Prognostic values of p53 and HER-2/neu coexpression in invasive bladder cancer in Taiwan

OBJECTIVES: To explore the clinical significance of p53 and HER-2/neu coexpression by immunohistochemistry in patients with invasive bladder cancer in Taiwan. METHODS: Paraffin-embedded tumor blocks were obtained from 67 patients with invasive bladder cancer subjected to radical cystectomy, bilateral lymph node dissection, and urinary diversion with or without systemic chemotherapy. Two observers (N.H.C. and T.S.T.), blinded to clinical outcome, reviewed the immunohistochemical staining for p53 (PAb1801) and HER-2/neu (Ab-17). The results were analyzed for progression-free survival and patient survival. RESULTS: Positive staining for p53 and HER-2/neu was found in 30 (44.8%) and 39 (58.2%) patients. In contrast to HER-2/neu, p53 expression was significantly associated with tumor grade and pathologic stage (p = 0.040 and 0.004, respectively), and tended to be related to the nodal status (p = 0.080). Most importantly, coexpression of p53 and HER-2/neu significantly correlated with nodal metastases (p = 0.020). Univariate and multivariate analysis revealed p53 and nodal status as two independent prognostic factors. Additionally, patients with p53 and HER-2/neu coexpression had the shortest time to relapse and overall survival, irrespective of whether adjuvant chemotherapy was given or not (p = 0.005 and 0.030). CONCLUSIONS: In invasive bladder cancer, p53 was an important prognostic factor since its expression correlated with tumor grade and stage, even nodal status, whereas HER-2/neu did not show prognostic significance. Tumors with p53 and HER-2/neu coexpression were associated with nodal metastases, probably resulting in decreased progression-free survival. Although some basic studies provide some important supports, studies including larger patient cohorts would still be required to prove the hypothesis that p53 and HER-2/neu-coexpressing tumors have a worse prognosis and are more resistant to a cisplatin-based multidrug regimen.     

Overexpression of p53 and HER-2/neu proteins as prognostic markers in early stage breast cancer.

OBJECTIVE: Overexpression of the p53 and HER-2/neu oncogenes are the two most common genetic abnormalities associated with breast cancer. Shorter survival time has been reported in patients with tumors with p53 or HER-2/neu. This report analyzes a retrospective cohort of early stage breast cancers for both oncogenes and relates overexpression to clinicopathologic parameters and survival. METHODS: Immunostaining for p53 and HER-2/neu was performed on 230 paraffin-embedded specimens of stage I and II breast cancers diagnosed and treated at Duke University Medical Center between 1984 and 1987. Positive staining for both p53 and HER-2/neu in paraffin-embedded tissues indicates an underlying genetic abnormality: point mutations in the p53 gene and amplification of the HER-2/neu gene. RESULTS: In this cohort of patients, 24% were positive for p53 and 17% for HER-2/neu. Four per cent were positive for both oncogenes. Significant correlations were found between p53 immunostaining and increasing tumor size, stage, and low estrogen and progesterone receptor contents. Univariate analysis showed that p53 and HER-2/neu were indicators of overall and failure-free survival. An additive effect on survival was observed in patients with both oncogene abnormalities. Nodal status, HER-2/neu, and p53 all attained independent prognostic value in a multivariate analysis. CONCLUSIONS: The p53 and HER-2/neu oncogenes have proven but limited prognostic value. An approach that combines several molecular genetic markers with established pathologic criteria may help physicians to make more accurate predictions of prognosis in patients with early stage breast cancer.     

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目的　研究HER 2 /neu(c erbB 2 )在结、直肠恶性肿瘤中的表达及其与肿瘤分期的相关性。方法　收集 2 0 0 2年 1月至 2 0 0 3年 5月治疗的 2 8例结、直肠恶性肿瘤的临床资料。按Dukes分期标准进行分期 ,其中A、B期共 17例 (17/2 8,6 0 7% ) ,C、D期 11例 (11/2 8,39 3% )。采用HER 2单克隆抗体试剂套盒行免疫组织化学染色 ,并以染色细胞数目的多少及染色程度为分级标准 ,认为 2 以上 (含 2 )为过表达 (报告为 ～ 的 ,记为阴性 )。结果　该蛋白在A、B期肿瘤中的过表达率为 11 8% (2 /17) ;C、D期肿瘤中过表达率为 5 4 5 % (6 /11)。该蛋白的过表达率在有转移和无转移的病例之间差异有显著意义 (P <0 0 5 )。结论　虽然在结、直肠恶性肿瘤病例中HER 2 /neu的过表达率不高 ,但仍提示HER 2 /neu过表达程度与肿瘤的进展或侵袭性生物学行为相关。     

