Utility of C-erbB-2 in tissue and in serum in the early diagnosis of recurrence in breast cancer patients: comparison with carcinoembryonic antigen and CA 15.3.

To evaluate the utility of c-erbB-2, carcinoembryonic antigen (CEA) and CA 15.3 in the early diagnosis of recurrence, serial serum determinations of these antigens were performed in 200 patients (follow-up 1-4 years, mean 2.2 years) with primary breast cancer and no evidence of residual disease (NED) after radical treatment (radical mastectomy or simple mastectomy and radiotherapy). Eighty-nine patients developed metastases during follow-up. C-erbB-2, CEA and CA 15.3 were elevated (> 20 U ml-1, > 10 ng ml-1 or > 60 U ml-1 respectively) before diagnosis in 28%, 30% and 47% of the 89 patients with recurrence, with a lead time of 4.5 +/- 2.4, 4.9 +/- 2.4 and 4.8 +/- 2.4 months respectively. Tumour marker sensitivity was clearly related to the site of recurrence, with the lowest sensitivity found in locoregional relapse and the highest in patients with liver metastases. When patients with locoregional recurrences were excluded, sensitivity improved: 31% (c-erbB-2), 33% (CEA) and 56% (CA 15.3), with 76% having at least one of the three tumour markers. C-erbB-2 sensitivity in early diagnosis was significantly higher in patients with c-erbB-2 overexpression in tissue (8/10, 80%) than in those without overexpression (1/30, 3.3%) (P = 0.0001). Likewise, higher levels of both, c-erbB-2 and CA 15.3 at diagnosis of recurrence, higher sensitivity in early diagnosis of relapse and a higher lead time were found in PR+ patients (CA 15.3, P < 0.0001) or in PR- patients (c-erbB-2, P = 0.009). Specificity of the tumour markers was 100% for all three markers (111 NED patients). In conclusion, c-erbB-2 is a useful tool for early diagnosis of metastases, mainly in those patients with c-erbB-2 overexpression in tissue. Using all three markers simultaneously it is possible to increase the sensitivity in the early diagnosis of recurrence by 11.2%.     

C-erbB-2 protein in the sera of breast cancer patients

Summary The c-erbB-2 protein was measured in sera of patients with breast cancer or benign breast diseases to study the significance of this protein as a tumor marker. The mean value and positive rate for this protein (assuming 20 U/ml as the cut-off value) were 11.8 U/ml (0%) in benign breast disease (n=30), 11.8 U/ml (3.1%) in stage I/II primary breast cancer (n=64), 38.2 U/ml (29.4%) in stage III/IV primary breast cancer (n=17), 17.9 U/ml (33.3%) in locally recurrent breast cancer (n=12), 298.4 U/ml (51.0%) in recurrent breast cancer with distant metastases (n=51), and 12.9 U/ml (0%) in those with no evidence of recurrence (n=57). Thus, the serum c-erbB-2 protein level was significantly higher in the distant metastatic group. In patients with distant metastases, there was a close association between expression of c-erbB-2 protein in the primary tumor and the serum c-erbB-2 protein level. On the basis of these results, serum c-erbB-2 protein was thought to be useful as a tumor marker for postoperative monitoring of breast cancer, especially in patients positive for expression of this protein in primary cancer tissue.     

Comparison of serum CEA, PHI, and TPA as tumor markers in breast cancer patients

The purpose of this study was to evaluate the clinical significance of different serum tumor markers in patients with breast cancer who developed recurrent disease. Determined were tissue polypeptide antigen (TPA), carcinoembryonic antigens (CEA), and phosphohexose isomerase (PHI). Serum samples of 411 breast cancer patients with either locoregional or metastatic recurrence were analyzed. Positive rates of all three markers depended on the clinical stage of the disease, with highest rates of elevated titers in advanced disease. In comparison, CEA and TPA are more sensitive markers than PHI. According to the site of recurrence, CEA exhibited the highest rate of elevated titers in patients with bone metastases and PHI in patients with visceral metastases. Using PHI in combination with CEA, sensitivity (ie, at least one marker is elevated) was increased by 6-20% compared to the results obtained with single marker analysis. However, for easier interpretation of the tumor marker results in clinical practice, it may be helpful to employ a product value of CEA and PHI.     

Serum c-erB-2 levels in monitoring of operable breast cancer patients.

