Serum CA549 in primary breast cancer: comparison with CA15.3 and MCA.

We carried out a comparison of three commonly used mucin markers, CA549, CA15.3 and MCA. Serum samples from 184 healthy women and 237 patients with primary breast cancer were evaluated. The markers were measured using commercially available immunometric assays. Like CA15.3 and MCA, CA549 was significantly associated with tumour size and lymph node status, being an effective indicator of tumour bulk. CA549 was significantly correlated with both CA15.3 and MCA. Positive/negative concordance rate was very good (93.7%) between CA549 and MCA. Conversely, CA15.3 was positive and CA549 negative in 20.4% of cases. Axillary status was not significantly different in the latter group of patients and in cases in which CA15.3 and CA549 showed concordant results. From the present findings we draw the following major conclusions: 1. CA549 and MCA are highly correlated and their association should not provide additional information; however, they should not be considered interchangeable since they may behave differently in individual cases. 2. CA549 and CA15.3, although well correlated, are discordant in a significant number of cases. Longitudinal studies are needed to verify the usefulness of the association between the two markers. 3. The three evaluated mucin markers are not interchangeable in individual patients; if a patient is monitored with a marker, she should be followed up with the same marker.     

CA 15.3: early results of a new breast cancer marker

A new antigen associated with breast cancer, CA 15.3, was determined in the serum of 690 breast cancer patients and controls. After establishing a maximum normal level of 40 U/ml in 140 healthy subjects and 350 patients with benign diseases, CA 15.3 was investigated in 190 breast cancer patients: CA 15.3 serum levels were statistically different in patients with no evidence of disease (20.6 +/- 11.2 U/ml), metastatic patients in response (33.5 +/- 24.0 U/ml) and metastatic patients not responding to therapy (stable disease, 98.9 +/- 50.4; progression, greater than 200). CA 15.3 serum levels seem to correlate with the extent of metastatic breast cancer. Further studies are needed to establish the role of this marker in the management of breast cancer patients.     

Diagnostic value of CA 549 in pleural fluid. Comparison with CEA,CA 15.3 and CA 72.4

Several tumor markers have been evaluated in pleural fluid, but their clinical role has not been firmly established. The aim of this study is to determine the diagnostic value of carbohydrate antigen 549 (CA 549) levels in pleural fluid, and to compare it with another previously studied tumor markers: carcinoembryonic antigen (CEA), CA 15.3 and CA 72.4. We prospectively studied 252 patients with pleural effusion: 101 malignant (20 mesothelioma) and 151 of several benign diseases. The levels of the tumor markers were measured by immunoradiometric assays (RIA). CA 549 in pleural fluid has an acceptable sensitivity (0.49), with high specificity (0.99). The best combination of tumor markers for differentiating malignant from benign effusions was CA 549+CEA+CA 15.3, with a sensitivity of 0.65, specificity of 0.99 and accuracy of 0.85. The addition of any one tumor marker assay consistently improved the diagnostic value of cytology. In our study, none of the tumor markers was organ-specific. When mesothelioma and hematological malignancy were ruled-out, the combination of CA 549+CEA+CA 15.3, improved the results up to a sensitivity of 0.77, specificity of 1 and accuracy of 0.92. In conclusion, CA 549 assay has an acceptable sensitivity with high specificity. The best combination of tumor markers in this series with a high relative frequency of mesothelioma and low frequency of breast carcinoma was CA 549+CEA+CA 15.3. Individual tumor markers or their combination increased the sensitivity of pleural cytology.     

Serum levels and biochemical characteristics of cancer-associated antigen CA-549, a circulating breast cancer marker

