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.     

C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators.

A series of 346 patients with primary operable breast cancer and a series of 145 patients with advanced breast cancer were investigated for c-erbB-3 protein expression using the monoclonal antibody RTJ1. Formalin-fixed, paraffin-embedded tumour samples were stained using a standard immunochemical method and staining was assessed on a four-point scale. The study aimed to observe the expression of the c-erbB-3 protein and investigate any relationship between expression and established prognostic indicators and prognosis. In both the primary and advanced series breast tumour tissue was found to stain heterogeneously for c-erbB-3. The staining was observed to be predominantly cytoplasmic and the majority of tumours exhibited moderate positivity. However, 15% and 35% of cases in the primary operable and advanced series respectively displayed strong positive staining. No significant difference was found between the staining in the primary and advanced series. In the primary operable breast cancers, no significant associations were demonstrated with overall survival, disease-free interval, regional recurrence, the presence of distant metastases, age, menopausal status, oestrogen receptor status, histological grade, lymph node stage, vascular invasion and c-erbB-2 protein expression. However, a significant association was seen between the degree of c-erbB-3 immunoreactivity and both tumour size (P < 0.01) and tumour type prognostic group (P = 0.05). No overall association with local recurrence was seen when the four groups of c-erbB-3 expression were analysed (P = 0.12), but when those tumours showing no or weak staining were compared with those showing moderate and strong immunoreactivity it was seen that the latter were significantly more likely to develop local recurrence (P = 0.03). In the series of patients with advanced disease, no significant associations were demonstrated with survival, UICC criteria, age, menopausal status, oestrogen receptor status, histological grade, c-erbB-2 status or the presence of vascular invasion. In conclusion this study found variable expression of c-erbB-3 protein in human breast carcinoma and an association with some recognised prognostic factors in those patients with primary operable breast carcinoma. It seems, however, unlikely that c-erbB-3 protein expression will emerge as a powerful enough prognostic factor to be of value in clinical practice.     

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.     

Expression of c-erbB-2 Oncoprotein in Gastric Carcinoma: Correlation with Histopathologic Characteristics and Analysis of Ki-67

Amplification and overexpression of the c-erbB-2 gene has been demonstrated in several tumors and thought to be important determinants of biologic behaviors of carcinomas. In this study, correlation between c-erbB-2 expression und histopathologic parameters, including proliferative activity of gastric carcinomas was evaluated. Paraffin-embedded tissue sections from 62 patients who underwent curative resection of gastric carcinoma were analyzed immunohistochemically for the expression of c-erbB-2 and Ki-67. Strong membrane staining for c-erbB-2 was detected in 11 of 62 gastric carcinomas (17,7%) and no positive reaction was evident in noncancerous tissue. The incidence of c-erbB-2 positivity in intestinal type carcinomas (24,3%) was higher than that of diffuse type carcinomas (4,76%). Positive staining for c-erbB-2 was present in one of the 9 (11,1%) early gastric carcinomas and 10 of 53 (18, 8%) advanced gastric carcinomas. However, no statistically significant relationships were found between c-erbB-2 expression and histopathologic type, depth on invasion, the tumor size or lymph node metastases. Among the metastatic lymph nodes, 3 were positively stained with c-erbB-2 whereas the primary tumors of two cases had been found to be negative. Additionally, no correlation was found between c-erbB-2 reactivity and proliferative activity of carcinoma cells. The results suggest that expression of c-erbB-2 protein may occur selectively in intestinal type of gastric carcinomas. However, c-erbB-2 expression is not a reliable marker of malignant potential in gastric carcinomas.     

Clinical significance of soluble c-erbB-2 levels in the serum and urine of patients with gastric cancer

BACKGROUND: Both tissue c-erbB-2 expression and serum levels the shed protein have been shown to correlate with tumour stage in a range of adenocarcinomas. This study measured serum and urinary c-erbB-2 levels in patients with gastric cancer, assessing their role in cancer-specific survival and the effects of resectional surgery. PATIENTS AND METHODS: Serum and urinary c-erbB-2 concentrations were measured with commercial enzyme-linked immunosorbent assay in 41 healthy controls and in 54 gastric cancer patients. Serum and urinary c-erbB-2 levels in cancer patients were determined before and 7 days following tumour surgery. RESULTS: Preoperative serum and urinary c-erbB-2 levels in gastric cancer patients were significantly higher than those in controls although there were no significant associations between these levels and tumour pathology. Serum c-erbB-2 levels decreased significantly after radical resection of the primary tumour and were an independent prognostic factor for survival, whereas there were no changes in urinary c-erbB-2 levels after surgery or an association with patient survival. CONCLUSION: Gastric cancer patients show higher serum and urinary c-erbB-2 levels compared to healthy controls. Preoperative serum c-erbB-2 concentration decreases significantly after radical resection of the primary tumour and is an independent prognostic factor for patient survival.     