BACKGROUND: Various methods and criteria are used to determine protein overexpression of c-erbB-2 and the clinical utility of c-erbB-2 is under investigation. We have reported previously that the levels of cytosol c-erbB-2 in breast cancer were significantly different between the clinical stages. METHODS: The levels of c-erbB-2 protein were determined in sera from 210 breast cancer patients using a sandwich enzyme immunoassay between November 1996 and March 1998. The cut-off level was set at 5.4 ng/ml for healthy female blood donors. RESULTS: First, serum c-erbB-2 levels were analyzed in 73 preoperative breast cancer patients with stage I-IIIB disease. The range and median values were 2.3-32.3 and 4.8 ng/ml, respectively. The positive rate was 38%. Overexpression of serum c-erbB-2 was significantly associated with tumor size, clinical stage, histological grade, lymphatic invasion, nodal status and overexpression of cytosol c-erbB-2, but not with hormonal receptor status and other clinico-pathological factors. Second, c-erbB-2, CEA and CA15-3 in sera were examined in 157 postoperative breast cancer patients. In the 137 disease-free patients, specificities of c-erbB-2, CEA and CA15-3 were 72, 93 and 99%, respectively, but in the 20 first recurrent patients, these sensitivities were 80, 25 and 25%, respectively. CONCLUSIONS: These results suggest that serum c-erbB-2 protein is a useful marker for predicting aggressive behavior and first recurrence of breast cancer.     

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.     

Clinical value of CEA and CA125 regarding relapse and metastasis in resectable non-small cell lung cancer

BACKGROUND: The aim of the present study was to evaluate the value of serum Carcinoembryonic Antigen (CEA) and CA125 antigen assay for monitoring the activity of non-small cell lung cancer (NSCLC) after curative surgical resection. PATIENTS AND METHODS: Serum CEA and CA 125 were determined preoperatively and at every postoperative visit, in 113 patients with NSCLC (TNM stages I, II, IIIA). Both markers were assayed by magnetic particle enzyme immunoassay. RESULTS: Tumor recurrence was more frequent in patients with preoperative CA 125 levels above the cut-off (15 U/ml) (28 out of 47) (59.5%) than in those with low values (18 out of 66) (27.2%) (p < 0.001). The 36-month disease-free survival was lower for patients with elevated CA 125 (37%) than among those with low levels (72%) (p = 0.006). High CA 125 was an independent predictor of the risk of postoperative recurrence (Hazard Ratio: 3.02)(95% CI: 1.41-6.49). No relationship was detected between preoperative serum CEA and risk of recurrence. High preoperative CA125 indicated elevated risk for disseminated recurrence (Hazard Ratio: 7) (95% CI: 2.39-20.51), but not for locoregional failure. No significance was detected for CEA, either in locoregional or disseminated recurrence. Forty-six subjects (40.7%) developed tumor recurrence. At the diagnosis of relapse, serum CEA was elevated in 16 patients (34.7%) and CA125 in 26 (56.5%). Sensitivity was higher in the case of disseminated recurrence (63% for CA125 and 43.3% for CEA) and decreased in locoregional relapse (43.7% for CA125 and 18.7% for CEA). The specificity was 97% for CEA and 59% for CA125. CONCLUSION: Serum CA125 is a useful prognostic marker in NSCLC. The predictive information is especially useful to estimate the risk of disseminated recurrence. Serial determinations of CEA and CA125 during the postoperative follow-up do not show enough sensitivity/specificity to recommend their use for diagnosis of tumor relapse.     

Detection of C-ERBB-2 Related Protein in Sera from Breast Cancer Patients Relationship to ERBB2 gene amplification and c-erbB-2 protein overexpression in tumour

The level of a c-erbB-2 related protein was determined in sera from 168 breast carcinoma patients, 12 females with benign breast disease, and 66 female controls using an ELISA (enzyme linked immunosorbent assay) kit. Elevated c-erbB-2 related protein level was detected in one of 13 preoperative sera (8%), two of 62 postoperative sera from patients without recurrent disease (3%), and 55 of 93 sera collected at recurrent disease (59%). Elevated serum levels were detected significantly more often in patients with distant metastases than in patients with recurrent disease restricted to locoregional areas (68% versus 19%). Presence of elevated serum level was associated with ERBB2 gene amplification and c-erbB-2 protein overexpression in tumour. None of the patients who had normal ERBB2 gene copy number in tumour had elevated serum levels. Although the usefulness in postoperative prediction of the presence of micrometastases is somewhat questionable, the results suggest c-erbB-2 related protein to represent a novel tumour marker in serum and other body fluids from breast cancer patients at the time of diagnosis and during treatment monitoring.     