CA-549 is a circulating breast cancer-associated antigen that reacts with monoclonal antibody BC4E 549. Biochemical characterization of CA-549 revealed that it is an acidic (isoelectric point 5.2) glycoprotein that exhibits two bands by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions of apparent molecular weights of 400,000 and 512,000. Immunohistochemical staining of unfixed frozen tissue sections of human breast tumors and a variety of benign tissues with BC4E 549 revealed no preferential staining of tumor over benign breast tissue and cross-reactivity with a wide range of other benign tissues including kidney, liver, lung, colon, pancreas, ovary, and spleen. Serum levels of CA-549 were initially tested by an enzyme-linked immunosorbent assay inhibition using BC4E 549. This assay showed that CA-549 concentrations were elevated in 19 of 27 sera from patients with advanced breast cancer compared to 0 of 22 and 0 of 129 sera from benign breast disease patients and healthy females, respectively. These preliminary data suggested that CA-549 was a useful breast tumor marker; thus BC4E 549 was adapted to a sandwich immunoradiometric assay format suitable for routine use in the clinical laboratory and its performance was evaluated on a panel of 668 serum samples. The test detected significant concentrations of CA-549 in the sera of 40 of 80 patients with advanced breast cancer, 1 of 30 with early breast cancer, 4 of 19 with advanced lung cancer, 2 of 40 with advanced colon cancer, and 5 of 29 with advanced prostate cancer. The test showed a high degree of specificity, producing false-positives in only 3 of 79 benign breast patients, 2 of 25 benign liver patients, 2 of 70 benign colon patients, 2 of 19 benign lung patients, 0 of 20 benign prostate patients, and 3 of 257 healthy individuals. These data represent an overall 50% sensitivity and 98% specificity as a test for advanced breast cancer. These data indicate that this immunoradiometric assay is a useful test for the detection of circulating CA-549 in advanced breast cancer patients and suggest that it may prove useful as a monitor in the management of that disease.     

The use of CA15.3 as a serum tumour marker in breast carcinoma

There is, as yet, no tumour marker which is sufficiently specific and sensitive for use in the routine assessment of breast cancer patients. CA15.3 is a recently described tumour marker determined by two monoclonal antibodies. We have estimated CA15.3 by immunoradiometric assay in 187 patients attending a breast clinic. Eighty-one patients with benign disease were used as controls and 32 U/ml was taken as the upper limit of the normal range (means + 3SD = 31.7). Of 58 women with Stage I and II disease, only four had abnormal concentrations of CA15.3 and all are disease-free at a mean follow-up of 31 months. Seven women with normal CA15.3 concentrations developed recurrent disease at a mean of 18.7 months (range 10-25 months). Seven-day postoperative values were significantly lower than pre-operative values. There was no association between the CA15.3 value and the axillary nodal status. The patients with disseminated disease had a wide range of CA15.3 concentrations and there was no association between the CA15.3 concentration and the apparent tumour load.     

Follow-up of metastatic breast cancer patients with a mucin-like carcinoma-associated antigen: comparison to CA 15.3 and carcinoembryonic antigen

During a follow-up program, breast cancer patients were monitored with serum analyses of mucin-like carcinoma-associated antigen (MCA), CA 15.3 and carcinoembryonic antigen (CEA). Minimum as well as maximum marker values of the individual patterns were selected for further evaluation. Marker levels of risk patients differed significantly from those of patients with metastases. In several risk patients, elevated marker levels (especially of MCA) preceded clinical diagnosis of metastases for several months. In cases with already diagnosed metastases, sensitivity of MCA was comparable to CA 15.3 or CEA. The type of metastases determined marker sensitivity, concentration and the difference between maximum and minimum values.     

Estimates of circulating breast cancer-associated antigen CA 15-3 as a monitoring marker in patients with breast cancer

CA 15-3 is a newly developed tumor marker detected by breast tumor-associated antigen 115D8/DF3 and is being studied as a monitoring marker in breast cancer patients (pts), even though its sensitivity as a screening marker is not so high. The cut off value of CA 15-3 was set at 27 U/ml. We assayed the plasma CA 15-3 levels of breast cancer pts from June 1985 for the purpose of estimating it as a monitoring marker in comparison with CEA. In the monitoring of over 2,000 postoperative pts, 23 were discovered to have metastatic lesions. For prediction of recurrence, CA 15-3 was useful for 11 pts (48%), while CEA was useful for 8 pts (35%), and CA 15-3 or CEA were useful for 14 pts (61%). Although it was little useful for local recurrence, CA 15-3 was highly useful for the prediction of organ & bone recurrence in 7/11 pts (64%). With regard to monitoring of the clinical course of metastatic carcinoma of the breast, the levels of CA 15-3 were positive in 47/68 pts (69%), while in contrast CEA was positive in 42/68 pts (62%). The trend of CA 15-3 was also highly correlated with the clinical course. CA 15-3 thus appears to be a better marker, especially as a monitoring marker, than CEA for breast cancer. Additional research will be required on this marker, but it seems likely that CA 15-3 combined with CEA would provide better information for the monitoring of breast cancer patients.     

