Correlation between human epidermal growth factor receptor family (EGFR, HER2, HER3, HER4), phosphorylated Akt (P-Akt), and clinical outcomes after radiation therapy in carcinoma of the cervix

OBJECTIVE: To investigate prognostic significance of and correlations between HER1 (EGFR), HER2 (c-erb-B2), HER3 (c-erb-B3), HER4 (c-erb-B4), and phosphorylated Akt (P-Akt) in patients treated with radiation for cervical carcinoma. METHODS: Fifty-five patients with stages I-IVA cervical carcinoma were treated with definitive radiotherapy. Tumor expression of each biomarker was quantitatively scored by an automated immunohistochemical imaging system. Parametric correlations were performed between biomarkers. Univariate and multivariate analysis was performed with disease-free survival (DFS) and overall survival (OS) as primary endpoints. RESULTS: Correlations were observed between expression of HER2 and HER4 (P = 0.003), and HER3 and HER4 (P = 0.004). Decreased HER2, HER4, and P-Akt expressions were significant for diminished DFS on univariate analysis (P = 0.04, P = 0.008, and P = 0.02, respectively). Increased EGFR, and diminished HER2, HER4, and P-Akt expression were significant or showed trends toward significance for diminished OS on univariate analysis (P = 0.07, P = 0.008, P = 0.09, and P = 0.08, respectively). After controlling for pretreatment factors, multivariate analysis revealed HER2 associated with improved OS (P = 0.05). CONCLUSIONS: These data emphasize that significant correlations exist between the differential expression of various HER family receptors. Multivariate analysis revealed only increased HER2 expression associated with improved OS after controlling for pretreatment clinical factors. These data emphasize the importance of continued basic and translational research on the HER family of receptors in cervical carcinoma.     

The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma

Abstract. Skirnisdóttir I, Sorbe B, Seidal T. The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I–II) epithelial ovarian carcinoma.
Epithelial ovarian cancer is a heterogeneous disease and many biologic and molecular factors are important for its development and progression, including growth rate, metastatic potential, chemo- and radiosensitivity, and prognosis. Even in the early stages (FIGO I–II), many questions persist about the biologic behavior, optimal treatment, and prognosis.
In a series of 106 patients with epithelial ovarian cancers in FIGO stages IA-IIC, a number of known prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to two important growth factor receptors for oncogenesis (HER-2/neu and EGFR). Immunohistochemical techniques were used. All patients received adjuvant radiotherapy 4–6 weeks after the primary surgery. In a univariate analysis, the expression of the HER-2/neu receptor was not associated with any of the clinicopathologic factors studied or survival status. Positive EGFR staining was associated with poor survival in a univariate analysis. Co-expression of HER-2/neu and EGFR was most frequently seen in serous tumors and positive staining for HER-2/neu alone was associated with mucinous tumors. Both endometrioid and clear cell tumors belonged to the largest subgroup with concomitant negativity for both HER-2/neu and EGFR. In a multivariate Cox analysis, the tumor grade and EGFR status of the tumors were independent and significant prognostic factors. A therapeutic strategy for epithelial ovarian cancer might be to decrease EGFR expression by gene therapy in combination with adjuvant radiotherapy or chemotherapy.     

E-Cadherin complex protein expression and survival in ovarian carcinoma

OBJECTIVE:The aim of this study was to analyze the correlation between expression of E-cadherin complex proteins, epidermal growth factor receptor (EGFR), and c-erbB-2 and disease outcome in advanced-stage ovarian carcinomas. METHODS: Sections from 75 primary ovarian carcinomas (=37) and metastatic lesions (=38) from 45 patients diagnosed with advanced-stage ovarian carcinoma (FIGO stage III-IV) were immunostained and evaluated for staining pattern, extent, and intensity. Patients were divided in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cutoff of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. RESULTS: Comparison of all primary and metastatic lesions showed upregulation of gamma-catenin protein expression in the latter (P = 0.05). When segregated according to disease outcome, the expression of all studied proteins, with the exception of EGFR, was more diffuse in tumors of short-term survivors. The presence of cytoplasmic staining for c-erbB-2 was associated with poor survival in the entire cohort (P = 0.007), as well as in primary tumors alone (P = 0.003), in survival analysis. Similar results were seen in the evaluation of primary tumors for gamma-catenin (P = 0.002). CONCLUSIONS: gamma-Catenin, and possibly c-erbB-2, are valid markers of poor survival in advanced-stage ovarian carcinoma.     