Decision making using postoperative CEA and CA 15-3 for detection of breast cancer recurrence

To determine the clinical implications of postoperative levels of serum carcinoem-bryonic antigen (CEA) and CA 15-3 as follow up parameters for breast cancer, a retrospective study was conducted on 157 patients who underwent curative surgery for breast cancer. Twenty-three patients had recurrences and 134 patients were without recurrence for more than one year after measuring the tumor markers. The receiver operating characteristic (ROC) curves indicated that CA 15-3 performed more accurately than CEA in discriminating between patients with recurrence (n = 23) and those without (n=134). Of 23 patients with recurrence, CEA was elevated above the normal range (>2.9 ng/ml) in 32% and CA 15-3 was elevated above the normal range (> 20 U/ml) in 67%. The elevation of the markers preceded the clinical appearance of metastases in 2 patients for CEA and in 5 patients for CA 15-3. False positive rates for CEA and CA 15-3 in the 134 patients without recurrence were 4% and 10%, respectively. Nevertheless, these rates became 0% when the cut-off values were doubled. When the postoperative serum level of either CEA or CA 15-3 exceeds twice the upper limit of the normal range or when, in patients with unfavourable prognostic characteristics (node positive or large tumor), either of these values is between the upper limit of the normal range and double the value, recurrent breast cancer must be assumed. For such patients, further investigations with high-sensitivity radiographic modalities are warranted because early treatment may be able to provide survival benefit.     

The immunoscintigraphic use of Tc-99m-labelled monoclonal anti-CEA antibodies (BW 431/26) in patients with suspected primary, recurrent and metastatic breast cancer

The discrepancy between serum CEA levels and CEA tissue expression in patients with breast cancer is well known. Whereas immunohistochemistry shows positive CEA expression in 70-90%, the serum CEA levels are often within the normal range. We performed immunoscintigraphy and SPECT with a Tc-99m labelled anti-CEA monoclonal antibody (MAb BW 431/26) in 46 women with suspected breast cancer or recurrence. The results of anti-CEA immunoscintigraphy, mammography, serum CEA levels and immunohistochemistry were evaluated according to the histology of the tumor. Histology verified breast cancer or recurrence (pT1 [n = 7], pT2 [n = 17], pT3 [n = 3], pT4 [n = 3]) in 30 out of 46 patients; benign breast disease such as fibrocystic disease, fibroadenoma, fatty necrosis or chronic mastitis was responsible for suspicious mammographic findings in 16 patients. Immuno-SPECT showed 25 true-positive, 5 false-negative, 11 true-negative and 5 false-positive findings (sensitivity 83%, specificity 69%). Anti-CEA immuno-SPECT of 2 patients with bone metastasis showed all lesions previously detected by bone scintigraphy to be CEA-expressing metastases. In contrast, serum CEA levels were slightly elevated in only 5 out of 30 patients with histologically verified breast cancer (sensitivity 17%). The results of immuno-histochemistry were surprising; tissue CEA expression could be demonstrated in only 5 patients with breast cancer. According to our experiences with this Tc-99m labelled anti-CEA MAb, immuno-SPECT is a suitable additional method for the diagnosis of breast cancer and especially of recurrence. Pre-operative serum CEA levels give no support for the differentiation between benign and malignant breast tumors.     

Clinical relevance of soluble c-erbB-2 for patients with metastatic breast cancer predicting the response to second-line hormone or chemotherapy.

