival difference among groups stratified by TA90-IC status. We hypothesized that the TA90-IC ELISA would separate high-risk and low-risk groups more effectively in the postoperative period, when tumor burden has been reduced. We also hypothesized that serial postoperative TA90-IC assays would detect recurrent disease earlier than routine clinical and radiographic evaluation. We therefore analyzed TA90-IC levels in serum samples prospectively collected after resection of clinically local or regional melanoma and then correlated these values with disease-free recurrence and overall survival (OS).

	PATIENTS AND METHODS

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Patient Population
The prospective melanoma database at the John Wayne Cancer Institute was used to identify patients undergoing definitive surgical treatment of clinically local or regional melanoma between January 1, 1980, and December 31, 1990. Individuals were randomly selected from this group, and the records of the John Wayne Cancer Institute melanoma serum bank were reviewed to identify 166 patients with multiple serum samples. A single baseline sample obtained within 4 months after surgery (but before the initiation of adjuvant therapy) was correlated with survival. Multiple samples obtained every 3 to 6 months during postoperative surveillance were correlated with disease recurrence.

All patients underwent wide excision of the primary site with a margin 2 cm, and 151 underwent complete regional lymphadenectomy. Thirty-five of the 151 patients participated in a trial evaluating lymphatic mapping and sentinel lymphadenectomy before complete regional lymph node dissection.⁸ Table 1 lists the demographic and pathologic data for the population. Sixty-seven percent of primary lesions were of Breslow thickness 0.75 to 4.0 mm, and lymph node metastases were identified in 69 of the 151 patients who underwent complete lymphadenectomy. Median age of the 166 patients was 45 years (range, 15 to 79 years).

The location and time of each recurrence were recorded and correlated with TA90-IC status. Minimum postoperative follow-up for surviving patients was 84 months. Median follow-up for the entire group was 67 months (range, 2 to 181 months). All patients gave informed consent to participate in a study of tumor-associated antigen expression, which had been approved by the institutional review boards of the University of California, Los Angeles, and Saint John’s Health Center, Santa Monica, California.

TA90 Immune Complex Assay
The serum ELISA for TA90-IC has been described in detail elsewhere.³ Briefly, sera were diluted 1:60 in 0.025 mol/L of phosphate-buffered saline and 0.5% Triton X-100, pH 7.2. Diluted sera were then placed in the wells of ELISA plates, which had been coated with murine anti-TA90 monoclonal antibody (AD1-40F4). Plates were incubated at 37°C for 45 minutes and washed to remove unbound proteins. F(ab')₂ fragment of goat antihuman IgG conjugated to alkaline phosphatase was added at a predetermined dilution. The plates were incubated again for 45 minutes and then washed to remove unbound conjugate. This step was followed by the addition of 1 mg/mL of p-nitrophenyl phosphate in 10% diethanolamine. After incubation for 1 hour, absorbance was measured at 405 nm. Samples were assayed in duplicate, corrected for nonspecific binding, and compared with standard positive and negative controls. Assays were performed by laboratory personnel who had no knowledge of the patient’s identity or clinical status. Sera were considered positive if the absorbance was 0.410 optical density (OD) at 405 nm.⁷

This assay has been carefully standardized with standard operating procedures and has been approved on inspection by the Clinical Laboratory of Improvement Amendments. Multiple analyses performed on the same serum sample in a coded manner have validated its reproducibility within ± 5%.³ The cutoff for a positive absorbance value was determined by screening 59 normal individuals. At a mean ± 3 SD of normal OD, none of the 59 normal controls were positive. This criterion was then applied to populations of patients with various solid tumors and to 250 normal individuals. Of the patient group, 51% to 83% had OD values above the cutoff; of the normal group (which did not include the initial 59 normal individuals), only 3.2% (8 cases) had OD values above the cutoff. TA90-IC status based on this cutoff has been confirmed as a significant prognostic factor in other high-risk melanoma populations as well.^3,7,10,11

Clinical Correlation and Statistical Analysis
Survival analysis. TA90-IC status in the first 4 months after surgery was correlated with OS and disease-free survival (DFS). All patients had one baseline TA90-IC value obtained within 4 months of surgery. Those with TA90-IC values 0.410 OD were considered positive, and those with values less than 0.410 OD were considered negative. Both OS and DFS were measured from the time of surgery; DFS ended with the detection of recurrence by physical examination or radiographic studies. Survival curves for TA90-IC positive and negative cohorts were constructed with the Statistical Analysis System (SAS Institute, Cary, NC), and statistical significance was evaluated by using the log-rank test. Univariate and multivariate analyses were performed by using the Cox proportional hazards model; TA90-IC status was included with standard prognostic variables (age, sex, Breslow depth, Clark level, lymph node status, histologic type, primary site, ulceration, residual melanoma in the wide excision specimen, and adjuvant therapy). Results were considered significant if the P value was less than .05.