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma

OBJECTIVE: Endometrial carcinosarcomas are aggressive biphasic neoplasms traditionally treated as a high-grade uterine sarcoma. Epidermal growth factor receptor (EGFR) and HER2/neu (HER2) tyrosine kinases have been implicated in the development and progression of several human cancers and are targets for therapeutic intervention. The aim of this study was to evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. METHODS: Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed endometrial carcinosarcoma were immunostained with commercially available antibodies to EGFR and HER2. Fluorescent in situ hybridization for HER2 gene amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR expression were correlated with several prognostic variables. RESULTS: EGFR expression was identified in the majority of tumors (45/55, 82%). HER2 overexpression (3+) was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11 (20%) cases. EGFR expression and HER2 gene amplification did not show significant correlation with disease progression, disease-free survival or overall survival. The carcinomatous component of tumors more frequently showed HER2 overexpression as compared to the sarcomatous component (25% vs. 4%, P = 0.008). The sarcomatous component of tumors more frequently showed EGFR overexpression as compared to the carcinomatous component (44% vs. 24%, P = 0.04). CONCLUSIONS: EGFR and HER2 appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous and sarcomatous elements of these tumors showed consistent differences in HER2 and EGFR expression patterns supporting biologic differences between these components. Studies evaluating the clinical utility of HER2 or EGFR targeted therapy in these tumors appear warranted.     

The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer

Both cyclooxygenase 2 (COX2) and human epidermal growth factor receptor 2 (HER2, also called c-erbB-2) overexpression have been related to a worse prognosis in epithelial ovarian cancer (EOC), but the data are conflicting and the percentage of tumors with overexpression varies widely in different studies. The aim of this study was to investigate the potential prognostic value of COX2 and HER2 expression in EOC. A further purpose was to investigate a possible coexpression of the two markers, and finally, to elucidate the agreement between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for evaluation of the HER2 status in EOC. Immunostaining was performed for COX2/HER2 together with FISH analysis for HER2 gene amplification in 160 patients with EOC, FIGO stages IIB-IV. Follow-up was more than 10 years. COX2 overexpression was found in 20.0% of the tumors. With HER2 staining, 64.4% were scored as 0, 24.4% as 1+, 6.9% as 2+, and 4.4% as 3+. Median survival time for COX2-negative tumors was 21.6 versus 36 months for COX2-positive tumors. The longer survival for COX2 positive was significant by both univariate analysis (P= 0.015) and multivariate analysis (P= 0.025). Positive immunostaining for HER2 was associated with poor overall survival (P= 0.03). Agreement between IHC and FISH was seen in all cases (P < 0.0000001). With long-term observation, patients with negative COX2 expression had significantly shorter survival compared to patients with COX2-positive tumors. Positive HER2 expression also notified a grave prognosis, but the low rate of overexpression reduces its potential clinical application.     

Prognostic impact of KI67, p53, human epithelial growth factor receptor 2, topoisomerase IIα, epidermal growth factor receptor, and nm23 expression of ovarian carcinomas and disseminated tumor cells in the bone marrow

