An evaluation of CA 549, a circulating marker of breast cancer using a procedure for comparison with CA 15.3.

A serum assay of CA 549 (Hybri-BREScan CA 549 degrees, Hybritech), a new tumor marker, was performed in 129 patients with breast cancer and 35 healthy women, in parallel with CA 15.3 (ELSA-CA 15.3 degrees, CIS Biointernational). Comparing 95 women with primary breast carcinoma and 35 controls, Relative (or Receiver) Operating Characteristic (ROC) analysis revealed that the Area Under ROC Curve (AUC) of CA 15.3 was significantly higher than that of CA 549, indicating that, for our population, the first marker was more effective. Parallel and series analyses were also performed using ROC AUC and revealed that the combination of these two tests did not give more information than the CA 15.3 test alone; however, they did not in any way constitute diagnostic tools. In our experience, the best field of application for CA 549 seems to be the therapeutic monitoring and early detection of breast cancer recurrences. However, further investigations on a larger scale are necessary to assess more precisely the place of CA 549 in following the clinical course of breast cancer patients.     

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.     

Preoperative CA 15.3 and prognosis in primary breast cancer

CA15.3 is a breast cancer-associated antigen encoded by the MUC-1 gene. The clinical applications of CA 15.3 are the monitoring of response in advanced breast carcinoma and the early detection of recurrences. We have investigated the prognostic value of CA 15.3 in primary breast cancer. Preoperative serum CA 15.3 was measured in 478 patients with early breast cancer. Positive CA 15.3 was defined as > 30 U/ml. CA 15.3 positivity was correlated with patient outcome in terms of disease-free survival (DFS). Seven per cent of patients had elevated serum CA 15.3. A positive association was found between CA 15.3 positivity and tumour size. Twenty-one per cent of the patients with T3 and T4 tumours had high serum concentrations of CA 15.3; while only six per cent of patients with T1 and T2 tumours had elevated concentrations of CA 15.3 (p < 0.0001). There was no correlation between CA 15.3 serum levels and menopausal status, axilary lymph node status, estrogen receptor status, p53 and erbB-2 status, and CEA serum levels. With a median follow-up of 24 months, we found that elevated CA 15.3 levels predicted a poor clinical outcome. The probability of disease-free survival at two years was 73% in patients with high preoperative CA 15.3 compared with 90% in patients with normal CA 15.3 levels (logrank p = 0.003). The association of CA 15.3 with DFS was also analysed with a Cox analysis, and was found to be independent of tumour size. The multivariate analysis showed that poor disease-free survival was significantly associated with high CA 15.3 (p = 0.04), large tumour size (p = 0.001), estrogen receptor negative status (p = 0.008), overexpression of erbB-2 (p = 0.04), and overexpression of p53 protein (p = 0.03). Preoperative serum CA 15.3 is significantly related to clinical outcome in patients with early breast cancer. High CA 15.3 indicates a poor prognosis and this is independent from tumour size. Whether the poor prognosis associated with CA 15.3 is related with the role of mucins in the adhesion of cancer cells needs to be investigated.     

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.     

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 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.     

Intensive post-operative follow-up of breast cancer patients with tumour markers: CEA, TPA or CA15.3 vs MCA and MCA-CA15.3 vs CEA-TPA-CA15.3 panel in the early detection of distant metastases

Background  

In breast cancer current guidelines do not recommend the routine use of serum tumour markers. Differently, we observed that CEA-TPA-CA15.3 (carcinoembryonic (CEA) tissue polypeptide (TPA) and cancer associated 115D8/DF3 (CA15.3) antigens) panel permits early detection and treatment for most relapsing patients. As high sensitivity and specificity and different cut-off values have been reported for mucin-like carcinoma associated antigen (MCA), we compared MCA with the above mentioned tumour markers and MCA-CA15.3 with the CEA-TPA-CA15.3 panel.     

Markers in breast cancer: Does CEA add to the detection by CA 15.3?

211 patients with various stages of breast cancer were studied by both the CA 15.3 and CEA markers to assess whether the latter may increase the screening sensitivity of the former. While both markers were equally specific, CA 15.3 was seen to be much more sensitive than CEA (p<0.0001). Also, the addition of the CEA did not add appreciably (7%) to positive detection by CA 15.3. There appears to be no advantage to including CEA in a marker panel to follow the course of breast carcinoma.     

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.     

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.     

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.     

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).     

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.     

