Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer.

Using the 21N polyclonal antibody, we immunohistochemically stained 314 primary breast carcinomas to identify those tumors overexpressing the c-erbB-2 oncoprotein and to ascertain the prognostic significance of this expression on disease-free and overall survival. Positive membrane staining was present in 52 (17%) of these carcinomas of which 7 (13%) were ductal carcinomas in situ. There was no significant relationship between c-erbB-2 positivity and (a) age at diagnosis, (b) menopausal status, (c) tumor size, (d) lymph node status, (e) estrogen receptor status, or (f) whether or not the patient had disseminated disease outside the axillary fields. However, c-erbB-2-positive tumors were significantly associated with poorer grade (P = 0.02). Patients who were positive for this oncoprotein had a shorter disease-free survival (P = 0.002) and reduced overall survival (P = 0.0001). Overexpression of this oncoprotein was predictive of a worse prognosis in lymph node-positive disease (P = 0.003) and in patients presenting with grade II tumors (P = 0.001). Stratifying the patients on the basis of estrogen receptor status suggested that c-erbB-2+/estrogen receptor-negative status was predictive of a poorer prognosis when compared with the other subgroups (P less than 0.001). Primary and recurrent tumor tissues were available from 42 of the 314 patients. Identical patterns of c-erbB-2 expression occurred in 95% of cases, arguing against a direct role for c-erbB-2 expression in the process of tumor dissemination. The high incidence of staining in ductal carcinomas in situ suggests that expression of this oncoprotein is an early event in tumorigenesis. Finally, multivariate analysis indicated that the c-erbB-2 oncoprotein was an independent prognostic indicator for overall survival in breast carcinoma patients.     

Prognostic significance of c-erbB-2 expression in node negative breast cancer.

The prognostic value of c-erbB-2 oncogene expression was studied retrospectively in a consecutive series of 230 node negative breast cancers, followed-up for at least 7 years after primary treatment. The expression of c-erbB-2 oncoprotein was determined on formalin-fixed paraffin-embedded tissue, using a monoclonal anti-c-erbB-2 antibody by the avidin-biotin immunoperoxidase method. Positive immunostaining was observed in 20.9% of cases, whereas strong diffuse positivity was recorded only in 8.7% of cases. C-erbB-2 gene product showed no association to T category or nuclear grade. A significant association of c-erbB-2 expression to prognosis was observed only for cases showing a strong diffuse immunostaining, but such an association was no longer statistically significant at multivariate analysis adjusting for other prognostic factors such as T category and nuclear grading. C-erbB-2 expression is of no value to predict the clinical course of node negative patients in the current 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.     

c-erbB-2 oncoprotein expression in primary and advanced breast cancer.

Immunoreactivity for c-erbB-2 oncogene product expression has been investigated in patients with breast cancer using the polyclonal antibody 21N. Three series of patients were studied, 602 presenting with primary operable cancer, 57 with stage 3 and 123 with stage 4 disease. Representative tissue sections of each primary tumour were stained using a standard immunoperoxidase technique. Invasive tumour membrane immunoreactivity was assessed and identified in 15% of patients with primary operable cancer and 20% in the advanced breast cancer group. The results demonstrate a relationship between poorer survival and oncogene expression in all three patient groups. Patients in the primary operable cancer group with membrane oncoprotein expression had a poorer outcome, 35% 10-year survival, compared with those in which membrane expression was absent, 55% 10-year survival. The median survival of patients with stage 3 disease with c-erbB-2 membrane positivity was 17 months compared to 24 months with membrane negativity. In stage 4 disease median survival with membrane expression was 8.8 months compared to 19.7 months with no membrane expression. In addition in the series of primary cancers a correlation existed between histological grade and membrane immunoreactivity. Multivariate analysis showed histological grade to be a more powerful prognostic factor than c-erbB-2 protein expression. In conclusion, this study demonstrates, in a large series of patients presenting to one centre, that c-erbB-2 protein expression is a prognostic indicator in patients with primary operable and advanced breast disease.     

Prognostic significance of immunohistochemical c-erbB-2 proto-oncogene expression and nuclear DNA content in human breast cancer.