Examination of tumor biological factors for prognostic and predictive indicators is not part of routine testing in ovarian cancer. As in other tumors, the detection of hematogenous tumor spread could help to estimate the risk of metastatic disease. We examined the expression of p53, KI67, topoisomerase IIalpha (Top IIa), epidermal growth factor receptor (EGFR), human epithelial growth factor receptor 2 (HER2) and nm23 in tumor tissues from 90 patients with ovarian cancer. All underwent bone marrow (BM) aspiration and screening for disseminated tumor cells in the bone marrow (DTC-BM) at primary diagnosis. BM aspiration, cytospin preparation, and immunocytochemical staining with the anticytokeratin antibody (A45-B/B3) were done following a standardized protocol. The expression of p53, KI67, Top IIa, EGFR, HER2, and nm23 was evaluated by immunohistochemistry on paraffin-embedded tissue samples and classified by percentage of stained cells or immunoreactive score (IRS). The prognostic impact of the individual factors together with standard histologic parameters was calculated by univariate and multivariate analyses. Expression rates for HER2 (2+/3+: 34.5%), KI67 (median 30%), p53 (median IRS 5), and Top IIa (median IRS 4) were relatively high, whereas nm23 (median IRS 2) and EGFR (IRS 0: 61%) showed weak staining. In 21/90 patients (23.3%), DTC-BM (>/=1/2 x 10(6) cells) could be detected. The presence of DTC-BM was inversely related to nodal status (P = .015) but not to the other factors examined. Tumor stage (P = .02), lymph node involvement (P = .003), grade (P = .046), postoperative tumor residue (P < .001), peritoneal seeding (P = .02), and KI67 (P = .046) significantly correlated with overall survival (OS) after a median observation time of 28 months (2-105). The finding of ascites was borderline significant (P = .050). The presence of DTC-BM (P = .04) and KI67 positivity (P = .02) predicted reduced distant disease-free survival. By multivariate analysis, postoperative tumor residue remained an independent factor for OS (P = .02, relative risk = 4.6). As a primarily locoregional disease, tumor stage and postoperative tumor residue are the main determinants of prognosis in patients with ovarian cancer. However, even in advanced stages, examination of tumor biological factors could help to stratify subgroups of patients and establish targeted therapies.     

Racial differences in the overexpression of epidermal growth factor type II receptor (HER2/neu): a major prognostic indicator in uterine serous papillary cancer

OBJECTIVE: A difference in survival rates between black and white patients with cancer of the corpus uteri is well established. This study was conducted to determine whether the overexpression of HER2/neu oncogene is associated with poor outcome in uterine serous papillary endometrial cancer, which is a highly aggressive variant of endometrial cancer, and whether a racial difference in the frequency of HER2/neu overexpression may contribute to the disparity in endometrial cancer survival. STUDY DESIGN: Immunohistochemical evaluation was used to examine HER2/neu expression in paraffin blocks from 27 women with stage IA to IV uterine serous papillary endometrial cancer. Univariable analysis was performed and followed by multivariable analysis with Cox's proportional hazard model to evaluate whether HER2/neu expression was associated with poor outcome in uterine serous papillary endometrial cancer. RESULTS: Black patients tended to be younger (P = .02) and have higher HER2/neu expression than white patients (trend P = .02). Seven of 10 black patients (70%) showed heavy (3+) expression, compared with 4 of 17 white patients (24%; P = .04). The association of heavy HER2/neu expression with race persisted after age was controlled through stratification (P = .05). Earlier deaths from uterine serous papillary endometrial cancer were seen among heavy HER2/neu expressers (P = .002), black patients (P = .04), and patients < or = 65 years old (P = .04). However, multivariate Cox regression showed that short survival was associated significantly with heavy HER2/neu expression (P = .02) but not with age (P = .07) or race (P = .35), which indicates that HER2/neu expression accounted for much of the race disparity in survival in this patient population. CONCLUSION: Overexpression of HER2/neu in uterine serous papillary endometrial cancer is an independent variable that is associated with poor outcome, occurs more frequently in black women, and may contribute to racial disparity in survival. HER2/neu expression may guide clinical treatment of patients with uterine serous papillary endometrial cancer and may have implications for the implementation of novel treatment strategies.     

Immunohistochemical bcl-2 expression, p53 overexpression, PR and ER status in endometrial carcinoma and survival outcomes

