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.     

Influence of circulating c-erbB-2 serum protein on response to adjuvant chemotherapy in node-positive breast cancer patients

This retrospective case control study investigated the therametricvalue of the circulating c-erbB-2 gene product (Her-2,NEU) as (1) an eligibility criterion for highdoses of chemotherapy and (2) response to standardadjuvant chemotherapy in node-positive breast cancer patients. Preoperativec-erbB-2 levels were measured in 211 locally advanced(> 3 nodes positive), pre- and perimenopausal breastcancer patients to determine if circulating levels ofthe gene product can assist in the determinationof appropriate therapeutic options.152 of 211 breast cancer patients received post-operativelya combination chemotherapy including the anthracycline analog mitoxantrone,while 59 patients were treated with conventional CMFtherapy. Using 120 fmol/ml as a cut-off level,elevated c-erbB-2 values were found in 26 (12.3%)patients with locally advanced breast cancer. In univariateanalysis significant survival differences were detected when c-erbB-2positive patients were compared with c-erbB-2 negative patients.However, no significant survival differences were detected, whenc-erbB-2 positive patients were compared according to regimenof adjuvant treatment.In multivariate analysis c-erbB-2 was an independent prognosticfactor for predicting disease-free survival, but not foroverall survival. High levels of c-erbB-2 were associatedwith low estrogen and progesterone receptor concentrations ofthe tumor cytosol. There was no correlation betweenelevated c-erbB-2 values and age, tumor size ordegree of nodal involvement. c-erbB-2 was a betterpredictor of risk of recurrence than extent ofnodal involvement or hormone receptor status.     

Prognostic factors for noncurative gastric cancer: univariate and multivariate analyses.

We performed univariate and multivariate analyses of possible prognostic factors related to postoperative clinical course of patients with advanced gastric cancer. Noncurative resection was done for 119 patients with hepatic metastasis, peritoneal seeding, extensive lymph node metastasis, or direct invasion to adjacent organs, either alone or in various combinations. In the univariate analysis, 6 of 17 items such as peritoneal seeding, lymphatic invasion, vascular invasion, mode of invasion, extent of lymphadenectomy, and width of serosal invasion significantly correlated to the prognosis. The multivariate analysis indicated that three inherent pathologic factors, mode of invasion, lymph node metastasis, and hepatic metastasis, and one treatment factor, extent of lymphadenectomy, were significant variables predictive of the prognosis and that the prognosis was expected to be very poor in cases of infiltrative type, nodal involvement to tertiary nodes, presence of hepatic metastasis, and lymphadenectomy less than R3. Prognosis in terms of the extent of lymphadenectomy shows that extensive lymphadenectomy (R3) proved to be significantly effective in prolonging survival time, even after noncurative gastrectomy. We recommend extensive lymphadenectomy to prolong survival time for such patients.     

组蛋白酶和c-erbB-2在乳腺癌中的表达

目的探讨乳腺癌病人c-erbB．2和cath-D表达与临床病理及预后的关系。方法通过免疫组化法，检测128例乳腺癌病人的c-erbB-2和cath-D的表达。结果cath-D和c-erbB-2表达与肿块大小、淋巴结转移显著相关（P〈0．0001）。c-erbB-2表达比不表达病人预后差（P=0．01）。结论c-erbB-2阳性表达和cath-D阳性表达者，恶性程度高，易转移、预后差。     

Determination of c-myc amplification and overexpression in breast cancer patients: evaluation of its prognostic value against c-erbB-2, cathepsin-D and clinicopathological characteristics using univariate and multivariate analysis