Immunoreactivity of the c-erbB-2 proto-oncogene product and nuclear DNA content were assessed in specimens from 211 breast cancer patients with a mean follow-up of 16 years (range 13-19 years). A routine immunoperoxidase technique was used and cytometrical DNA assessments were performed on cytodiagnostically identified tumour nuclei, using image analysis. C-erbB-2 cell membrane staining was observed in 29% of the cases and was found to be related to tumour size (P = 0.02), histopathological grade (P = 0.02) and nuclear DNA content (P < 0.01). In univariate analysis immunohistochemical c-erbB-2 expression was of prognostic significance among node-positive patients (P = 0.02), but not among women with node-negative disease. This prognostic ability was reduced by multivariate analysis and was no longer significant. In contrast, nuclear DNA content was significantly related to distant recurrence-free survival even in multivariate analysis after adjustment for nodal status and tumour size (P < 0.01). In conclusion, the findings of the present study indicate that c-erbB-2 expression is of limited prognostic value in a subgroup of patients, whereas nuclear DNA content seems to provide significant prognostic information even in node-negative patients.     

Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer

Sections of formalin-fixed, paraffin-embedded tissue from 185 primary breast carcinomas were stained immunohistochemically using a polyclonal antibody against the c-erbB-2 oncoprotein. Positive staining, which is known to correlate with gene amplification, was associated with earlier relapse, shorter postrelapse survival, and shorter overall survival. Lymph node, epidermal growth factor receptor, and estrogen receptor status, tumor size, and histological grade also had prognostic significance but, applying multivariate analysis, only lymph node status was a more important predictor of relapse-free and overall survival than staining for the oncoprotein. Positive staining was correlated with negative estrogen receptor status and high histological grade, but there was no association with either lymph node or epidermal growth factor receptor status or tumor size. Expression of the c-erbB-2 oncoprotein appears to be an important independent indicator of prognosis in human breast cancer.     

Prognostic significance of expression of c-ERBB-2 oncoprotein in breast cancer patients]

The c-erbB-2 oncogene, is a member of tyrosine kinase oncogene family and expected to play a role in the regulation of cell growth. In the present study, prognostic significance of the expression of c-erbB-2 oncoprotein was investigated by immunocytochemical assay with 130 primary breast cancer patients. The positive expression of c-erbB-2 oncoprotein was found in 53 out of 130 patients (40.8%). There was no significant correlation between expression of c-erbB-2 oncoprotein and conventional prognostic factors, estrogen receptor (ER), axillary lymph node metastasis and epidermal growth factor receptor (EGFR). Relapse free survival rate of the patients with positive c-erbB-2 expression was significantly worse than those with negative at 49 month after operation. Similar result was found in overall survival rate but the difference was not significant. Furthermore, when patients were stratified by regional nodal status, in the patients with lymph node metastasis, the prognosis of the patients with positive c-erbB-2 expression was significantly worse than those with negative, while no significant difference was found in the patients without lymph node metastasis. These results suggest that c-erbB-2 oncoprotein may act as a prognostic factor independently, predicting the prognosis of breast cancer patients.     

Prognostic value of immunohistochemical expression of the c-erbB-2 oncoprotein in metastasic prostate cancer.

It is well established that the activation of proto-oncogenes could trigger uncontrolled cell growth and cancer development. Although this correlation has already been evidenced in several human tumors, no conclusive studies have related oncogene activation with the development of prostatic neoplasia. Nevertheless, some reports suggest that c-erbB-2, which is a prognostic marker in breast cancer, could be implicated in the development of prostatic adenocarcinoma. We have studied the expression of the c-erbB-2 oncoprotein in primary prostatic tissue in a series of 70 patients with metastasic disease, by means of immunohistochemistry. The NCL-B 11 anti-c-erbB-2 monoclonal antibody was used, and the immunoreactivity was quantified by image analysis. The overall rate of prostatic-tissue sections presenting positive c-erbB-2 immunostaining was 64.3%. No significant relation was observed between histological grade and c-erbB-2 over-expression or severity of the disease, based on the extent of metastases. The average specific survival in patients with c-erbB-2 over-expression was 33 months, while it was 54 in patients with c-erbB-2 negativity; p < 0. 034. These results, as well as the logistic-regression analysis, suggest that expression of c-erbB-2 oncoprotein would be considered as an independent prognostic factor of metastatic prostate cancer. Moreover, it could discriminate between the prognosis of patients with Gleason score 2 to 7 and those with score 8 to 10. Our results suggest that the expression of c-erbB-2 oncoprotein in primary prostatic tissue could have a prognostic value in patients with metastatic prostate cancer. Int. J. Cancer (Pred. Oncol.) 84:421-425, 1999.     

Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up.

PURPOSE: To study retrospectively the long-term prognostic significance of HER-2 oncoprotein expression in breast cancer (BC). PATIENTS AND METHODS: Two hundred nine consecutive female patients with invasive operable BC from a defined urban population were observed for a median of 30 years. Tissue expression of HER-2 oncoprotein was demonstrated by using an immunoperoxidase procedure. RESULTS: Fifty-five (26%) patients had cancer and a positive HER-2 oncoprotein stain reaction. They had significantly worse 10- and 25-year survival rates than those patients who had a negative stain reaction in their cancer (31% v 48% and 31% v 39%, respectively; P = .004). HER-2 expression was also associated with a poorer survival among patients who had axillary nodal metastases (P = .003; n = 104), but not among those patients who did not have metastases. HER-2 expression was related to the ductal histologic type, poor histologic grade, and high mitotic count, but not to tumor size, axillary nodal status, DNA ploidy, or S-phase fraction (SPF). In a multivariate analysis among patients with nodal metastases, HER-2 expression was an independent prognostic factor (P = .04) that predicted poor survival. However, if the entire series was entered onto the analysis, it did not emerge as an independent factor. CONCLUSIONS: HER-2 oncoprotein expression has long-term prognostic significance for predicting poor survival in BC, and it has an independent prognostic value among patients who presented with axillary nodal metastases. This result is contradictory to the argument that HER-2 expression is only a marker for drug resistance because the patients were not given adjuvant drug therapy.     

Prognostic value of Helix pomatia in breast cancer. International (Ludwig) Breast Cancer Study Group.

Six hundred and eighty-four primary breast cancers from the International (Ludwig) Breast Cancer Study Group (IBCSG) were studied for Helix pomatia lectin (HPA) binding. There was a weak correlation between lymph node-positive and HPA positive (P = 0.04). In our series there was a large advantage in disease-free survival (DFS) and overall survival (OS) for node-negative patients (P < 0.0001 DFS and OS). However, there was no such advantage for HPA-negative patients (P = 0.23 DFS and P = 0.32 OS). We conclude that in this randomised patient group HPA is of no clinical predictive value.     

Immunohistochemical detection of p53 and c-erbB-2 proteins: Prognostic significance in operable breast cancer

We examined the associations of p53 expression and/or c-erbB-2 expression with Ag-NOR counts and clinicopathologic variables in 111 breast cancer patients, and assessed whether expression of either p53 or c-erbB-2 would be useful prognostic indicators. There was no significant association between p⁵³ expression and c-erbB-2 expression, but p53 expression and c-erbB-2 expression, especially in combination, were shown to be significantly associated with Ag-NOR counts and axillary lymph node metastasis. Although p⁵³ expression and c-erbB-2 expression were significant prognostic factors by univariate analysis, they did not appear to be independent prognostic factors by multivariate analysis, in which nodal status was introduced using the Cox model. When nodal status was excluded from the model, however, concurrent p⁵³ and c-erbB-2 expression did have a significant prognostic value. Therefore, it was suggested that concurrent p⁵³ and c-erbB-2 expression provides valuable prognostic information for breast cancer patients in whom axillary lymph node dissection has not been performed.     