Expression of cyclooxygenase-2 in breast carcinogenesis and its relation to HER-2/neu and p53 protein expression in invasive ductal carcinoma

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in the successive steps of breast carcinogenesis and to determine its correlation with HER-2/neu and p53 expression in invasive ductal carcinomas of the breast. Immunohistochemical staining with anti-COX-2 antibody was performed in normal breast tissue, usual hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Expression of COX-2 in invasive ductal carcinoma was correlated with immunohistochemical expression of HER-2/neu and p53 protein. COX-2 expression was found to be progressively elevated along the continuum from normal breast tissue to invasive ductal carcinoma (P<0.001). COX-2 expression significantly correlated with p53 and HER-2/neu protein expression (P<0.05 and P<0.001). On multivariate analysis, only TNM stage and elevated COX-2 expression correlated with survival. Our results suggest that COX-2 may be involved in the carcinogenesis of the breast and may be an independent prognostic indicator in patients with invasive ductal carcinoma. HER-2/neu and p53 are likely to be involved in the regulation of COX-2 expression in invasive ductal carcinomas of the breast.     

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.     

Histopathologic characteristics predicting HER-2/neu amplification in breast cancer

The HER-2/neu gene is a proto-oncogene that is amplified in 10-30% of breast cancers. New drugs for targeted therapy, such as Herceptin, are effective for patients with HER-2/neu-positive tumors, making it necessary to have a noncostly and accurate method to assess HER-2/neu status. We studied the correlation of findings made by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) staining and the possibility of combining IHC and other clinicopathologic characteristics of breast tumors to predict FISH-determined HER-2/neu status. The clinicopathologic characteristics analyzed were the size of the tumor, p53, lymph-vascular invasion, estrogen/progesterone receptors (ER/PR), tumor grade, axillary lymph node status, and patient age. A total of 199 cases of invasive breast cancer studied at the UCLA Pathology Laboratory during 2003 were included in this study. Tumors with IHC 0, 1+, 2+, and 3+ scores were found to be FISH positive in 3.5%, 6.4%, 25.7%, and 81.5% of the respective groups. Our study showed a strong association between the FISH-negative and IHC scored 0 and 1+ tumors, suggesting that the FISH test may not be necessary in these cases (p<0.0001). Although the concordance between IHC 3+ and FISH positive is high, 18% of the patients with overexpression of HER-2/neu fail to show gene amplification by FISH. HER-2/neu positivity was found to be proportionally associated with increasing grade in infiltrating ductal carcinoma (p<0.0001). p53-positive tumors are more likely to be HER-2/neu amplified (p=0.0003). Tumors that are negative for ER/PR are also associated with HER-2/neu positivity by FISH (31.15%, p=0.0016). FISH-determined HER-2/neu status is not associated with histologic type, tumor size, nodal status, lymph-vascular invasion, or patient age.     