C-myc and c-erbB-2 amplification and/or overexpression as well as total cathepsin-D (CD) concentration have been reported to be associated with poor prognosis in breast cancer. The prognostic significance, however, remains somewhat controversial, partly because of discrepancies among the different methodologies used. We determined the amplification and overexpression of c-myc oncogene in 152 breast cancer patients and examined its prognostic value in relation to c-erbB-2 amplification and overexpression, high concentration of CD (> or = 60 pmol mg(-1) protein) and standard clinicopathological prognostic factors of the disease. High CD concentration, as well as c-myc amplification and overexpression, proved to be the best of the new variables examined for prediction of early relapse (ER; before 3 years). After multivariate analysis only CD remained significant, which suggests that the prognostic power of these variables is similar. Using univariate analysis we proved that c-myc amplification and overexpression were highly significant for disease-free survival (DFS) (P = 0.0016 and P = 0.0001 respectively) and overall survival (OS) (P < 0.0001 and P = 0.0095 respectively), although by multivariate analysis c-myc overexpression was statistically significant only for DFS (P = 0.0001) and c-myc amplification only for OS (P = 0.0006). With regard to c-erbB-2, only its overexpression appeared to be significant for DFS and OS, although after multivariate analysis its prognostic power was weaker (P = 0.030 and P = 0.024 respectively). c-myc amplification and overexpression exhibited a tendency for locoregional recurrence (LRR) (P = 0.0024 and P = 0.0075 respectively), however, their prognostic value was lower after multivariate analysis and only CD remained significant.     

乳腺癌组织中survivin、c-erbB-2基因的表达与预后的关系

目的:探讨乳腺癌组织中survivin基因和c-erbB-2基因的表达与预后的关系。方法:用免疫组化S-P法检测80例乳腺癌组织中survivin、c-erbB-2的表达,分析其与腋淋巴结转移和5年无病生存率之间的关系。结果:survivin基因在乳腺癌中阳性表达率为68.75%(55/80)、c-erbB-2基因阳性表达率为36.25%(29/80),均与腋淋巴结转移正相关,与5年生存率负相关(P<0.05);survivin和c-erbB-2表达与肿瘤病理类型、发病年龄、临床分期无明显相关性(P>0.05);survivin和c-erbB-2基因表达相互呈正相关(P<0.05)。结论:凋亡抑制基因survivin和原癌基因c-erbB-2可能在乳腺癌的发生、发展过程中起重要作用,联合检测能更好地判断乳腺癌的预后。     

Prognostic factors in stage IV gastric cancer: univariate and multivariate analyses

Background. The prognosis of stage IV gastric cancer is poor with the 5-year survival rate still being about 10%. Methods. We classified 130 patients with stage IV gastric cancer into four groups: peritoneal metastasis, liver metastasis, lymph node metastasis, and multiple factor groups, according to the factors that determined stage IV in each patient and compared survival in the four groups. We also performed univariate and multivariate analyses of various prognostic clinicopathological factors. The 5-year survival rate in the patients with stage IV gastric cancer was 7.4%. Results. No significant differences were observed in survival among the four groups. Univariate analysis showed significant differences in survival among the categories of lymphatic invasion ( P = 0.0045), venous invasion ( P = 0.0024), peritoneal metastasis ( P = 0.0019), postoperative chemotherapy ( P = 0.0385), curability ( P = 0.0001), and lymph node dissection ( P = 0.0001). In the curability B group, survival was prolonged in the postoperative chemotherapy group. Multivariate analysis revealed the highest relative hazard (RH) for lymph node dissection (RH, 2.261), followed, in descending order, by curability (RH, 1.905), peritoneal metastasis (RH, 1.896), lymphatic invasion (RH, 1.736), and venous invasion (RH, 1.481). Conclusion. As prognostic factors in stage IV gastric cancer, the tumor factors of peritoneal metastasis and vessel invasion, and the treatment factors of curability and lymph node dissection may be important, and active treatment appears to improve survival. Received: March 2, 2000 / Accepted: June 2, 2000     

Prognostic and predictive value of c-erbB-2 (HER-2/neu) gene amplification in human Breast Cancer

Amplification of the c-erbB-2 (HER-2/neu) proto-oncogene is detected in 10-30% of human breast cancers and has been shown to be accompanied by the overexpression of its protein in the cancer cell membrane. c-erbB-2 gene amplification is one of the first genetic alterations to be used clinically as a prognostic indicator, a predictive factor of response to doxorubicin (adriamycin) chemotherapy, and a test of patient eligibility for therapy with trastuzumab, a humanized anti-c-erbB-2 antibody. There are two types of tests to detect c-erbB-2 amplification/overexpression: immunohistochemistry and fluorescence in situ hybridization (FISH). Accurate identification of cases with c-erbB-2 amplification/overexpression requires an optimized combination of immunohistochemical and FISH tests.     

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.     