CA 242, a new tumour marker for pancreatic cancer: a comparison with CA 19-9, CA 50 and CEA.

The serum expression of a novel tumour marker, CA 242, defined by monoclonal antibody C 242, was studied in 179 patients with pancreatic cancer. The results were compared with CA 19-9, CA 50 and CEA. CA 242 is a carbohydrate closely related, but not identical, to CA 19-9 and CA 50. The overall sensitivity of the CA 242 assay was 74%: 55% in stage I, 83% in stage II-III and 78% in stage IV disease. The specificity calculated from 112 patients with benign diseases was 91%. CA 19-9 had a higher sensitivity of 83%, but the specificity was only 81%. When comparing the markers by receiver operating characteristic analysis, the sensitivities were almost identical at all specificity levels. The CA 242 level was elevated in 7%, 15% and 7% of patients with benign pancreatic, biliary and liver disease respectively. The corresponding figures for CA 19-9 were 19%, 28% and 15% respectively. The sensitivity of CA 242 was higher than that of CA 50 and CEA at all specificity levels. In conclusion, tumour marker CA 242 seems to be a useful diagnostic tool for the diagnosis of pancreatic cancer, and is an alternative to CA 19-9. The advantage of CA 242 over CA 19-9 is its higher specificity when using the recommended cut-off levels of the assays.     

Prognostic role of CA15.3 in 7942 patients with operable breast cancer

To assess the prognostic value of presurgical CA15.3 in a large cohort of patients with early breast cancer. A total of 7.942 consecutive patients with breast cancer operated at the European Institute of Oncology between 1998 and 2005 and with presurgical values of CA 15.3 available were included. We explored patterns of recurrence by baseline CA 15.3 values. Mean CA15.3 was 17.0 U/ml. CA15.3 was associated with age, tumor size, nodal involvement, Ki-67 labeling index, grade, HER2 expression, molecular subtype, and perivascular invasion. CA15.3 was independently associated with distant metastases [HR > 20 U/ml vs. ≤ 20 U/ml: 1.34 (95% CI 1.15-1.56)] and death [HR > 20 U/ml vs. ≤ 20 U/ml: 1.30 (95% CI 1.11-1.53)]. When considering CA15.3 as continuous variable, we observed a constant risk of metastasis and death from the lowest values to about 15-20 U/ml, and then a significantly increasing risk with increasing values of CA15.3. Finally, CA15.3 provided significant additional information to the common prognostic factors to predict the occurrence of metastases (C-index P value 0.04). In patients with operable breast cancer, presurgical CA15.3 value is an independent prognostic factor for metastases and deaths. CA15.3 provides additional information to the common prognostic factors and should be considered in the adjuvant therapeutic algorithm.     

A comparison of CA-549 with CA 15-3 and MCA in patients with metastatic breast cancer.

CA 15-3, MCA, and CA-549 levels were determined in the serum of 56 patients with metastatic breast cancer, all of whom had visceral and/or bone metastases. CA 15-3 was positive in the serum of 37 patients, MCA in the serum of 38 patients, and CA-549 in the serum of 39 patients. All 3 markers were positive in 36 patients, and all 3 were negative in 16 patients. In the serum of 4 patients only 1 or 2 markers were slightly elevated. Thus, the results were identical in 52 of the 56 patients. It is concluded that CA 15-3, MCA, and CA-549 are sensitive markers for advanced breast cancer, and that no advantage can be expected by combining them.     

c-erbB-2 oncoprotein, CEA, and CA 15.3 in patients with breast cancer: prognostic value