Concentrations of soluble c-erbB-2 were determined in the sera of 64 patients with distant metastasis from advanced breast cancer receiving second-line hormone or chemotherapy in comparison to 35 breast cancer patients without detectable recurrent disease and 17 healthy blood donors. The sera of non-metastatic breast cancer patients contained s-erbB-2 concentrations similar to those of healthy blood donors. Patients with distant metastasis from advanced breast cancer had significantly higher values of s-erbB-2 in comparison to patients with non-disseminated disease (mean: 59.6 vs. 11.6 U/ml; p = 0.022). A significant correlation was observed between s-erbB-2 serum levels and serum LDH concentrations (p < 0.001), levels of alkaline phosphatase (p < 0.001), and the presence of hepatic metastasis (p = 0.001). Time to tumor progression was significantly shorter in patients with s-erbB-2 levels above 40 U/ml (mean: 23.4 vs. 56.7 months; p = 0.002). Furthermore, breast cancer patients with hepatic metastasis and those with elevated s-erbB-2 serum levels above 40 U/ml had limited response to hormone or chemotherapy. Non-responders had significantly higher s-erbB-2 levels (mean: 270.3, range: 42-500 U/ml;) compared with the responder group (mean: 23.1, range: 0-149 U/ml; p < 0.001). Logistic regression analysis indicated that elevated s-erbB-2 serum levels above 40 U/ml independently predicted an unfavorable response to second-line hormone or chemotherapy in patients with advanced metastatic breast cancer.     

Prognostic significance of serum c-erbB-2 protein in breast cancer patients

Summary The tissue expression of c-erbB-2 protein in breast cancer is a marker of poor prognosis in a number of studies. More recently it has also been suggested that c-erbB-2 expression may predict response to systemic therapy in patients with advanced breast cancer. The measurement of c-erbB-2 protein in the serum of breast cancer patients has now been reported, but the significance of this finding is not clear. In this study an ELISA assay was used to measure c-erbB-2 in the sera of 23 normal controls, 46 benign breast disease patients, and 119 breast cancer patients. Elevated serum c-erbB-2 protein levels were detected in 13% (3/23) of normal controls, 15% (7/46) of benign disease patients, 15% (7/46) of Stage I/II patients, 26% (9/35) of Stage III patients, and 21% (8/38) of Stage IV patients. The tissue expression of the c-erbB-2 protein showed no association with detection of the serum c-erbB-2 protein (p = 0.31). In the 67 Stage III and IV patients who had assessable disease the presence of the c-erbB-2 protein in the serum bore no relationship to response to hormonal therapy (p = 0.71). Serum detection of the c-erbB-2 protein in Stage I/II patients predicted for a worsening of both survival outcome (p = 0.002) and disease free interval (p = 0.002). A worse outcome was also seen for the Stage III patients (p = 0.04) and Stage IV patients, although the latter did not reach statistical significance (p = 0.27).This study found that the presence of c-erbB-2 in the serum of breast cancer patients was of prognostic significance for all stages of disease.     

Prognostic significance of telomerase activity and some tumor markers in non-small cell lung cancer

The prognosis of non small cell lung cancer (NSCLC) has remained disappointing over the last decades even in localized stages. Numerous prognostic factors have been investigated which might select patients for additional treatment. The objective of the current study was to assess the prognostic significance of telomerase activity, serum anti-p53 antibodies (anti-p53a), c-erbB-2 and CEA in patients with NSCLC. The study included 60 patients with histological proven NSCLC besides 60 controls (30 smokers and 30 nonsmokers). Patients were divided into four stages according to their histopathology. All patients were subjected to; determination of telomerase activity by telomeric repeat amplification protocol (TRAP) assay in tumor tissue specimens and adjacent normal lung tissues, also, determination of preoperative serum anti-p53a, c-erbB-2 and CEA. Telomerase activity was detected in 40 of 60 (66.6%) of NSCLC tissue specimens using the TRAP assay. As regard the stages, telomerase activity was positive in 5 of 15 patients (33.3%) with stage I NSCLC, in 11 of 20 patients (55%) with stage II NSCLC, in 9 of 10 patients (90%) with stage III NSCLC and in all patients (100%) with stage IV NSCLC. More cases of positive telomerase activity were observed in the group with advanced disease and in the group with poorly differentiated tumors. Telomerase activity was not detected in any normal lung tissue. The concentrations of serum anti-p53a, c-erbB-2, CEA were significantly higher in patients with NSCLC in comparison to the smoker and nonsmoker controls and their levels increased according to the stage of disease. Logistic regression test showed a relation between telomerase positivity and anti- p53a but no relation with c-erbB2, CEA. Telomerase activity was detected in most of NSCLC tissues; it was detected more frequently in advanced disease than early-stage disease. Anti-p53, c-erbB-2 and CEA were significantly higher in patients with NSCLC than controls and this increment was more evident in late stages of the disease. So, these biological markers might be useful predictors of prognosis. They may be helpful in defining groups of patients with NSCLC who could benefit from adjuvant treatments, also these markers can be used as therapeutic targets.     