乳腺肿瘤癌基因c—erbB—2,c—myc的表达及其临床意义

应用免疫组织化学方法，研究６１例乳腺良、恶性病变ｃ－ｅｒｂＢ－２、ｃ－ｍｙｃ的癌基因的表达情况。４６例乳腺癌中ｃ－ｅｒｂＢ－２和ｃ－ｍｙｃ阳性率分别为５０％（２３／４６）和４５．７％（２１／４６）１５例乳腺良性病变中阳性率分别为６．７％（１／１５）和５３．５％（８／１５）。     

A comparison between flow cytometric assessment of S-phase fraction and Nottingham histologic grade as prognostic instruments in breast cancer

Flow cytometric DNA analysis with assessment of S-phase fraction and DNA ploidy was compared to Nottingham histologic grade. The study population consisted of 654 patients who presented between 1987 and 1996 with primary operable breast cancer and whose tumours had been analysed for S-phase fraction and DNA ploidy at the time of surgery. Grade, tumour size, node status, steroid receptor status, age, S-phase fraction and DNA ploidy were analysed univariately and multi-variately in a Cox proportional hazard analysis. In the univariate analyses all parameters were statistically significantly associated with breast cancer mortality during the follow-up period of 2–11 years. The most powerful predictor of death from breast cancer in the multiple regression analysis was grade. Patients with grade 1 tumours have excellent prognosis. We conclude that tumour grade is a strong prognostic indicator applicable to all breast cancer patients, regardless of size and nodal status, and advocate its general use.     

MYEOV: a candidate gene for DNA amplification events occurring centromeric to CCND1 in breast cancer

Rearrangements of chromosome 11q13 are frequently observed in human cancer. The 11q13 region harbors several chromosomal breakpoint clusters found in hematologic malignancies and exhibits frequent DNA amplification in carcinomas. DNA amplification patterns in breast tumors are consistent with the existence of at least 4 individual amplification units, suggesting the activation of more than 1 gene in this region. Two candidate oncogenes have been identified, CCND1 and EMS1/CORTACTIN, representing centrally localized amplification units. Genes involved in the proximal and distal amplicons remain to be identified. Recently we reported on a putative transforming gene, MYEOV, mapping 360 kb centromeric to CCND1. This gene was found to be rearranged and activated concomitantly with CCND1 in a subset of t(11;14)(q13;q32)-positive multiple myeloma (MM) cell lines. To evaluate the role of the MYEOV gene in the proximal amplification core, we tested 946 breast tumors for copy number increase of MYEOV relative to neighboring genes or markers. RNA expression levels were studied in a subset of 72 tumors for which both RNA and DNA were available. Data presented here show that the MYEOV gene is amplified in 9.5% (90/946) and abnormally expressed in 16.6% (12/72) of breast tumors. Amplification patterns showed that MYEOV was most frequently coamplified with CCND1 (74/90), although independent amplification of MYEOV could also be detected (16/90). Abnormal expression levels correlated only partially with DNA amplification. MYEOV DNA amplification correlated with estrogen and progesterone receptor-positive cancer, invasive lobular carcinoma type and axillary nodal involvement. In contrast to CCND1 amplification, no association with disease outcome could be found. Our data suggest that MYEOV is a candidate oncogene activated in the amplification core located proximal to CCND1.     

Prognostic significance of c-erb-B2 amplification in fine-needle biopsies of breast cancer patients not operated at diagnosis

Prognostication of breast cancer patients, not operated at diagnosis, poses a clinically difficult problem. To use gene amplification we examined cytological samples and determined c-erb-B2 gene copy number with semiquantitative PCR. Control experiments showed the same gene-copy number in aliquots that were either air-dried (and MGG-stained), fixed in methanol (and air-dried), or snap-frozen in liquid nitrogen. Therefore we examined the prognostic value of c-erb-B2 amplification in 95 breast cancer patients that had not been operated at diagnosis (up to 12 years previously). Tumor cells were obtained from routine archival cytological smears. 15 patients (16%) had developed amplification. Univariate and multivariate analysis showed that c-erb-B2 amplification is a significant prognostic factor (p < 0.0001). Hence routine cytological MGG smears can be used for prognostic determination.     