Immunohistochemical expression of bcl-2, p53, PR and ER in cases with endometrial carcinomas arrayed on a tissue microarray (TMA) was tested and correlated with clinicopathologic features, overall survival (OS), cancer-related survival (CRS) and disease-free survival (DFS). Seventy-seven patients with endometrial cancer were reviewed. Slides were evaluated by two pathologists blinded to patient clinical characteristics and survival data. Mean age of patients was 62.5 years (range 35-80), median follow up 60 months (range 9-120). Seventy-nine percent of patients were FIGO Stage I; 39% of the cases showed bcl-2 cytoplasmic staining and its expression was significantly correlated with low-grade tumor differentiation and age < or = 60 years. Nuclear p53 overexpression was detected in 23.4% of the cases and was significantly correlated with advanced stages (IIB-IV), non-endometrioid histology, nodal metastasis and advanced age (> 60 years). PR and ER were positive in 63.6% and 30% of the cases, respectively. Analysis of p53 overexpression and bcl-2 expression in relationship with PR and ER status showed a direct correlation between bcl-2 expression and PR positivity (p = 0.001). In a multivariate analysis FIGO staging was the only clinicopathologic parameter independently correlated with DFS. In conclusion p53 overexpression was directly associated with unfavorable clinicopathologic factors such as advanced stage, histologic subtype, advanced patient age and nodal metastasis. Bcl-2 expression was related with younger age, favorable grade and PR expression by tumor cells. Patient survival was not related to the tested biomarkers.     

子宫内膜浆液性乳头状癌组织中Her-2/neu基因的扩增和蛋白表达及其意义

目的 检测Her-2/neu基因在子宫内膜浆液性乳头状癌(UPSC)中的扩增和蛋白表达情况,并分析其临床意义.方法 回顾性分析1996年1月-2006年1月在复旦大学附属肿瘤医院手术治疗的36例UPSC患者的临床病理资料,分别用显色原位杂交和免疫组化法检测Her-2/neu基因在UPS组织中的扩增和蛋白表达情况,并对两种方法进行对比分析;采用单因素log-rank检验、多因素Cox同归法分析影响UPSC预后的因素.同时随机选择同期收治、临床资料完整的136例Ⅰ型子宫内膜样腺癌作为对照,行免疫组化法检测其Her-2/neu蛋白的表达.结果 免疫组化法检测显示,UPSC患者Her-2/neu蛋白阳性表达率为36.1%(13/36), Ⅰ型子宫内膜样腺癌患者为6.6%(9/136),两者比较,差异有统计学意义(P=0.000).显色原位杂交法检测显示,UPSC患者Her-2/neu基因高度扩增率为11.1%(4/36).显色原位杂交和免疫组化法检测的符合率为100%.36例UPSC患者中,手术病理分期Ⅲ～Ⅳ患者的Her-2/neu蛋白阳性表达率为50.0%(11/22),明显高于Ⅰ～Ⅱ期患者的14.3%(2/14,P=0.030);而不同肌层浸润深度、病理类型构成、病理分化程度及有无脉管侵犯、p53蛋白、雌激素受体(ER)、孕激素受体(PR)表达患者间Her-2/neu蛋白阳性表达率比较,差异均无统计学意义(P>0.05).单因素分析显示,Her-2/neu蛋白表达、肌层浸润深度和手术病理分期是影响UPSC患者预后的危险因素(P<0.05);多因素分析显示,Her-2/neu蛋白表达和肌层浸润深度是影响UPSC患者预后的独立危险因素(P<0.05).Her-2/neu蛋白阳性表达的13例患者中,8例子化疗者平均牛存时间(20个月)较5例未化疗者(42个月)短,但差异无统计学意义(P=O.370).结论 UPSC组织中Her-2/neu蛋白阳性表达与手术分期晚显著相关,Her-2/neu蛋白表达和肌层浸润深度是影响UPSC预后的独立危险因素.     

The prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erb B-2 and cathepsin-D in ovarian cancer patients receiving platinum with cyclophosphamide or paclitaxel chemotherapy

PURPOSE: To evaluate the prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erbB-2 and cathepsin-D in epithelial ovarian cancer (EOC). METHODS: We analyzed 100 patients with ovarian carcinoma, FIGO Stage IC-IV who underwent primary cytoreductive surgery and received adjuvant chemotherapy with cyclophosphamide and a platinum analogue (CP) (n = 46) or paclitaxel and a platinum analogue (TP) (n = 54). Immunohistochemical expression was studied on paraffin-embedded tissue from the primary tumor. RESULTS: After a median follow-up of 55 months median progression-free survival (PFS) and overall survival (OS) were 16 and 41 months, respectively. Positive bcl-2 staining and absence of cathepsin-D expression were associated with an increased complete response rate in the CP group (p = 0.011 and p = 0.003) but not in the TP group. PFS and OS were not associated with the expression of any of the markers studied. FIGO stage (p = 0.006) and histology (p = 0.047) were the only independent prognostic factors for survival. CONCLUSION: Bcl-2 and cathepsin D expression are associated with response to CP but not TP chemotherapy. P53, bcl-2, c-erb B-2 and cathepsin D expression was not correlated with PFS and OS in our study.     