Helix pomatia agglutinin lectin-binding oligosaccharides of aggressive breast cancer

Predicting long-term outcome after breast-cancer diagnosis remains problematic, particularly for patients with clinically small, axillary lymph node- negative tumours. Evidence suggests that the lectin Helix pomatia agglutinin (HPA) identifies oligosaccharides associated with poor-prognosis cancer. Our aim was to identify oligosaccharides that bind HPA in aggressive breast cancers. Breast-cancer cell lines (MCF-7, BT-549 and BT-20) and a cell line from human milk (HBL-100), which showed a range of HPA-binding intensities, were used to extract HPA-binding glycoproteins. Oligosaccharides were released using anhydrous hydrazine and separated on a range of HPLC matrices. We investigated whether HPA-binding oligosaccharides from cell lines were present in human breast-cancer tissues, using 69 breast-cancer specimens from patients with between 5 and 10 years' follow-up. A monosialylated oligosaccharide was over-expressed in the cell line that bound HPA strongly. Further analysis by normal-phase HPLC showed that the 2-aminobenzamide-conjugated oligosaccharide had a hydrodynamic volume of 4.58 glucose units (HPAgly1). Increased expression of HPAgly1 was associated with HPA staining of breast-cancer specimens (Student's t-test p = 0.025). Analysis of oligosaccharide levels and disease-free survival after treatment for breast cancer indicated a shorter disease-free interval for patients with elevated levels of HPAgly1. This is the first time that histochemical lectin staining has been correlated with biochemical mapping of oligosaccharides. Using this approach, we have identified a monosialylated HPA lectin-binding oligosaccharide present in breast-cancer cells grown in vitro which is elevated in breast-cancer specimens that bind the lectin.     

c-erbB-2 oncoprotein expression in primary human tumors

Using a specific antiserum (21N) to the c-erbB-2 oncoprotein, a total of 405 primary malignant human tumors arising in the breast (n = 191), lung (n = 110), colon/rectum (n = 23), bladder (n = 48), prostate (n = 23), and skin (n = 10) were stained immunohistochemically to detect those tumors that over-expressed this putative transmembrane receptor. Malignant cells showed intense positivity for this oncoprotein in 17% of the breast carcinomas, 4% of the colorectal tumors, 2% of the bladder tumors, and 1% of the nonsmall cell lung carcinomas. No positive staining was evident in the prostate, skin, or small cell lung carcinomas. This study shows that over-expression of the c-erbB-2 oncoprotein is common in breast cancer but relatively rare in the other malignancies studied. In addition, this oncoprotein can be identified readily in routine paraffin-embedded tissue.     

Prognostic impact of cathepsin D and c-erbB-2 oncoprotein in a subgroup of node-negative breast cancer patients with low histological grade tumors

Some node-negative breast cancer patients, with initially good prognosis, relapse from their cancer and are poorly identified. In the present study, based on prospective data of 197 tumors, we measured cathepsin D (cath D, n=197), pS2 protein (n=125), c-erbB-2 oncoprotein (n=100) and epidermal growth factor receptor (EGF-R, n=99) to better define the risk of relapse of node-negative patients in comparison with that defined by the clinical and histological factors. The median follow-up in surviving patients was 75 months. Univariate analysis indicated that patients with histological grade III tumors (the Scarff, Bloom and Richardson classification) had a much poorer prognosis than those with histological grade I or II tumors (P=0.0027 for relapse-free survival and P=0.0156 for overall survival). When the population of node-negative patients was divided by tertiles, high cath D levels showed a significant association with an early relapse (P=0.0316). Using cut-off values, patients with high cath D (> or =25 pmol/mg protein) or c-erbB-2 oncoprotein (> or =4 Human Neu Unit/microg protein) levels, had a significant worse relapse-free survival (P=0.0147 and 0.0417, respectively). No prognostic information was supported by pS2 protein or EGF-R measurements. In multivariate analysis, histological grade, cath D and c-erbB-2 oncoprotein remained independent predictors of recurrence (P=0.005, 0.0361 and 0.0321, respectively). By combining low levels of cath D and c-erbB-2 oncoprotein in histological grade I or II tumors, we identified a subgroup of patients with a 100% relapse-free survival probability at 6 years of follow-up. Moreover, the subgroup of patients with histological grade I or II tumors and high values of both cath D and c-erbB-2 oncoprotein showed a prognosis as poor as the subgroup defined by histological grade III alone, respectively 66% and 70% relapse-free survival at 6 years of follow-up. In conclusion, the combination of conventional prognostic factor (histological grade) and biochemical factors (cath D and c-erbB-2 oncoprotein) enabled us to identify, in this preliminary study, a subgroup of patients having an increased risk of relapse in a group (node-negative patients with low histological grade tumors) considered as good prognosis.     