Expression of c-erbB-2 oncoprotein in gastric carcinoma. Immunoreactivity for c-erbB-2 protein is an independent indicator of poor short-term prognosis in patients with gastric carcinoma.

Correlations of c-erbB-2 protein expression with clinical outcomes of gastric carcinomas were studied in 189 gastric carcinomas. There were 23 (12.2%) carcinomas with evidence of c-erbB-2 protein in which the reaction was localized to the cell membrane. There was no significant association between c-erbB-2 staining and the macroscopic or histologic type of the carcinomas. c-erbB-2-stained tumors were more likely to be associated with serosal invasion, nodal involvement, and peritoneal metastasis, than c-erbB-2-unstained ones. In addition, c-erbB-2 was stained in none of early gastric carcinomas. The 5-year survival rates of the c-erbB-2 protein-positive and the protein-negative group were 11% and 50%, respectively. When the c-erbB-2 tissue status and seven clinicopathologic variables as conventional prognostic factors were entered simultaneously into the Cox regression model, serosal invasion, hepatic metastasis, peritoneal metastasis, nodal status, and c-erbB-2 tissue status emerged as independent prognostic variables. The results suggested that c-erbB-2 protein expression might be enhanced in advanced stages during the progression of gastric carcinoma. In this particular group of patients, immunoreactivity for c-erbB-2 protein is an indicator of poor short-term prognosis.     

Microsatellite alterations in liver fluke related cholangiocarcinoma are associated with poor prognosis

In this study we measured serum and urinary c-erbB-2 levels in 63 patients with colorectal cancer and 29 healthy controls, assessing their role in cancer-specific survival and the effects of resectional surgery. Serum and urinary c-erbB-2 levels were measured by an enzyme-linked immunosorbent assay, preoperatively and 7 days following tumor resection. Preoperative serum c-erbB-2 concentrations were significantly higher in the cancer patients and correlated with disease stage and the presence of liver metastases. Urinary c-erbB-2 was detected more often in cancer patients, although levels did not differ from controls and there was no association with any clinicopathological variable. Serum c-erbB-2 levels decreased significantly in those patients resected for cure and were an independent prognostic factor for cancer-specific survival with higher preoperative concentrations correlating with worse overall survival. These findings suggest that serum assessment of c-erbB-2 concentration may be valuable in defining colorectal cancer prognosis.     

c-erbB-2 expression in small-cell lung cancer is associated with poor prognosis

Small-cell lung cancer (SCLC) carries a bad prognosis despite good initial response to chemotherapy. It is therefore important to identify molecular markers that influence survival as potential new therapeutic targets. In our study, expression of the tyrosine kinase c-erbB-2 (HER2/neu) receptor in tumor tissues of 107 consecutive newly diagnosed patients with primary SCLC was quantified using a monoclonal antibody directed against the c-terminal domain of c-erbB-2. A clear-cut positive expression of c-erbB-2 was observed in 13% of patients. Surprisingly, c-erbB-2 was an independent prognostic factor (RR = 2.16; p = 0.014) when a proportional-hazard model was adjusted to stage (limited vs. extensive disease) and performance status (WHO I-IV), the most relevant clinical parameters. Similarly, a significant association between c-erbB-2 and survival was obtained if a larger number of clinical parameters were included into the analysis, namely response to chemotherapy, TNM stage, lactate dehydrogenase (LDH), neuron-specific enolase (NSE), gender and age (p = 0.033). Interestingly, c-erbB-2 expression was more relevant for patients with advanced tumors. In the subgroup of patients with bad performance status (WHO II-IV), median survival of patients with undetectable c-erbB-2 expression was 274 days compared with only 23 days for patients with clear-cut positive c-erbB-2 immunohistochemistry (p = 0.0031; log-rank test). Similar results were obtained for patients with extensive disease (p = 0.028) and high TNM stages (T>2 or N>1 or M1; p < 0.068, all comparisons). In contrast, c-erbB-2 expression was not associated with survival in patients with limited disease (p = 0.97), low TNM stages (p > 0.56, all comparisons) and good performance status (p = 0.97). In conclusion, c-erbB-2 is expressed in more than 10% of SCLC. Expression of c-erbB-2 is an independent prognostic factor of survival. The effect of c-erbB-2 expression seems to become more important in advanced stages of the disease. Since c-erbB-2 is a therapeutical target in other types of cancer, further studies to identify the role of c-erbB-2 in SCLC are clearly warranted.     