The association of HER-2/neu amplification with breast cancer recurrence

HYPOTHESIS: Amplification of the HER-2/neu oncogene in 25% of breast cancers is associated with a shortened disease-free survival. DESIGN: Retrospective analysis of a patient population referred to a tertiary care facility for HER-2/neu testing. The mean follow-up was 56 months. SETTING: Large, urban, tertiary care hospital. PATIENTS: From 1995 to 1999, a consecutive sample of 190 patients with breast cancer had tissue samples tested for overexpression of the cell surface oncoprotein by immunostaining (IM) or amplification of the HER-2/neu oncogene by fluorescence in situ hybridization or both. Forty-nine subjects were excluded because they had tissue samples tested at our institution but received their treatment elsewhere. All patients tested for HER-2/neu after diagnosis with breast cancer in 1999 (n = 47) were excluded from analysis because of short follow-up time. One patient was excluded who had in situ ductal carcinoma. The remaining 93 patients were analyzed. RESULTS: Of 93 patients, 40 (43%) had gene amplification. Overall, patients with oncogene amplification had a shorter median disease-free interval (22 months) compared with controls (40 months) (P =.003). Analysis by the Cox regression model showed that the HER-2/neu status remained significantly associated with time to relapse even after adjusting for age and tumor grade (P =.002; adjusted relative risk, 2.4; 95% confidence interval, 1.4-4.4). No association was found between gene amplification and tumor grade (P =.98), estrogen/progesterone receptor status (P = .29 and P = .43, respectively), or lymph node status (P = .98). Seventy-two patients (77%) eventually had disease recurrence, with 18 (25%) of these recurring locally. CONCLUSIONS: The HER-2/neu oncogene is an independent prognostic indicator of a subset of breast cancers that are at high risk of early recurrence, regardless of tumor grade, estrogen/progesterone receptor status, and lymph node status. Patients amplifying the HER-2/neu oncogene have a shorter disease-free survival than patients without the oncogene.     

Adverse outcome and resistance to adjuvant antiestrogen therapy in node-positive postmenopausal breast cancer patients-The role of p53

The prognostic and predictive relevance of p53 immunoreactivity is used here as a tentative approach for defining more accurately the benefit of adjuvant hormonal therapy in postmenopausal node-positive breast cancer patients. Ninety-seven postmenopausal patients with axillary lymph node metastasis were treated with an antiestrogen for a period of 3 years after primary surgery and radiotherapy. The p53 status of the primary tumor was assessed by immunohistochemistry and 24% of the samples showed positive expression of p53. Within the average follow-up time of 59 months, disease recurrence was diagnosed in 34 patients (35%). Multivariate analysis showed high clinical stage, negative estrogen receptor status and p53 positivity to be independent prognostic factors predicting both shortened disease-free survival and worse overall survival. p53 immunoreactivity was associated with worse clinical outcome irrespective of hormone receptor status. The data suggest that adjuvant therapy with antiestrogens is insufficient in this patient population with p53-positive tumors.     

血管生成对乳腺癌的预后价值及与p53表达的关系

目的　探讨血管生成对乳腺癌的预后价值 ,以及与p5 3和ER的关系 ;方法　利用免疫组化法 ,检测 5 9例乳腺癌的FⅧ ,p5 3的表达 ,采用计算机图像分析系统 ,检测肿瘤微血管面积(MEA )。结果　 ( 1)肿瘤越大 ,肿瘤分级越高 ,其MEA越高 (均为P <0 .0 5 ) ;( 2 )有腋淋巴结转移者的MEA明显高于无淋巴结转移者 (P <0 .0 5 ) ;( 3 )复发患者的MEA明显高于无复发者 (P <0 .0 1) ;( 4 )未发现MEA与 p5 3和ER有相关性。 结论　血管生成可作为乳腺癌一个独立的判断预后因子。     

Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer

BACKGROUND: The use of adjuvant chemotherapy in early breast carcinoma is controversial, with most advocating its use in high-risk patients as defined by specific clinicopathologic parameters. Both bcl-2 and p53, which play a role in determining tumor growth by their effects on apoptosis and cell proliferation respectively, may serve to delineate this subset more accurately. The purpose of this study was to determine the prognostic value of bcl-2, Bax, and mutant p53 in stage I breast cancer. STUDY DESIGN: A total of 75 patients with stage Ic breast carcinoma diagnosed from 1989 to 1992 were identified retrospectively and clinicopathologic parameters such as age, tumor size, estrogen receptor (ER) and progesterone receptor (PR) status, disease-free survival and overall survival obtained. Paraffin-embedded formalin-fixed tissues were immunostained with bcl-2, Bax and p53 monoclonal antibodies using a standard avidin biotin peroxidase reaction. Stained slides were evaluated by two independent pathologists for staining intensity and percentage of cells staining positively. Cox regression was used for multivariate survival analysis using the clinicopathologic parameters and molecular markers. Chi-square tests were used for frequency tables. RESULTS: Mean patient age was 58 years (range 29 to 79 years) with a median followup of 80 months from time of diagnosis. The most common histopathology was infiltrating ductal carcinoma. Neither bcl-2 nor Bax expression was associated statistically with disease-free or overall survival. Expression of mutant p53 was associated with a significant decrease in both 5-year disease-free survival (70% versus 98%, p 相似文献   