The long term prognostic significance of c-erbB-2 in primary breast cancer.

The expression of the c-erbB-2 oncogene has been evaluated using an immunohistochemical technique with the 21N polyclonal antibody in paraffin embedded tissue from 465 patients treated between the years 1975-1981 for Stage I and II breast cancer. One hundred and four (22%) patients exhibited positive staining. This was not associated with any other variables. Expression of the oncogene was associated with significantly poorer survival which was independent of other tumour variables.     

Prognostic significance of prolactin receptors in human breast cancer

Overall survival and relapse free survival (RFS) were studied in 547 patients according to the presence of prolactin receptors (PRL-R), either free or total (after 3 M MgCl2 desaturation). All these patients were surgically treated for locoregional disease in the same institution between 1978 and 1984. In actuarial survival studies, RFS was higher in total PRL-R positive patients in the whole population (P less than 0.02). When the population was divided into two groups, according to either the presence or the absence of node metastasis or the presence or absence of estradiol receptor, the higher RFS was restricted to node positive (P less than 0.001) and to estradiol receptor positive patients (P less than 0.01). The Cox analysis on RFS showed that free PRL-R alone was a significant prognostic factor in estradiol receptor positive patients; total PRL-R alone was never significant; when considered together with steroid receptors, free as well as total PRL-Rs were significant prognostic factors in some subgroups of patients.     

肿瘤标志物Bcl-2和c-erbB-2在乳腺癌中的表达及其临床意义

目的 探讨肿瘤标志物Bcl-2和c-erb B-2在乳腺癌中的表达和两者的相关性.方法 应用免疫组化方法对70例乳腺恶性肿瘤标本和24例纤维腺瘤标本进行Bcl-2和c-erbB-2癌基因蛋白检测. 结果 Bcl-2和c-erbB-2在乳腺癌中的阳性率分别为68.1%和67.1%;在纤维腺瘤中的阳性率分别为87.5%和0%.Bcl-2和c-erbB-2的阳性表达与有无淋巴结转移呈显著相关.乳腺癌中Bcl-2和c-erbB-2的阳性表达呈负相关(r=-0.28).结论 乳腺癌中Bcl-2的高表达提示患者的预后较好,c-erbB-2 的高表达提示患者预后较差.     

Further analysis of predictive value of Helix pomatia lectin binding to primary breast cancer for axillary and internal mammary lymph node metastases.

We investigated the relation between Helix pomatia (HPA) staining of primary breast cancer and the presence of axillary (AX) or internal mammary (IM) metastases, and evaluated its predictive value for AX or IM metastases in comparison with the use of clinical variables. There was a significant association between the HPA staining and AX or IM metastases. When HPA staining was regarded as an indicator of AX metastases, a diagnostic accuracy of 72%, a sensitivity of 69% and a specificity of 75% were achieved. As an indicator of IM metastases, these values were 64%, 76% and 62%, respectively. In predicting the presence of AX metastases using a discriminant function with clinical AX status, location of tumour and tumour size, diagnostic accuracy, sensitivity and specificity were 79%, 69% and 87%, respectively. In predicting the presence of IM metastases using the discriminant function with clinical AX status and tumour size, these values were 74%, 71% and 75%, respectively. Therefore, it was concluded that the HPA staining may be useful, but it was equivalent with the discriminant function with clinical variables in prediction of AX or IM metastases.     

Pattern of expression of c-erbB-2 oncoprotein in human fetuses

The pattern of expression of the c-erbB-2 oncoprotein was investigated in whole mount preparations of 11 human fetuses by immunocytochemistry using two polyclonal antibodies, 20N and 21N. c-erbB-2 was widely expressed within all three germ layers. Expression remained relatively constant in epithelial, mesodermal and extraembryonic tissues, but varied over time during the development of the fetal skeleton. Western blotting failed to detect c-erbB-2 in normal fetal tissues but did confirm expression in a microvillous membrane preparation of placenta. c-erbB-2 expression is widespread in the human fetus and occurs at an earlier stage than epidermal growth factor receptor.