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.     

Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay

c-erb-2 amplification and overexpression are currently attracting a great deal of attention because a new adjuvant therapy using an antibody against the c-erbB-2 gene product, trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), has proved effective in treating breast cancer with amplification and/or overexpression of c-erbB-2. Aberrations of c-erbB-2 have also been detected in ovarian, endometrial and gastric carcinomas at varied frequencies. Amplification of the c-erbB-2 locus (17q12-q21.32), overexpression of c-erbB-2 protein (p185) and serum levels of soluble c-erbB-2 protein fragments (p105) were examined in gastric cancer patients using fluorescence in situ hybridization (FISH), immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Overexpression of c-erbB-2 protein was found in 29 (8.2%) of the 352 gastric carcinomas analyzed. In FISH analysis, all tumors with 3+ immunostaining and 1 of 5 tumors with 2+ staining showed high-level amplification of c-erbB-2. Pre-operative serum p105 was quantified in serum specimens from 129 patients with gastric cancer and 28 patients with benign diseases. There were no significant differences in the serum p105 levels among 11 patients with c-erbB-2-overexpressing carcinomas, 118 patients with c-erbB-2 non-overexpressing carcinomas and 28 controls, although a single case of gastric carcinoma overexpressing c-erbB-2 with extensive liver metastasis had a higher level than the cut-off value. The mechanisms of overexpression of p185 and high-level amplification of c-erbB-2 in gastric adenocarcinomas seem similar to those well-established in breast cancers. Patients having gastric adenocarcinoma with c-erbB-2 amplification are potential candidates for a new adjuvant therapy using humanized monoclonal antibody.     

C-erbB-2 expression does not predict response to docetaxel or sequential methotrexate and 5-fluorouracil in advanced breast cancer

Breast cancer patients with c-erbB-2-positive tumours seem to benefit from anthracycline-based adjuvant chemotherapy. The predictive value of c-erbB-2 for taxane sensitivity is not yet clear. The purpose of this study was to assess whether c-erbB-2 expression is associated with clinical sensitivity to docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). A total of 283 patients with metastatic breast cancer were initially enrolled in a randomised multicentre trial comparing docetaxel with sequential MF in advanced breast cancer. Paraffin-embedded blocks of the primary tumour were available for 131 patients (46%). c-erbB-2 status was determined by immunohistochemistry using a polyclonal antibody to the c-erbB-2 protein. C-erbB-2 expression was scored in a semi-quantitative fashion using a 0 to 3+ scale. Staining scores 2+ or greater were considered positive. Response evaluation was performed according to World Health Organization (WHO) recommendations. Overall 54 (42%) patients had c-erbB-2-positive tumours. There was no association between treatment outcome and c-erbB-2 overexpression. The overall response rates (RR) (n=128) among c-erbB-2-negative and -positive patients were 35 and 44%, respectively (P=0.359). In the MF arm (n=62), the RR was somewhat higher in the c-erbB-2 overexpressors (33% versus 18%, P=0.18). In the docetaxel arm the RRs were very similar, regardless of the c-erbB-2 expression (53% versus 53%). While several studies have suggested a prognostic and putative predictive significance of c-erbB-2 overexpression in early breast cancer, the significance of c-erbB-2 expression as a predictive factor for response to various cytotoxic treatments in advanced breast cancer is still controversial. In this study, c-erbB-2 expression could not predict response to either MF or T. Thus, tumours over-expressing c-erbB-2 are not uniformly more sensitive to taxanes and c-erbB-2 expression cannot yet be applied clinically as a predictive factor for response in advanced breast cancer.     

The presence of soluble c-erbB-2 in saliva and serum among women with breast carcinoma: a preliminary study.