The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 healthy subjects, 58 patients with benign breast diseases, and 413 patients with breast cancer (186 locoregional, 185 with advanced disease, and 42 with no evidence of disease). Using 15 U/ml as the cut-off, no healthy subjects or patients with benign diseases and only 2.4% of no evidence of disease patients had elevated serum levels. Abnormal c-erbB-2 levels were found in 29% (101/370) of the patients with breast carcinoma (locoregional 9%, metastases 45.4%). CEA (cut-off 5 U/ml) and CA 15.3 (cut-off 35 U/ml) sensitivity was 18% and 16% in patients with locoregional disease and 61% and 70% in those patients with advanced disease, respectively. A trend toward higher serum levels of all three tumor markers in patients with nodal involvement or greater tumor size was found, but was statistically significant only with CEA (p < 0.01). By contrast, c-erbB-2 was related to steroid receptors, in both locoregional and metastatic tumors. When the prognostic value of these markers was evaluated, patients with abnormally high presurgical CEA and c-erbB-2 had a worse prognosis than those patients with normal values, in both node-negative (p < 0.05 and p < 0.001, respectively) and node-positive patients (p < 0.556 and p < 0.001, respectively). By contrast, no relationship was found between CA 15.3 values and prognosis. Multivariate analysis showed that CEA and c-erbB-2 were also prognostic factors. The correlation between serum and tissue levels of c-erbB-2 was studied in the tumors of 161 patients. Significantly higher c-erbB-2 serum levels were found in patients with overexpression in tissue by immunohistochemistry, in both locoregional and advanced disease (p=0.0001). Serum concentrations in patients with advanced disease were related to the site of recurrence, with significantly higher values in patients with metastases (mainly in those with liver metastases) than in those with locoregional recurrence. In summary, c-erbB-2 serum levels seem to be a useful tumor marker in the prognosis of patients with breast cancer. Using all three tumor markers, sensitivity was 35% in patients with locoregional breast cancer and 88% in patients with recurrence.     

Is tissue polypeptide antigen still a useful tumor marker in breast carcinoma? Comparison with CA15.3 and MCA

Serum levels of tissue polypeptide antigen (TPA) are related to the proliferative activity and to the mass of the malignancy, differently from any other available tumor marker. We therefore evaluated TPA in comparison with CA15.3 and MCA (mucinous-like carcinoma-associated antigen) in patients with primary breast cancer. TPA was measured in tumor cytosol and in serum. Cytosol and serum TPA levels were not significantly correlated. Serum TPA was higher in patients with locally more advanced disease and in receptor-negative cases. The relation between TPA and disease spread was not directly dependent on tumor bulk, whereas CA15.3 and MCA were highly correlated to the number of positive lymph nodes and tumor size. No correlations were found between TPA and CA15.3 or MCA, and the positivity concordance rate between TPA and CA15.3 or MCA was very low. Patients with higher TPA serum levels showed a worse prognosis in cases with and in those without axillary metastases. From our data we conclude that TPA provides information different from that obtained with breast-specific tumor markers and could therefore be useful in association with CA15.3 and/or MCA in the management of patients with breast cancer.     

Serum tumor marker CA 15.3 and stage are the two most powerful predictors of survival in primary breast cancer

The extreme drug resistance (EDR) assay has not been widely studied in the setting of non-metastatic breast cancer. We evaluated the feasibility of performing the assay in 144 primary breast tumor specimens from two institutions by determining the rate of successful tumor culture for assays, number of drugs evaluated per assay, and time from tumor biopsy to receipt of results. We also sought to determine factors that are associated with assay success. An exploratory analysis was performed to detect possible associations between estrogen receptor (ER), progesterone receptor (PR) and HER2/NEU over-expression and extreme drug resistance demonstrated by the assay for specific chemotherapeutic agents. Of 144 tumor specimens submitted, tumor was successfully cultured for assay in 101(70%) of cases. A median of five drugs was evaluated per assay (range 2–9). Results were obtained in a median of 8days (range 2–29). Young age, high tumor grade, PR negativity, and higher tumor submission weight were predictive for a successful assay. EDR was observed in 7–15% of tumors to doxorubicin, cyclophosphamide, 5-fluorouracil (5FU) and mitoxantrone, but EDR to paclitaxel was observed in 35%. Extreme drug resistance to 5-FU was associated with negative ER and PR status. There was a trend toward association between EDR to paclitaxel and HER2/NEU over-expression. The EDR assay may be successfully performed in the majority of tumors, and assay results are available in a timely fashion such that adjuvant treatment drug selection could be guided by results. These results may be helpful for designing possible future trials that evaluate the assay's role in adjuvant chemotherapy selection.     