Detection of recurrence. To analyze the relationship between TA90-IC status and recurrence, multiple serial TA90-IC values were plotted against time and correlated with recurrence detected by clinical examination or radiographic studies. The TA90-IC assay was considered positive when OD was 0.410 on two consecutive determinations. Individual patients were designated as true-negative, true-positive, false-negative, or false-positive on the basis of their TA90-IC status before recurrence ( Fig 1). Sensitivity, specificity, and positive and negative predictive values for recurrence were calculated based on this classification. Significance of the association between TA90-IC status and recurrence was determined with Fisher’s exact test. Excluded from these calculations were four patients who did not have at least one TA90-IC value measured within 6 months before recurrence.

View larger version (22K): [in this window] [in a new window]   Fig 1. Correlation between multiple serial TA90-IC values and recurrence. (A) Negative TA90-IC and no recurrence (true-negative); (B) positive TA90-IC before recurrence (true-positive); (C) consistently negative TA90-IC before recurrence (false-negative); (D) consistently positive TA90-IC but no evidence of recurrence with long-term follow-up (false-positive) in a patient receiving CancerVax vaccine therapy.

	RESULTS

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View larger version (17K): [in this window] [in a new window]   Fig 2. Overall survival of 166 patients stratified by postoperative TA90-IC status within 4 months of surgery.

View larger version (16K): [in this window] [in a new window]   Fig 3. Disease-free survival of 166 patients stratified by postoperative TA90-IC status within 4 months of surgery.

View larger version (15K): [in this window] [in a new window]   Fig 4. Overall survival of 69 AJCC stage III patients stratified by postoperative TA90-IC status within 4 months of surgery.

View larger version (15K): [in this window] [in a new window]   Fig 5. Overall survival of 60 AJCC stage II patients stratified by postoperative TA90-IC status within 4 months of surgery.

The relationship between several prognostic factors and OS was examined by univariate analysis. In addition to TA90-IC status, the variables studied included the patient’s age and sex; the primary melanoma’s anatomic site, Breslow depth, Clark level, histologic type, and ulceration; the tumor status of the regional lymph nodes; the presence of residual melanoma in the wide excision specimen; and the use of any adjuvant therapy. Univariate analysis assigned significance to TA90-IC status, Breslow depth, nodal status, histologic type, primary site, and adjuvant therapy ( Table 2). Only TA90-IC status (P = .0001) and Breslow depth (P = .0034) predicted OS in multivariate analysis (Table 2). TA90-IC status (P = .0001) and Breslow depth (P = .0079) were also the only significant predictors of DFS in multivariate analysis. Similar results were obtained using the TA90-IC OD and number of involved lymph nodes as continuous variables (data not shown).

	DISCUSSION

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Among the several markers for melanoma described in the literature are manganese, superoxide dismutase, serum S-100 protein, tyrosinase protein, and lipid-associated sialic acid.^17-19 These markers can be identified in some patients with early-stage melanoma, but none has sufficient sensitivity to reliably detect subclinical metastatic disease. Reverse-transcriptase polymerase chain reaction analysis of peripheral blood for melanoma-associated mRNA expression has been suggested for identifying occult metastatic disease.^20-23 Although this technique is very sensitive, prospective evaluation of its clinical applicability thus far suggests its prognostic value might be improved by combination with another marker.

Nearly 100% of melanoma patients whose tumors express TA90 develop anti-TA90 IgM and/or IgG antibodies spontaneously.²⁴ Patients receiving CancerVax develop humoral and delayed-type hypersensitivity responses to TA90 after immunization.^10,24,25 In an analysis of AJCC stages III and IV melanoma patients receiving CancerVax, a high IgM and delayed-type hypersensitivity response to TA90 correlated positively with survival, whereas a strong IgG response correlated inversely with survival.^10,25 These observations formed the basis of a highly predictive immunologic survival model for patients treated with CancerVax.¹⁰ However, although anti-TA90 titers have significant prognostic impact, TA90-IC status is the single best prognostic factor.^10,11 Moreover, evidence of TA90 in a serum specimen is more meaningful than evidence of anti-TA90 antibodies, because antibodies to an antigen can persist in the circulation long after the source of the antigen has been eliminated, whereas the antigen itself is present only when its source (a tumor cell) is also present.