小鼠乳腺癌中p53与bcl-2/bax基因表达的相关性研究

目的探讨p53基因和bcl-2/bax基因在乳腺癌发病机制中的作用以及它们之间的相互关系。方法以小鼠乳腺癌BCML-TA299可移植模型为研究对象,用免疫组织化学染色法观测α-干扰素(INF-α)干扰后p53基因与bcl-2/bax表达的关系。结果实验性乳腺癌BCML-TA299治疗组荷瘤鼠生存期较对照组延长,且随着时间的推延治疗组肿瘤的体积明显低于对照组的肿瘤体积;治疗组与对照组比较,肺转移率低。对照组p53蛋白阳性表达率为92.01±0.48,而治疗组中p53呈阴性表达。对照组瘤组织bcl-2蛋白表达为50.21±0.52,bax蛋白表达为12.08±0.13;治疗组瘤组织bcl-2蛋白表达为12.01±0.2,bax蛋白表达为48.19±0.57。对照组p53蛋白表达与bcl- 2呈正相关,而与bax呈负相关(P<0.05);治疗组中p53呈阴性表达,bcl-2和bax表达与对照组结果相反。结论bcl-2和bax的表达受p53调节。p53、bcl-2/bax在乳腺癌发病机制中起着较重要的作用。     

HER2/neu表达对乳腺癌术后应用CMF化疗病人预后的影响

目的：研究HER2/neu癌基因在乳腺癌组织中的表达，探讨其对接受手术及CMF（环磷酰胺、氨甲碟呤和氟脲嘧啶）辅助化疗病人预后的影响。方法：选择1995年至2001年间112例接受手术和术后行CMF化疗的乳腺癌病人的组织标本，用免疫组织化学方法检测原发肿瘤HER2/neu蛋白及雌孕激素受体的表达，结合临床病理资料并分析其与5年生存率的关系。结果：本组乳腺癌组织中HER2/neu的过度表达率为21．4％（n=24）。经随访13～104月，整体病人的5年无病生存率为85．3％，5年总体生存率为91．1％。HER2／neu过度表达者的5年无病生存率为43．2％，而HER2/neu表达缺失者为71％（P=0．01）。HER2/neu过度表达者的5年总体生存率为49．2％，而HER2/neu表达缺失者为83.3％（P=0．02）。同时，生存率亦与肿瘤大小和孕激素受体密切相关。结论：乳腺癌组织中HER2/neu蛋白的过度表达与接受手术及术后CMF化疗病人的预后密切相关，可以作为预测其复发及转移的重要指标。     

Prognostic significance of the coexpression of p53 protein and c-erbB2 in breast cancer

BACKGROUND: The expressions of p53 protein and c-erbB2 have been thoroughly analyzed as prognostic factors for breast cancer. However, the prognostic significance of the coexpression of p53 protein and c-erbB2 remains controversial. METHODS: The immunohistochemical expression of p53 protein and c-erbB2 was evaluated in 242 women with breast cancer. RESULTS: According to the combination of p53 protein and c-erbB2, a group negative for both (125 cases), a group positive for either one of these two parameters (99 cases) and a group positive for both (18 cases) were identified. The group positive for one factor had a significantly (P = 0.0045) worse disease-free survival (DFS) than the group negative for both, while the group positive for both had a significantly (P = 0.0023) worse DFS than the group positive for one factor. A multivariate analysis indicated that the relative risk of p53 protein alone and cerbB2 alone was 2.18 and 2.93, respectively, while the relative risk of the group positive for one factor and the group positive for both was 2.29 and 6.37, respectively . CONCLUSIONS: Breast cancer with a coexpression of p53 protein and c-erbB2 was thus found to have a more significant prognostic value than those with a positive expression for either of these two biological parameters, while the prognostic significance of these two parameters themselves remained independent of each other.     