Expression of the chromatin remodeling factor Rsf-1 is upregulated in ovarian carcinoma effusions and predicts poor survival

OBJECTIVE: We recently identified Rsf-1, a chromatin remodeling gene, as a potential oncogene that is frequently amplified and overexpressed in ovarian serous carcinoma. However, its clinical role in ovarian cancer effusions is not clear. In the present study, we assessed the clinical significance of Rsf-1 overexpression in ovarian carcinoma effusions. METHODS: Formalin-fixed paraffin-embedded sections from 168 effusions (134 peritoneal, 34 pleural) were analyzed for Rsf-1 expression using immunocytochemistry. Matched primary tumors (n=48) and solid metastases (n=73) from 48 patients were additionally studied. Rsf-1 expression in tumor cells in effusions was analyzed for possible association with clinicopathologic parameters and survival. RESULTS: Rsf-1 protein expression was found in carcinoma cells in 157/168 (93%) effusions. Of these, 70 (45%) stained weakly and 87 (55%) strongly. Specimens from patients diagnosed with FIGO stage IV disease had higher staining score (extent x intensity) compared with stage III tumors (P=0.008). Rsf-1 expression level was significantly lower in primary tumors and solid metastases (P<0.001 for extent, intensity and score). Univariate survival analysis for 59 patients with post-chemotherapy recurrence effusions demonstrated a significant association between higher Rsf-1 staining and shorter overall survival (OS; P=0.009 for staining extent and intensity, P=0.02 for staining score). FIGO stage was the only clinical parameter associated with OS in this group (P=0.032). In Cox analysis, Rsf-1 expression (P=0.022 for staining extent and intensity, P=0.045 for staining score) and FIGO stage (P=0.035) were independent predictors of shorter survival. CONCLUSIONS: Rsf-1 is frequently expressed and upregulated in ovarian carcinoma cells in effusions and is a novel prognostic marker for patients with post-chemotherapy recurrent disease. The above findings support a role of Rsf-1 in mediating disease progression and aggressive clinical behavior in this subset of ovarian carcinoma patients.     

P63 and EGFR as prognostic predictors in stage IIB radiation-treated cervical squamous cell carcinoma

OBJECTIVES: The purpose of this study was to determine the relation between p63, p53-related gene, epidermal growth factor receptor (EGFR), and spontaneous apoptosis in relation to radiotherapy in patients with FIGO stage IIB cervical carcinoma, who had undergone radiation and concurrent chemotherapy, retrospectively. METHODS: Eighty-four patients with FIGO stage IIB squamous cell carcinoma (SCC) of the uterine cervix, who were treated with radiotherapy and concurrent chemotherapy between 1991 and 1996, were included in the present study. The clinicopathologic features, patterns of treatment failure, and survival data were compared with the expressions of p63 and EGFR, which were determined by immunohistochemistry and with apoptosis by TUNEL on tissue-arrayed slides. Univariate and multivariate analyses were performed to determine the prognostic factors that influence patient survival. RESULTS: Overall the indices of the expressions of p63 and EGFR in stage IIB cervical carcinoma were 18.7 and 26.6%, respectively, and these were found to be correlated. EGFR expression was significantly associated with extrapelvic failure (P = 0.03), whereas p63 was associated with locoregional failure (P = 0.03). The spontaneous apoptotic index showed no prognostic value, but the immunoreactivities of p63 and EGFR were associated with a worse prognosis by both univariate (P = 0.01 and 0.04, respectively) and multivariate analysis (95% CI:2.0-4.4, RR:3.2 and 95% CI:4.9-8.7, RR:6.7, respectively). CONCLUSIONS: The expression of p63 gene is associated with poor survival and locoregional failure, whereas EGFR expression was found to be a prognostic predictor of extrapelvic failure. Both molecules were found to be potent molecular risk factors in patients with FIGO stage IIB SCC of the uterine cervix, who had received radiotherapy and concurrent chemotherapy.     