We previously reported the significance of a single preoperative TA90-IC value in patients with early-stage melanoma.⁷ The TA90-IC ELISA identified occult metastatic disease with a sensitivity of 77% and specificity of 76%. This far exceeds the ability of other marker assays to detect occult metastasis from melanoma or other malignancies.^17-19,26 TA90-IC status was an independent predictor of both recurrence and survival, stratifying patients into groups with a 25% to 30% difference in 5-year OS and DFS.

In the present study, TA90-IC status in the early postoperative period was highly predictive of both recurrence and survival. As hypothesized, the survival differences between TA90-IC positive and negative groups were more dramatic than in the previous study.⁷ Patients were stratified into groups with a 50% and 48% difference in recurrence and survival, respectively. TA90-IC status was an independent predictor of recurrence and survival, and was the strongest prognostic factor in the multivariate model, surpassing both tumor thickness and nodal status.

The magnitude of risk stratification seen in this study may be sufficient to allow selection of patients for adjuvant therapy. For example, most patients and physicians would be enthusiastic about adjuvant treatment if there were a 76% risk of recurrence (seen in the TA90-IC–positive group). On the contrary, many patients and physicians might not consider adjuvant therapy if there were a 26% risk of relapse (seen in the TA90-IC negative group). Fortunately, the assay has its greatest prognostic value in the early postoperative period, when decisions regarding adjuvant therapy must be made. The prognostic significance of the assay at this time point was not affected by subsequent adjuvant therapy.

TA90-IC status effectively stratified both node-positive and node-negative patients. The difference in 5-year survival between TA90-IC positive and negative groups was greater for stage II (63%) than stage III (30%) patients. The explanation for this is unclear but may relate to immunologic factors associated with nodal metastasis. The ability of the assay to identify stage II patients at very high risk of relapse is of great interest, because many of these patients would not be considered candidates for adjuvant therapy using currently accepted guidelines.

The TA90-IC assay became positive during postoperative follow-up in the majority of patients who developed recurrent disease. The assay had an overall sensitivity of 78% and specificity of 77%. Interestingly, most patients with false-positive and false-negative results had received adjuvant therapy with CancerVax plus BCG.⁹ Sensitivity and specificity in the CancerVax group were only 65% and 59%, respectively, compared with 92% and 86% for patients not receiving the vaccine. The increased frequency of false-positive results seen in patients receiving CancerVax relates to an abrupt increase in the TA90-IC value after vaccine induction (Fig 1D), which occurs in a minority of patients. This spike may represent a specific immune response to TA90 expressed by cells of the vaccine. A spike in TA90-IC did not correlate with recurrence or survival in this study (data not shown). The reason for the increased frequency of false-negative results in patients receiving CancerVax (Fig 1C) is unclear, but may relate to the induction of cytotoxic antibodies^10,24,25 and cytotoxic T lymphocytes, setting the stage for destruction of occult melanoma metastases with the release of TA90 antigen. The released antigen could then combine with antibody to create TA90-IC. Alternatively, it is possible that breakdown of the melanoma cells in CancerVax could release enough TA90 to combine with anti-TA90 antibody and create TA90-IC.

Our findings suggest that the TA90-IC assay may not accurately predict recurrence during postoperative adjuvant therapy with CancerVax. The test retains its prognostic value before vaccine treatment begins, however (Fig 1A,B). We verified this in a study of 125 patients with stage IV melanoma, who underwent surgical resection of all gross metastatic disease followed by adjuvant immunotherapy with CancerVax.¹¹ The TA90-IC status after surgery but before initiation of vaccine treatment was an independent prognostic factor for both OS and DFS. This indicates that the assay could be used to predict prognosis and select patients for vaccine therapy. The effect of other types of immunotherapy on TA90-IC expression is unknown.

In summary, the TA90-IC assay can stratify patients with stage II and III melanoma into very high- and low-risk groups in the early postoperative period. This may be useful in selecting patients for adjuvant systemic therapy. Prospective validation of these findings is underway in a multicenter trial. The assay also detects metastatic disease earlier than routine clinical and radiographic studies, allowing earlier treatment interventions for patients with recurrent disease. One problem with this sensitive assay is the long lead time between the development of a positive TA90-IC assay and the clinical or radiologic evidence of recurrence. In this regard, positron emission tomographic scanning of TA90-IC–positive patients may be helpful for identifying the site of recurrence.²⁷

	ACKNOWLEDGMENTS

 
Supported by grants CA 12582, CA 29605, and T32 CA 09689 from the National Cancer Institute, grant DAMD 17-94-J-4459 from the United States Army, and funding from the Wayne and Gladys Valley Foundation, Oakland, CA.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 8, 1999; accepted October 3, 2000.

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