Use of serial carcinoembryonic antigen and CA 15.3 assays in detecting relapses in breast cancer patients

Summary To evaluate the utility of CEA and CA 15.3 for early diagnosis of recurrence, serial serum determinations of both antigens were performed in 1023 patients (follow-up: 1–10 years, mean 6.2 years) with primary breast cancer (CA 15.3 in 533 cases) and no evidence of residual disease (NED) after radical treatment (radical mastectomy or simple mastectomy and radiotherapy). 246 patients developed metastases during follow-up.Results: CEA and CA 15.3 were elevated (> 10 ng/ml or > 60 U/ml, respectively) prior to diagnosis in 40% (98/246) and 41% (37/91) of the patients with recurrence, with a lead time of 4.9 ± 2.2 and 4.2 ± 2.3 months, respectively. When patients with locoregional recurrences were excluded, sensitivity improved to 46% (CEA) and 54% (CA 15.3), and to 64% with both tumor markers (CEA and/or CA 15.3). Higher levels of both CEA and CA 15.3 at diagnosis of recurrence, higher sensitivity in early diagnosis of relapse, and a higher lead time were found in ER+ (CEA) or PgR+ patients (CA 15.3) than in those that were negative for these receptors in the primary tumor (p < 0.001). Specificity of the tumor markers was 99% for both CEA (777 NED patients) and for CA 15.3 (444 NED patients), respectively. In conclusion, CEA and CA 15.3 are useful tools for early diagnosis of metastases, mainly in those patients with ER+ or PR+ tumors.     

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.     

Ki-67在早期乳腺癌诊治中的意义

早期乳腺癌(EBC)的预后差异非常大,重要的预后因素有肿瘤大小、组织学分级、脉管浸润情况、淋巴结转移情况等是有所帮助的,肿瘤的分子特征也正受到越来越多的关注,ER、Her-2已经被作为治疗反应和预后的预测指标.Ki-67虽然不作为必须的标记,但常用来作为增殖活性的静态标志,或通过治疗期间的多次测量,来反映动态变化的中间状态,以及作为疗效的替代指标.现应就Ki-67在早期乳腺癌的预后和治疗的预测价值作一综述.     

Evaluation of tumor marker CA15-3 in breast cancer

CA15-3, a new tumor marker for breast cancer, was determined in various malignant diseases including breast cancer and various benign diseases, and its clinical significance and usefulness were studied. In 18 normal individuals, the value of CA15-3 was 8.9 +/- 3.3 U/ml (mean +/- SD). In primary breast cancer, the positivity was 20% for Stage I, 0% for Stages II and III and 100% for Stage IV. Of 17 cases of recurrent breast cancer, 13 (77%) were shown to be positive. The therapeutic effect and the value of CA15-3 were well correlated with each other. As for other malignant tumors, positive cases were observed in 50% of recurrent cancer of the stomach and in 14% of malignant tumors of the biliary system. All of these cases were terminal-stage cancers. The CEA value determined simultaneously showed a good correlation, r = 0.87 (p less than 0.01) with CA15-3 in malignant tumors other than breast cancer. In breast cancer, however, the correlation between the two was low, r = 0.18. These results suggest that CA15-3 is not necessarily useful in the diagnosis of primary breast cancer, but is useful as an indicator of the effect of therapy for recurrent breast cancer and for the prediction of recurrence.     

A new biomarker in monitoring breast cancer: CA 549

Serum biomarkers are not very reliable in assessing outcome or predicting recurrence of breast cancer. Clinically, carcinoembryonic antigen (CEA) is widely used and is elevated in a majority of patients with metastatic breast cancer. However, it is falsely elevated in a wide range of nonmalignant conditions and correlates poorly with disease progression. We evaluated a newly described monoclonal antibody, CA 549, in an immunoradiometric assay which uses two monoclonal antibodies directed against tumor and milk fat globule membranes. CA 549 and CEA were studied in 682 patients, 331 of whom had breast diseases and 99 of whom were followed with multiple serum samples. Of 69 patients with benign breast diseases, 1.5% had elevated CA 549, 0% of 30 pregnant women had elevated CA 549, and 26% of patients with nonmalignant liver disease had CA 549 elevation. In metastatic cancer of prostate, ovary, endometrium, colon, and lung CA 549 was elevated in 12% to 50% of cases with levels less than 120 U/mL. In breast cancer, CA 549 was elevated in 11% of 88 patients who received adjuvant chemotherapy and had no evidence of metastasis; in 23% of 16 patients in complete remission after chemotherapy; in 63% of 52 patients in partial remission after therapy; and in 83% of 106 patients with progression of breast cancer compared with 63% with elevated CEA (P = .001). In diseases of the breast, CA 549 has a sensitivity In diseases of the breast, CA 549 has a sensitivity and specificity of 77% and 92% v 61% and 92% for CEA. Of 99 patients serially monitored with clinically documented breast cancer progression, regression, or stability of disease, CA 549 was statistically significantly superior to CEA in monitoring a greater than 25% change in those patients with metastatic progression (P = .03). CA 549 is a new serum marker that should be control tested in prospective clinical trials alone or in conjunction with other markers.