Expression of cyclooxygenase-2 in adenocarcinomas of the uterine cervix and its relation to angiogenesis and tumor growth

OBJECTIVE: The purpose of this study was to evaluate cyclooxygenase (COX)-2 expression in adenocarcinomas of the uterine cervix and its correlation with clinicopathologic features, angiogenesis, and tumor growth. METHODS: Thirty-nine cases of FIGO clinical stage I and II adenocarcinoma of the uterine cervix were examined by immunohistochemical studies with anti-COX-2. Microvessels were immunohistochemically labeled with an antibody to CD34. Computerized image analysis was used to evaluate microvessel density (MVD). The apoptotic cells were visualized by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) and proliferative cells were visualized by staining with Ki-67 antibody. RESULTS: Twenty-eight tumors (71.8%) were classified as COX-2 positive. COX-2 expression correlated with FIGO stage (P < 0.01). Tumors expressing COX-2 had a significantly higher MVD and Ki-67 index than those that did not express COX-2 (P < 0.05). However, COX-2 expression did not correlate with the apoptotic index. In univariate long-rank analysis, COX-2 expression, MVD, and FIGO stage were associated with shortened survival. However, FIGO stage and MVD were the only independent prognostic factors by multivariate analysis. CONCLUSIONS: Our results suggest that COX-2 expression in cervical adenocarcinomas may contribute to tumor progression by increasing angiogenesis and cell proliferation.     

Expression of HER-2/neu, epidermal growth factor receptor, vascular endothelial growth factor, cyclooxygenase-2, estrogen receptor, and progesterone receptor in small cell and large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathologic and prognostic study

We studied the immunohistochemical expression of HER-2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), estrogen receptor (ER), and progesterone receptor (PR) in uterine cervical small cell and large cell neuroendocrine carcinomas (SCNECs and LCNECs) from 24 patients seen at The University of Texas M.D. Anderson Cancer Center. The objectives were to determine their expression and prognostic role in survival. Twenty-three cases (95.8%) expressed VEGF. The tumors expressing EGFR, HER-2/neu, and COX-2 were modest in numbers: eight (33.3%), 10 (41.7%), and seven (29.2%), respectively. Only one tumor (4.2%) expressed ER, and only two tumors (8.3%) expressed PR. No significant differences in the expression of these factors were found between SCNECs and LCNECs or between stage I and stage II-III tumors. The median overall survival was 21.1 months (95% confidence interval [CI], 17.2-25.0 months). Only HER-2/neu expression was significantly associated with survival. Patients with negative HER-2/neu expression tumors had significantly shorter survival than those whose tumors were positive, 14.2 months (95% CI, 10.6-17.7 months) versus 33.1 months (95% CI, 0-76.92 months) (P = 0.03). There was a trend toward worse survival in patients with EGFR expression, but this finding was not significant. The combination of negative HER-2/neu expression and positive EGFR expression had the worst impact on survival.     

Prognostic value of P53 codon 72 polymorphism in invasive cervical cancer in Brazil

OBJECTIVE: The prognostic value of p53 codon72 polymorphism was analyzed in Brazilian women with cervical cancer. METHODS: The present study consists of 148 women diagnosed and treated for invasive cervical carcinoma (FIGO stages Ib-IIIb) between 1992 and 2002. Demonstration of p53 polymorphism was performed in DNA extracted from paraffin-embedded sections using the polymerase chain reaction (PCR). RESULTS: Among the 148 women, arg/arg was found in 99 (67%) and, arg/pro in 49 (33%). The overall survival (OS) curves (univariate) were different between arg/arg and arg/pro patients (P = 0.01). There was slightly increased risk of death for arg/arg patients (crude HR 2.2 CI 95% 1.2-4.0), which was not confounded by FIGO stages (adjusted HR 2.4 CI 95% 1.3-4.3). For disease-free survival (DFS), two situations were considered: (1) 124 women who received any treatment, and (2) 118 who received FIGO-recommended treatment. In the first group, 59% of arg/arg patients presented recurrence as compared to 32% in the arg/pro group (P = 0.02), whereas in the second group, 61% of the arg/arg and 34% arg/pro showed recurrence (P = 0.04). The risk of recurrence adjusted by FIGO stage for the 124 patients was 2.4 (CI 95% 1.0-3.7) and for the 118 it was 1.9 (CI 95% 1.0-3.4). These adjusted models showed no confounding and no interaction. CONCLUSIONS: Despite the prognostic significance of p53 polymorphism in univariate survival analysis, there was no or only marginal evidence on the independent prognostic value of p53arg/arg in multivariate analysis. The more ominous prognosis of the homozygous (arg/arg) patients was explained by the primary treatment, independent on the FIGO stage.     