Prognostic role of serum CA15.3 in 362 node-negative breast cancers. An old player for a new game

The aims of the present investigation were to evaluate the association between serum CA15.3 levels and other biological and clinical variables and its prognostic role in patients with node-negative breast cancer. We evaluated 362 patients operated upon primary breast cancer from 1982 to 1992 (median follow-up 69 months). Serum CA15.3 was measured by an immunoradiometric assay. The association between variables was investigated by a Principal Component Analysis (PCA) and the prognostic role of CA15.3 on relapse-free survival (RFS) was investigated by Cox regression models adjusting for age, oestrogen receptor (ER), tumour stage, and ER x age interaction, with both the likelihood ratio test and Harrell's c statistic. The prognostic contribution of CA 15.3 was highly significant. Log relative hazard of relapse was constant until approximately 10 (U/ml) of CA15.3 and increased thereafter with increasing marker levels. CA15.3 showed a significant contribution using as a cut-off point a value of 31 U/ml. However, the contribution to the model of the marker as a continuous variable is much greater. From these findings, we can conclude that: (i) CA15.3 is a prognostic marker in node-negative breast cancer; (ii) its relationship with prognosis is continuous, with the risk of relapse increasing progressively from approximately 10 U/ml.     

Clinical evaluation of a new tumor marker, CA 15-3, in breast cancer; a comparative study with CEA

Recently, a new RIA method has been developed by Centocor Co., utilizing the monoclonal antibody CA 15-3. We performed a clinical trial to evaluate its utility as a tumor marker for breast cancer in comparison with CEA. We set 15 U/ml as the cut-off value of serum CA 15-3 level from results acquired from controls; 10 volunteers and 17 patients with non-malignant diseases. The CA 15-3 positive rate among the cases of primary breast cancer was 13.3%, which was of poor diagnostic value. In the recurrent cases the positive rate of CA 15-3 was 72.0%, which was valuable compared with that of serum CEA, 52.0%. In the cases of primary cancers other than breast cancer, the positive rate of CA 15-3 was 6.9%.     

The tumour associated antigen CA15.3 in primary breast cancer. Evaluation of 667 cases

CA15.3 preoperatory serum levels have been determined in 667 patients with primary untreated breast cancer and in 193 controls. The relationships between CA15.3 and several clinical and pathological parameters were evaluated. CA15.3 levels showed a highly significant direct relationship with stage, T, pT, N and the number of positive lymph nodes. The close relationship between CA15.3 and the number of positive lymph nodes was also demonstrated in a subgroup of 406 patients in which more than ten lymph nodes had been examined. CA15.3 levels were correlated with tumour size in patients without axillary metastasis as well as with the number of positive lymph nodes in pT1 tumours. CA15.3 was significantly higher in medullary than in ductal carcinoma. No relationships were found between serum CA15.3 and receptor status. We conclude from the present findings that CA15.3 in primary untreated breast cancer is a marker of tumour burden as well as of the tendency of local invasiveness (relationship between CA15.3 and nodal status in pT1 tumours).     

Evaluation of the circulating glycoprotein CA549 in mammary cancer and other malignancies.

A prospective study was carried out on a recent marker for breast cancer, CA549, a mucine-like acid glycoprotein present in the fat membranes of human milk. Fifty healthy control subjects and 91 with benign conditions, 103 mammary cancer patients and 256 patients with other types of malignancy were studied. For comparison, CEA and CA15-3 were also investigated. The CA549 cutoff was 11 U/ml. In breast cancer the marker was below the cutoff in 9 cases (92.8%); in malignancies other than breast cancer it was above the cutoff in 5 to 50% of patients. In breast cancer it was raised in 83.3% of cases (CA15-3 showed 82.9% and CEA 50%). In breast cancer after radical surgery, CA549 was normal in patients who were in TNM stage I but above the cutoff in 57.1% of those at more advanced stages. The follow-up study is ongoing among these patients. In all the study conditions, CA549 favorably compared to CA15-3 values, with sensitivity and specificity greater than CEA.     

Comparison of TPS with CEA and CA 15.3 in follow-up of Chinese breast cancer patients

Serum levels of serum tissue polypeptide specific antigen (TPS) were compared with levels of carcinoembryonic antigen (CEA) and CA 15.3 with regards to their clinical values in Chinese breast cancer patients. A total of 81 patients were recruited and followed-up prospectively for disease recurrence and death. The median of follow-up was 33.1 months. CEA and CA15.3 correlated with the prognostic factors associated with poor prognosis. CA15.3 was associated with disease-free survival and overall survival. Multivariate analyses showed that the pre-operational serum CA15.3 level was an independent prognostic factor for disease-free survival. However, TPS was associated with neither prognostic factors nor patient survival. In conclusion, TPS is not a good serum tumor marker for breast cancer of Chinese patients, compared with CEA and CA 15.3.