Determination of cytosol c-erbB-2 protein in breast cancer by sandwich enzyme immunoassay

We determined cytosol c-erbB-2 protein levels using a sandwich enzyme immunoassay in benign breast disease and primary and recurrent breast cancer and analyzed the relationship between c-erbB-2 protein levels and clinicopathological factors. Overexpression of c-erbB-2 protein, the cut-off value being set at 18 ng/mg protein, was observed in 26 of the 139 cases of stages I-IIIB breast cancer (18.7%), four of the 12 cases of stage IV breast cancer (33.3%) and seven of the 13 recurrent breast cancer cases (53.8%). The levels of c-erbB-2 protein were significantly different between the stages. Overexpression of c-erbB-2 protein in stages I-IIIB breast cancer was associated with histological grade and serum CEA level, but not with other clinicopathological factors. In addition, there was an inverse correlation in the group of stages I-III plus IV breast cancer between c-erbB-2 protein expression and estrogen receptor status. Overexpression of c-erbB-2 protein can be easily determined in the cytosol fraction together with hormonal receptor by this method. The prognostic importance will be evaluated in ongoing adjuvant trials for operable breast cancer patients.      

Elevated levels of serum tumor markers CA 15-3 and CEA are prognostic factors for diagnosis of metastatic breast cancers

To investigate the prognostic value of tumor markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels at diagnosis of systemic recurrence. After primary treatments of locoregional breast cancers, serum CA 15-3 and/or CEA concentrations were regularly measured, and systemic recurrences were identified in 351 patients between January 1999 and December 2009. The association between tumor marker levels at systemic recurrence and survival were investigated by univariate and multivariate analyses. Elevated CA 15-3 and CEA levels were identified in 194 of 349 (55.6 %) and 111 of 308 (36.0 %) patients, respectively, at diagnosis of systemic recurrence. Elevated levels of CA 15-3 and CEA were correlated with visceral or multiple recurrences and elevated preoperative levels. Elevation of CA 15-3 was more prominent in younger patients and in primary node-positive tumors, while CEA was elevated in older patients at diagnosis and in estrogen receptor (ER)-positive tumors. Elevated tumor markers as well as ER negativity, short disease-free interval, and advanced stage at initial diagnosis showed independent prognostic significance on multivariate analysis. Among 306 patients for whom levels of both tumor markers at recurrence were available, 106 patients without elevation of either marker showed significantly better overall survival than those with elevated levels of either one or both markers, and the significance persisted in multivariate analysis. Elevated serum CA 15-3 and CEA levels at recurrence suggest increased tumor burden and may be prognostic for survival for metastatic breast cancer patients.     

Angiogenesis, p53, and c-erbB-2 immunoreactivity and clinicopathological features in male breast cancer

BACKGROUND AND OBJECTIVES: p53, c-erbB-2, and tumor microvascular density have been shown to be potential prognostic tools in female breast cancer. Our objective was to assess the significance of these biomarkers as prognostic factors in infiltrating male breast cancer. METHODS: A retrospective study of expression of p53, c-erbB-2, and tumor microvascular density was done on a group of 26 male breast cancer patients. Biotin-streptavidin immunohistochemical study with specific anti-p53, anti-c-erbB-2, and anti-CD34 antibodies was carried out on paraffin sections of breast carcinoma. The data of expression of the biomarkers were merged with clinicopathological data such as tumor grade, T class, TNM stage, estrogen receptor status, tumor recurrence, and patient survival. RESULTS: p53 and c-erbB-2 were expressed in 46% and 39% of carcinomas, respectively. No correlation was found between positive immunoreactivity of p53, and tumor grade, size, T class, TNM stage, and survival. Nor was any relation found between tumor size, T class, TNM stage, survival, and c-erbB-2 overexpression. c-erbB-2 overexpression was significantly higher in high grade carcinomas. Estrogen receptor (ER) were positive in 21 out of 26 of tumors (81%). No trends were observed between estrogen receptor status and clinicopathological parameters or survival (data not shown). There was a positive correlation between mean microvascular density (MVD), advanced T class, and survival: higher MVD counts were found in patients with advanced tumors and in those who had tumor relapses or died of metastatic disease. CONCLUSIONS: This study suggests that tumor microvascular density may serve as a potential prognostic tool in male breast carcinoma.     