The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study

OBJECTIVE: The prognostic and predictive relevance of HER-2/neu dysregulation in epithelial ovarian cancer is controversial. The purpose of our study was to document HER-2/neu expression patterns and their correlation with clinicopathologic parameters and survival in a large and biologically homogenous Caucasian patient collective. METHODS: Expression of HER-2/neu in ovarian cancer tissue was assessed by immunohistochemistry. Immunohistochemical staining was performed according to established protocols. Results were correlated to clinical data. RESULTS: HER-2/neu overexpression was detected in 6.9% (25/361) of the tumor samples and was significantly associated with tumor stage (P = 0.03), but not with lymph node involvement (P = 0.5), tumor grade (P = 0.3), histological type (P = 0.6), residual tumor (P = 0.4), serum CA-125 before therapy (P = 0.2), and patient age (P = 0.8). We found no significant influence of HER-2/neu overexpression on overall and disease-free survival independent of FIGO stage, tumor grade, and residual tumor mass. In a subset of 73 suboptimally debulked patients, women with response to first-line chemotherapy (complete remission [CR] + partial remission [PR]) and no response to first-line chemotherapy (stable disease [SD] + progressive disease [PD]) showed significantly different rates of HER-2/neu overexpression (0% [0/51] vs. 14% [3/22]; P = 0.02). CONCLUSIONS: Tumor overexpression of HER-2/neu in women with advanced ovarian cancer is rare and provides no prognostic information in addition to that provided by established clinicopathologic parameters. This multicenter study, however, indicates that HER-2/neu overexpression is a predictive factor for the response to first-line chemotherapy in suboptimally debulked patients.     

Expression of inducible nitric oxide synthase and cyclooxygenase-2 in ovarian cancer: correlation with clinical outcome

OBJECTIVES: Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) play a critical role in cancer development. We investigated iNOS and COX-2 expression in relation to clinical outcome in 78 International Federation of Gynecology and Obstetrics (FIGO) stage III ovarian serous carcinoma with a low grade of differentiation (G3). METHODS: Disease-free interval and cause-specific survival rates (Kaplan-Meier method) were compared using the log rank test. A multivariate analysis (Cox-proportional hazards models) was used to determine the independent effect of each variable on prognosis. Fisher's exact test was used to analyze the distribution of iNOS and COX-2 expression according to clinical complete response to chemotherapy and to the presence of a brief disease-free interval (< or =12 months). RESULTS: Overall 60 and 125 months cause-specific survival rates were 32% and 11%, respectively. In univariate analysis, iNOS (P=0.005 and P=0.003, respectively), COX-2 (P=0.002 and P=0.007, respectively), residual disease after surgery (P=0.017 and P=0.032, respectively), and FIGO stage (P=0.008 and P=0.025, respectively) were associated with survival and a disease-free interval. In multivariate analysis (Cox proportional hazards models), the factors that were found to be significantly independent predictors of disease relapse as well as survival were iNOS (P=0.014 and P=0.001, respectively), COX-2 expression (P=0.007 and P=0.029, respectively), and FIGO stage (P=0.026 and P=0.05, respectively). iNOS and COX-2 expressions were correlated with a brief disease-free interval (P=0.001) and clinical complete response to first-line chemotherapy (P=0.038 and P=0.033, respectively). CONCLUSIONS: The evaluation of iNOS and COX-2 expression may give additional prognostic information concerning the clinical outcome of patients with ovarian carcinoma and may encourage them to select more tailored therapies.     