乳腺癌Her-2与TOP2A基因表达对新辅助化疗效果的预测价值

目的探讨乳腺癌HER 2及TOP2A基因的表达及其与蒽环类药物化疗效果的关系。方法收集我院4年间收治的新辅助化疗患者5 8例标本,采用FISH方法检测所有患者新辅助化疗前癌组织HER 2及TOP2A基因的表达情况;全组患者采用FEC方案行新辅助化疗。化疗4周期后按RECIST标准评估疗效;分析HER 2和TOP2A基因的扩增与疗效的关系。结果全组患者HER-2基因扩增19例(1 9/5 8,3 2.8%),TOP2A基因扩增1 1例(1 1/5 8,1 9.0%),HER 2与TOP2A共扩增1 1例(1 1/5 8,1 9.0%);HER-2基因、TOP2A基因及HER-2和TOP2A基因共扩增均与化疗效果呈正相关[rs=0.52(P0.0 5),rs=0.5 3(P0.0 5)及rs=0.5 6(P0.0 5)]。结论乳腺癌组织中HER 2及TOP2A的扩增均对蒽环类化疗药物的疗效有预测作用,两者的共扩增更有利于预测蒽环类药物的疗效。     

CC3/TIP30蛋白在乳腺癌中的表达及其与HER-2/neu基因的相关性研究

目的 分析CC3/TIP30蛋白在乳腺癌中的表达及临床意义,并探讨CC3/TIP30与HER-2/neu的mRNA相关性.方法 采用免疫组化EnVision二步法检测2004年1月至2005年1月手术治疗并病理证实的112例乳腺癌标本中CC3/TIP30、HER-2/neu蛋白的表达,分析其表达与临床病理特征及预后的相关性,同时应用化学合成靶向敲除CC3/TIP30 mRNA的siRNA,并转染SK-BR-3细胞株48 h后,应用real-time PCR法测定CC3/TIP30、HER-2/neu基因mRNA的表达水平.结果 免疫组化显示CC3/TIP30蛋白在乳腺癌组织中表达与TNM分期、淋巴结转移、HER-2和分子分型相关(P=0.048、0.019、0.027、0.011),而与患者年龄、肿瘤大小,以及雌激素受体和孕激素受体表达状态无关.实时定量PCR结果示CC3/TIP30 siRNA转染导致CC3/TIP30 mRNA的表达下降,同时伴随着HER-2/neu基因mRNA水平的下降,差异有统计学意义(F=56.797,F=165.101;P均=0.000).分子分型为HER-2阳性型的乳腺癌患者中CC3/TIP30蛋白表达阳性、阴性组患者5年总生存率差异有统计学意义(X2=10.732,P=0.001).结论 CC3/TIP30蛋白表达缺失与乳腺癌的发生、发展有关,提示乳腺癌患者早期发生转移复发可能,可作为HER-2阳性型乳腺癌亚组分型的指标之一.     

Current diagnostic methods of HER-2/neu detection in breast cancer with special regard to real-time PCR

In this study we compare different diagnostic methods to measure HER-2/neu gene amplification in breast cancer with special regard to real-time polymerase chain reaction. Fifty specimens of breast cancer were analyzed, and the use of laser-assisted microdissection prior to PCR was investigated. A total of 38 of 50 cases showed HER-2/neu overexpression in immunohistochemistry. In the 2+ scored group, 2 of 23 cases turned out to be amplified after FISH analysis and 14 of 15 cases in the 3+ group were amplified. Of the 16 amplified cases, 3 initially were measured as nonamplified by real-time PCR but showed amplification after laser capture microdissection. One case showed amplification by PCR but turned out to have only one copy of chromosome 17 by FISH. All 0 or 1+ scored cases were measured as nonamplified both by FISH and PCR. Initial concordance rate between FISH and PCR was 92% and could be increased to 98% using laser-assisted microdissection. FISH and PCR showed high diagnostic accuracy and concordance while immunohistochemistry overestimates amplification within the 2+ scored group. Therefore, either FISH or PCR should be applied in cases scored 2+ by immunohistochemistry. Diagnostic accuracy of PCR can be increased using laser-assisted microdissection.