乳腺癌组织中Cath-D、c-erbB-2的表达及其与肿瘤标志物水平、淋巴结转移的相关性

目的观察乳腺癌患者病理组织中Cath-D、c-erbB-2的表达情况,并分析其与淋巴结转移、肿瘤标志物水平的相关性。方法选取接受手术治疗的乳腺癌患者为研究对象,同时选取同期接受手术治疗的乳腺纤维腺瘤患者为对照。观察乳腺癌(有、无淋巴转移组)、乳腺纤维腺瘤患者组织切片Cath-D、c-erbB-2阳性表达情况,比较乳腺癌(有、无淋巴转移组)、乳腺纤维腺瘤患者血清肿瘤标志物水平的差异,分析淋巴结转移的乳腺癌患者Cath-D、c-erbB-2阳性表达与肿瘤标志物水平的相关性。结果乳腺癌组患者的组织切片Cath-D、c-erbB-2阳性表达率均高于乳腺纤维腺瘤组(χ²=51.796、70.090,P均<0.001);有淋巴结转移的乳腺癌患者组织切片Cath-D、c-erbB-2阳性表达率高于无淋巴结转移组。乳腺癌组患者血清CEA、CA15-3、CA125水平高于乳腺纤维腺瘤组(t=52.270、58.784、76.349,P<0.001);乳腺癌组有淋巴结转移组患者血清CEA、CA15-3、CA125水平高于无淋巴结转移组(t=16.681、27.880、23.216,P<0.001)。有淋巴结转移的乳腺癌患者Cath-D、c-erbB-2阳性表达率与血清CEA、CA15-3、CA125水平正相关。结论乳腺癌患者病理组织中Cath-D、c-erbB-2阳性表达率较高,且与淋巴结转移和肿瘤标志物水平相关。     

c-erbB-2 (HER-2/neu) protein and drug resistance in breast cancer patients treated with induction chemotherapy

Expression of c-erbB-2 protein has been associated with poor prognosis and poor response to chemotherapy in breast cancer patients. In the present prospective study, we have analyzed whether c-erbB-2, p53 and P170 proteins may be determinants of tumor resistance in locally advanced breast cancer patients treated with induction chemotherapy. Biopsies (n = 60) were examined by immuno-histochemistry; in 62% of cases core or incisional biopsies were taken before drug administration, allowing comparison in paired biopsies of the cytological and molecular changes induced by treatment Sixty percent of the patients received relatively high doses of FAC or FEC (5-fluorouracil, doxorubicin or epirubicin and cyclophosphamide), and 40% received relatively high doses of doxorubicin or epirubicin alone. No significant changes were observed in the molecular markers studied following chemotherapy; in the few biopsies where changes appeared, the changes did not exhibit any significant or similar trend. For 30 of the patients who received FAC/FEC treatment, follow-up reached a median of 34 months. In these cases, neither the clinical (reduction in tumor size) nor the histological (evaluated after neoadjuvant chemotherapy) responses showed statistically significant differences between the patients who developed distant metastases and the disease-free patients. c-erbB-2 was over-expressed in 50% of patients who developed distant metastases vs. 7% of the disease-free patients. Disease free survival (DFS) curves between c-erbB-2-positive and c-erbB-2-negative patients were statistically significant. No correlation between p53 or P170 expression with DFS was found. Our results suggest that c-erbB-2 protein expression is associated with development of distant metastases in breast cancer patients treated with relatively high doses of anthracyclines in induction chemotherapy.     

Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor

BACKGROUND: Women with metastatic breast carcinoma have a highly variable clinical course and outcome. Intrinsic genetic heterogeneity of the primary breast tumor may play a role in this variability and may explain it in part. Therefore, the authors tested the hypothesis that the characteristics of primary breast tumors are important determinants of prognosis and survival in patients with metastatic breast carcinoma. METHODS: The prognostic significance of the biology of the primary tumor for outcome in patients with metastatic breast disease was assessed in 346 patients with lymph node positive breast carcinoma who developed distant, recurrent disease. Traditional prognostic indicators (age, tumor size, number of involved lymph nodes, sites of recurrence, disease free interval [DFI], adjuvant treatments, estrogen receptor [ER] expression, progesterone receptor [PgR] expression, S-phase fraction [SPF], and DNA ploidy), together with three newer biologic markers (c-erbB-2, p53, and bcl-2) were assessed. Sites of recurrence were defined as nonvisceral (bone and locoregional lymph nodes) or visceral (lung, liver, brain, and other organs). RESULTS: The median duration of survival was 17.8 months (95% confidence interval, 15.2-21.5 months). Univariate analysis showed that age > 50 years, visceral disease, and shorter DFI were associated significantly with poor outcome (P < 0.05). In addition, the molecular phenotype of the primary breast tumor was significant, with primary tumors that showed ER negativity and PgR negativity, high SPF, aneuploidy, accumulation of p53 protein, and lower bcl-2 expression, together with c-erbB-2 overexpression, all associated with a poorer clinical outcome (P < 0.05). In a multivariate analysis, older age, visceral disease, shorter DFI, PgR negativity, high SPF, and lower bcl-2 expression were significant predictors of worse survival (P < 0.05). CONCLUSIONS: In addition to traditional risk factors, bcl-2 negativity was associated significantly with a worse clinical outcome. Biologic features of primary tumors were correlated independently with outcome after first recurrence in patients with metastatic breast carcinoma and may be used as indicators of prognosis in the metastatic setting.     

A new tumor marker MCA in breast cancer diagnosis

The serum concentration of the new tumor marker MCA (mucinous carcinoma associated antigen) was determined by an enzyme immunoassay kit method, which is based on the use of a monoclonal antibody b12. The mean MCA values in breast cancer patients (n = 40) were significantly higher than in patients with benign breast disease (n = 55, p less than 0.001) and in control subjects (n = 37, p less than 0.001). When we used the cut-off level 11 KU/l for MCA, 6/37 (16.2%) of control subjects 7/55 (12.7%) of patients with benign breast disease, 18/40 (45.0%) of all breast cancer patients 11/19 (57.9%) of breast cancer patients with axillary node involvement, and 1/1 breast cancer patient with distant metastases were above this cut-off level. For comparison, at the cut-off level of 5 micrograms/l the CEA test was positive in 7/40 (18%) cancer cases, and in 6/19 (32%) of cancer patients with nodal involvement. Patients with axillary nodal metastasis showed higher values than patients without metastasis in both tests (p less than 0.01). The combination of MCA at 11 KU/l cut-off level and CEA at the 5.0 micrograms/l cut-off level reached the diagnostic sensitivity of 0.53, efficiency of 0.73, and specificity of 0.87. It seems that MCA is a promising tumor marker in breast cancer. Especially high values may have diagnostic significance.     

Comparison of circulating MAM-6 and CEA levels and correlation with the estrogen receptor in patients with breast cancer

MAM-6 and CEA serum levels of 136 staged breast cancer patients were determined concomitantly. The sensitivities of the MAM-6 assay using monoclonal antibody (MAb) 115D8 and a polyclonal CEA assay were equally low and only a limited number of patients with early stages of breast cancer showed elevated antigen levels. However, the sensitivity rose to 75% for MAM-6 and to 60% for CEA in stage-IV patients. The levels of both antigens correlated well in the sera of these patients, although MAM-6 serum levels were elevated more frequently, while only in a few cases were MAM-6-negative sera CEA-positive. A group of stage-II breast cancer patients who eventually developed distant metastases was followed in a longitudinal study. Tumor progression or regression was clinically determined and compared with the MAM-6 and CEA serum levels in order to establish the value of each assay for the monitoring of breast cancer. The course of the disease correlated significantly better with changes in MAM-6 antigen levels than with changes in CEA levels (p less than 0.05), being 79% and 42% respectively. The lower correlation of CEA levels with the course of the disease was mainly due to a lower sensitivity of the CEA assay for advanced breast cancer. The specificity of changing MAM-6 and CEA levels was not significantly different. The main advantage of the MAM-6 assay over the CEA assay is the higher sensitivity of the former. In a preliminary study among stage-IV patients a correlation was found between elevated MAM-6 levels and the presence of the estrogen receptor in the primary tumor.