Expression of carbohydrate antigens in advanced-stage ovarian carcinomas and their metastases-A clinicopathologic study

OBJECTIVE: Up-regulated expression or loss of expression of various carbohydrate antigens on the surface of cancer cells has been associated with a metastatic phenotype and poor survival in epithelial malignancies of different origins. The object of this study was to investigate the expression of carbohydrate antigens in two groups of patients diagnosed with advanced-stage ovarian carcinoma-one with an extremely favorable outcome and the other with a uniformly poor survival. METHODS: Sections from 76 paraffin-embedded blocks (primary ovarian carcinomas and metastatic lesions) from 45 patients diagnosed with advanced-stage ovarian carcinomas (FIGO stages III-IV) were immunohistochemically stained using five monoclonal antibodies for Lewis(y) (Le(y))(two antibodies), Sialyl Lewis(x) (Slex), Tn, and Sialyl Tn (STn) antigens. Patients were divided in two groups based on outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Staining results for primary tumors and metastases were analyzed separately. RESULTS: Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors and 3 and 25 months for short-term survivors. Staining for all four antigens was seen in the majority of cases (range = 72-96%) and tended to be comparable in primary tumors and their metastases. However, absence of immunoreactivity for STn was seen in 9/38 (24%) metastatic lesions and only 1/38 (3%) primary tumors. This finding did not reach statistical significance (P > 0.05). A combined pattern of membranous and cytoplasmic staining was predominant in the majority of cases. Enhanced staining for Le(y) and STn was detected in the invasive front of some tumors, while Slex and Tn immunoreactivity did not relate to cell location. Primary tumors and metastatic lesions of long-term survivors displayed immunoreactivity patterns that were comparable to those of short-term survivors. In the evaluation of survival curves, more diffuse staining for Slex showed marginal correlation with poor survival (P = 0.05), while a trend toward poorer survival was seen in tumors that were more extensively stained for Le(y) and Tn (P > 0.05). CONCLUSIONS: Le(y), Slex, STn, and Tn antigens are widely expressed in primary ovarian carcinomas and their metastases. Altered expression of Sialyl Tn is observed with tumor progression in a fraction of ovarian carcinomas. Expression of membrane carbohydrate residues is prevalent in tumors of both long-term and short-term survivors and does not appear to be a strong predictor of disease outcome. However, larger studies are needed to further elucidate the role of these molecules in ovarian carcinogenesis.     

The significance of p53 mutation and over-expression in ovarian cancer prognosis

Mutation of the p53 tumor suppressor gene is the most commonly observed genetic abnormality in human tumors and associations between p53 aberration and patient survival have been shown for several tumor types. Previous studies have found that approximately 50% of epithelial ovarian carcinomas exhibit abnormalities in the p53 gene. The aim of this study, therefore, was to examine the potential prognostic significance of aberrant p53 in patients with primary epithelial ovarian carcinoma. Using immunohistochemistry (IHC) and the anti-p53 antibodies CM1, PAb240 and PAb1801, p53 over-expression was observed in 20/39 (51%) tumors. When these results were combined with previously reported IHC and sequencing analyses, 37/61 (61%) tumors exhibited a p53 aberration. Although there was no significant difference between sequencing and IHC results, several cases gave discordant results, indicating that a combination of both methods may be required to estimate accurately the proportion of tumors with p53 aberrations. Univariate statistical analysis showed that p53 aberrations were significantly associated with tumor grade 3/4, FIGO stage III/IV, serous tumors and the presence of bulk (>2 cm) residual disease following surgery. In univariate survival analysis, tumor grade and stage, ascites and post-surgical residual tumor> 2 cm were associated with both overall survival (OS) and disease-free survival (DFS). p53 status, however, was not a predictor of either OS or DFS. Using the Cox proportional hazards model, only FIGO stage and post-surgical residual disease> 2 cm had an independent effect on OS and only stage was found to be an independent predictor of DFS. In conclusion, p53 mutation and overexpression does not appear to be a significant indicator of patient survival in this series of ovarian carcinomas.