乳腺癌钼靶X线表现与c-erbB-2癌基因相关性

Objective： To investigate the correlativity between mammographic features and c-erbB-2 of breast cancer. Methods： The mammographic features of 165 patients, including calcification, distinct, esion concentration, breast cysitic hyperplasia accompanied, were studied comparatively with c-erbB-2 gene stained with immunohistochemical technique. Results： Of 165 cases, calcification impression was 84 cases （50.91%）, indistinct 80 cases （48.40%）, lesions were concentrated of 87 case （52.73%）, accompanied breast cysitic hyperplasia 85 cases （51.52%）. Conclusion： Mammographic features of breast cancer could show the status of c-erbB-2, the positive chance is higher with calcification, indistinct, lesion concentration and accompa- nied breast cysitic hyperplasia.     

Detection of c-erbB-2 gene amplification in nipple discharge by means of polymerase chain reaction

Summary In a patient with non-palpable breast carcinoma, c-erbB-2 gene amplification was detected by means of polymerase chain reaction (PCR) in the small number of breast carcinoma cells present in nipple discharge. Amplification of the c-erbB-2 gene is more frequent in carcinoma in situ than in invasive types. Detection by a PCR-based method may help diagnose non-palpable breast carcinoma with nipple discharge. Since this gene amplification is related to high proliferation, it might provide useful preoperative information regarding intraductal carcinoma of comedo type and predict responses to chemotherapy.     

C—erbB—2,P^53,P^21基因过度表达与乳腺癌的预后

目的研究乳腺癌组织中C－erbB－2、P53、P21基因的过度表达与其预后的关系。材料和方法应用免疫组化方法对90例乳腺癌组织检测其C－erbB－2、P53、P21基因的表达情况。结果C－erbB－2、P53、P21在原发灶中的阳性表达率分别为64．4％，63．3％和35．6％。多基因的阳性表达率为57．8％。C－erbB－2、P53的阳性表达率明显高于P21（P＜0．01）。原发灶与转移淋巴结之间的基因过度表达率无显著差异。P53的阳性表达与癌肿大小，浸润程度，淋巴结转移及分期显著正相关。C－erbB－2的阳性表达与淋巴结转移和分期呈正相关。而P21则与上述指标无相关性。结论C－erbB－2、P53的过度表达提示乳腺癌预后差，多基因阳性提示乳腺癌预后差、C－erbB－2、P53、P21多基因过度表达的检测对乳腺癌的预后判断优于其中单个基因过度表达的检测。     

霜蛎消结胶囊对小鼠乳腺癌EMT6细胞移植瘤生长及其p53和c-erbB-2表达的影响

目的：建立小鼠EMT6乳腺癌移植瘤模型,观察霜蛎消结胶囊对小鼠EMT6乳腺癌移植瘤的抑制作用以及对p53和c-erbB-2表达的影响.方法：建立小鼠EMT6乳腺癌移植瘤模型,观察霜蛎消结胶囊对荷瘤小鼠免疫器官重量、小鼠移植性EMT6乳腺癌瘤重以及小鼠移植性EMT6乳腺癌p53和c-erbB-2表达的影响.结果：霜蛎消结胶囊的大、中、小3个剂量组与造模组比较,胸腺指数显著升高（P＜0.05）,霜蛎消结胶囊2.0 g/kg·bw和1.0 g/kg·bw剂量组均能明显抑制小鼠移植性EMT6瘤体的生长（P＜0.05）,霜蛎消结胶囊2.0 g/kg· bw剂量组和1.0 g/kg· bw剂量组织坏死面积明显大于对照组（P＜0.05）,实验组p53和c-erbB-2表达明显低于对照组（P＜0.05）.结论：霜蛎消结胶囊对小鼠移植性EMT6乳腺癌具有明显的抑制作用,其机理可能在于霜蛎消结胶囊可能起到下调突变型p53和c-erbB-2表达的作用,从而使肿瘤缩小,来发挥抗肿瘤作用.     

Detection of c-erbB-2 gene amplification in cervical scrapes positive for human papillomavirus (HPV)

c-erbB-2 gene amplification has been described in a variety of human cancers, but it has been poorly studied in noncancerous cytological samples from genital specimens positive for human papillomavirus (HPV). Furthermore, the relationship between this genetic event and the presence of high-risk and low-risk HPV types is poorly studied. Eighty-four noncancerous cytological samples from exocervical specimens that were positive for HPV types 6, 16, and 18 were analyzed for c-erbB-2 gene amplification using the genomic differential polymerase chain reaction with the single copy reference gene. An association between c-erbB-2 gene amplification and the group corresponding to HPV type 6 was found. Within the low-risk HPV group, c-erbB-2 amplification was associated to cervical intraepithelial neoplasia of grade I (CIN I). Because in the samples analyzed, most of the CIN I stage was characterized by a koilocytotic pattern, c-erbB-2 amplification could be related to this kind of cellular alteration. It would be important to study c-erbB-2 gene amplification and also gene expression in different CIN stages in order to determine its role and significance in cervical cancer.     