The protein c-erbB-2, also known as Her2/neu, is a prognostic breast cancer marker assayed in tissue biopsies from women diagnosed with malignant tumors. Present studies suggest that soluble fragments of the c-erbB-2 oncogene may be released from the cell surface and become detectable in patients with carcinoma of the breast. Consequently, the purpose of this study was to assay the c-erbB-2 protein in the saliva and serum of women with and without carcinoma of the breast and to determine whether the protein possesses any diagnostic value. To determine the diagnostic utility of this oncogene, the soluble form of the c-erbB-2 protein was assayed in the saliva and serum using ELISA in three different groups of women. The three groups consisted of 57 healthy women, 41 women with benign breast lesions, and 30 women diagnosed with breast cancer. To compare the relative diagnostic utility of the c-erbB-2 protein, CA 15-3 was also measured. The CA 15-3 measurements served as a "gold standard" by which to compare the c-erbB-2 protein's diagnostic effectiveness. We found c-erbB-2 protein in the saliva and serum of all three groups of women. The salivary and serological levels of c-erbB-2 in the cancer patients, however, were significantly higher (P < 0.001) than the salivary and serum levels of healthy controls and benign tumor patients. Additionally, the c-erbB-2 protein was found to be equal to or to surpass the ability of CA 15-3 to detect patients with carcinoma. The results of the pilot study suggest that the c-erbB-2 protein may have potential use in the initial detection and/or follow-up screening for the recurrence of breast cancer in women.     

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.     

c-erbB-2 and common prognostic factors in breast cancer patients

We report data on c-erbB-2, hormone receptors, and Ki-67 proliferation associated antigen in ninety-seven unselected breast carcinoma specimens. Immunohistochemical results and clinical data (age, axillary nodal involvement, menopausal status, tumor size) were compared. Positivity for c-erbB-2 staining was detected in the 46% of tumors. There was no correlation among c-erbB-2 status and age, menopausal status, tumor size, lymph nodes involvement or Ki-67 index. An inverse relationship of c-erbB-2 and estrogen and progesterone receptor status was detected, although not statistically significant. Increased levels of c-erbB-2 were observed in 40-50% of all the subsets of patients grouped on the basis of established prognostic factors. These higher levels could lead to the identification of further subsets of patients at higher risk of relapse. However, at present, the role of c-erbB-2 for clinical management of patients with breast cancer remains unclear.     

p53基因codon 72多态性与乳腺癌的相关性研究*

目的:研究p53基因codon 72 多态性与乳腺癌患者的年龄、病理分期、淋巴结转移、雌激素受体（ER）、孕激素受体（PR）、c-erbB-2、P53蛋白表达情况的相关性。方法:TaqMan探针方法检测277 例乳腺癌患者血液标本的p53基因codon 72多态性。免疫组化SP法检测匹配肿瘤组织中ER、PR、c-erbB-2 和P53蛋白的表达情况。SPSS16.0 软件行统计学分析,p53基因多态性与病理学特征关系用χ2检验,非条件Logistic回归分析基因多态性与ER、PR、c-erbB-2、P53蛋白表达的相关性,计算OR值及其95% 可信区间（95% CI）。 P<0.05为差异有统计学意义。结果:p53基因codon 72基因型为CC/CG/GG,频率分别为22.0% 、51.3% 和26.7% ,携带CC、CG、GG基因型的患者发病年龄逐渐降低,但无统计学差异;p53基因codon 72多态性与临床病理学特征无关,与ER、PR、c-erbB-2 和P53蛋白表达无相关性（P>0.05）。 肿瘤组织P53蛋白表达与ER、PR、c-erbB-2 蛋白表达密切相关（χ2=13.492,P=0.000;χ2=3.970,P=0.046;χ2=17.956,P=0.000）。 结论:p53基因codon 72多态性与P53蛋白表达及病理学特征无相关性,P53蛋白表达与ER、PR、c-erbB-2 蛋白表达关系密切。p53基因codon 72基因型与患者发病年龄的关系有待扩大样本量进一步研究。      

Soluble ectodomain of c-erbB-2 oncoprotein in relation to tumour stage and grade in human renal cell carcinoma.