Prognosis of breast cancer: Evidence for interaction between c-erbB-2 overexpression and number of involved axillary lymph nodes

The prognostic significance of c-erbB-2 oncogene amplification or overexpression in relation to axillary lymph node metastasis is controversial. We investigated this question in 159 cases of operable breast cancer: 56 patients with node negative disease and 103 patients with pathological involvement of axillary lymph nodes. c-erbB-2 overexpression was assessed by immunohistochemistry using a polyclonal antibody raised against a synthetic peptide fragment of the oncoprotein. The overall incidence of c-erbB-2 overexpression was 35%. c-erbB-2 overexpression was significantly related to survival when all patients were considered (P = 0.0124), and also for patients with positive axillary lymph nodes (P = 0.0026). c-erbB-2 overexpression had no influence on survival of node negative patients (P = 0.7972). A multivariate survival analysis using the Cox proportional hazard model revealed that number of involved lymph nodes, c-erbB-2 overexpression, ER status, and tumour size were independently related to prognosis (P = 0.0000, 0.0012, 0.0112, and 0.0204, respectively). When an interaction term was introduced in the Cox model between c-erbB-2 overexpression and number of involved axillary lymph nodes, a statistically highly significant interaction between these two factors was observed (P = 0.0002), suggesting that the expression of prognostic power of c-erbB-2 overactivity is related to the number of involved axillary lymph nodes. The 159 patients were then subdivided into three groups: node negative (-ve) (56); 1–6 node positive ( + ve) (55); and ≥7 node +ve (48). This cutoff criterion gave the most numerically equitable distribution of the 159 patients into three groups. The relative risk of death increased stepwise from 0.86 (95% CI 0.26–2.78) for node negative patients, to 1.95 (95% CJ 0.82–63) for 1–6 node positive patients, to 2.23 (95% Cl 1.15–4.35) for >7 node positive patients. Our results suggest that the prognostic influence of c-erbB-2 overexpression increases arithmatically with increasing number of involved axillary lymph nodes. © 1995 Wiley-Liss, Inc.     

Clinical utility of serial serum c-erbB-2 determinations in the follow-up of breast cancer patients

To evaluate the ability of serum c-erbB-2 protein to (1) indicate occult and manifest metastases and (2) reflect response to first-line therapy, serial serum c-erbB-2 measurements were performed in a retrospective series of 52 primary breast cancer patients who had developed metastatic disease during follow-up. The results were compared with CA 15-3. Preoperatively, 31% (16/52) of the primary breast cancer patients had elevated c-erbB-2 concentrations. The CA 15-3 positivity rate was 13% (7/52). After surgery, 10 of the 52 patients showed either stable but highly elevated or rising c-erbB-2 serum levels indicating serum c-erbB-2 producing minimal residual disease. Increasing CA 15-3 concentrations were seen in only three patients. Elevated serum c-erbB-2 levels predicted manifest metastases in 27 and 50% of the patients at 6 and 3 months, respectively, prior to clinical diagnosis. CA 15-3 was less sensitive. Only 16 and 32% of the patients had increased CA 15-3 serum concentrations at 6 and 3 months, respectively, prior to clinical detection. The positivity rates of c-erbB-2 and CA 15-3 were similar when metastases were clinically diagnosed. Elevated c-erbB-2 concentrations were found in 62% (32/52). The sensitivity of CA 15-3 was 56% (29/52). The association between serum profiles and response to first-line therapy was evaluated in detail for 45 patients. Serial c-erbB-2 and CA 15-3 measurements reflected disease course in 24 and 27 patients, respectively. The serum profiles of c-erbB-2 and CA 15-3 were similar in 17 patients. In summary, our results suggest that serial determinations of serum c-erbB-2 are useful to monitor breast cancer patients.