The soluble ectodomain of c-erbB-2 oncoprotein was measured using a sandwich enzyme immunoassay in sera from 184 patients with renal cell carcinoma before initiation of treatment. The median serum level was 2062 U ml(-1) (range 865-4905 U ml(-1)). Levels were unaffected by sex, age and renal function. An inverse relation between disease stage (P = 0.0017) and tumour grade (P = 0.0009) and the serum level of c-erbB-2 ectodomain was observed. Survival time for patients with serum levels above median level was significantly longer than for patients with lower levels (P = 0.003). In a multivariate analysis, c-erbB-2 oncoprotein lost its prognostic information, while tumour stage and tumour grade were identified as independent prognostic factors.     

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.     

Expression of c-erbB receptors, MMPs and VEGF in squamous cell carcinoma of the head and neck

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and cervical lymph node metastasis. The aim of this study was to investigate the expression of epidermal growth factor receptor (EGFR), c-erbB-2, vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in tumor samples of 91 HNSCC patients, and to study a possible correlation to various clinico-pathologic parameters. The expression of EGFR, c-erbB-2, VEGF, MMP-2, -3 and -9 was analyzed in the same paraffin embedded tissue by semi-quantitative immunohistochemical staining. High expression of EGFR, c-erbB-2, MMP-2 or -9 was associated with advanced clinical stages, nodal metastases and tumor-stages. However, high expression of VEGF or MMP-3 was not associated with any clinico-pathologic parameters except significant correlation between VEGF and the tumor site. There were significant correlations between EGFR, c-erbB-2, MMP-2 and -9 in HNSCC patients. Conversely, no correlation was found between VEGF or MMP-3 and the other markers. However, significant correlation was found between MMP-3 or -9 and VEGF. The results indicate that the expression of EGFR, c-erbB-2, VEGF or MMPs play an important role in tumor growth, invasion and metastasis in HNSCC. The authors conclude that EGFR, c-erbB-2, MMP-2 and -9 could be good independent prognostic markers, but not VEGF and MMP-3.     

c-erbB-2 and c-erbA-1 (ear-1) gene amplification and c-erbB-2 protein expression in Japanese breast cancers: their relationship to the histology and other disease parameters

We studied c-erbB-2 and c-erbA-1 (ear-1) gene amplification, and c-erbB-2 protein expression in 123 primary Japanese breast cancers. c-erbB-2 amplification was found in 19 of the 123 tumors (15%), and c-erbA-1 was coamplified in 7 of the 19. The presence or absence of c-erbB-2 amplification correlated with the grade of cellular atypism (P = 0.008), or that of mitotic index (P = 0.002), but not with the histologic types. The tumor size (P = 0.04) and the lymph node status (P = 0.06) were associated, but the patients' age, the TNM stage, or the presence or absence of estrogen or progesterone receptors was not associated, with c-erbB-2 amplification. There were no differences in the histologic type, cellular atypism, mitotic index, and other disease parameters between tumors with c-erbB-2 amplification only and those with coamplification of c-erbB-2 and c-erbA-1. Paraffin sections from all 19 tumors with c-erbB-2 amplification, and those from only one of 104 tumors without the amplification were positively stained with polyclonal anti-c-erbB-2 protein antibody. Since the correlation between the amplification and the protein expression was excellent, such immunohistochemical studies may be substituted for the time-consuming DNA studies using Southern blotting.     

晚期恶性肿瘤患者的sTfR、TPO与骨髓功能关系的初步报道

目的：观察分析恶性肿瘤患者血中TfR、TPO的表达水平及其作为骨髓功能监测指标的意义。方法：用双单克隆抗体夹心酶联免疫吸附法（ELISA）方法，检测了17例首治的晚期恶性肿瘤患者血中sTfR、TPO水平。结果：2例sTfR升高，1例伴有上消化道大出血，另1例伴有脾功能亢进症；12例sTfR正常，3例减低，肿瘤患者中，12例有贫血。14例患者的血清TPO增高，其中伴有贫血的11例，正常的7例，增高的5例。结论：晚期肿瘤患者多伴有贫血，sTfR未能反馈性增高可能与恶性肿瘤患者存在着骨髓抑制或铁代谢异常有关。TPO水平增高并非仅主要受血小板低下的调节已有报道；本组结果也证实这一结论，TPO血中浓度是否与肿瘤性贫血有关，有待进一步研究。因此结合sTfR与TPO分析方能更全面地反映骨髓功能。