Correlation Between ErbB2 Expression and Survival Rates of Osteosarcoma Patients
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Objective:To investigate the expression of ErbB2in patients with osteosarcoma and to determine the relation between ErbB2status and survival rate.Methods:Specimens were collected from 81osteosarcoma patients and immunohistochemical method was used to assay the expression of ErbB2.Results:Of the 81tumors examined,51(61%)demonstrated high levels of ErbB2expression.The presence of increased levels of ErbB2in osteosarcoma was significantly associated with the increased probability of event-free(P0.05)and overall survival(P0.05).Conclusion:In patients with osteosarcoma,ErbB2expression is associated with probability of event-free and overall survival.Cite
Objective The purpose of this study is to prove that the multidrug resistance of osteosarcoma is mediated by p-gp, with an attempt to evaluate the relation between p-gp level and pulmonary metastasis in osteosarcoma Methods The expression of p-gp were retrospectively examined by immuno-histochemistry (LSAB) in 84 patients with osteosarcoma from 1994 to 1998 The intensity of antibody staining and the positive percentage of p-gp were semiquantitatively assessed P-gp-positive and p-gp-negative, mcf-7/ADM and mcf-7 cell lines were used as standards to validate methods and control for variability Human osteosarcoma cell line, HOS-8603 and OS-732, were selected as control sample Based on clinical follow up results, statistical analysis was performed with the SPSS (statistical package) in order to estimate the relation between expression of p-gp and one year lung metastasis by rank correlation, the odds ratio for risk factors of lung metastasis by Logistic regression analysis, the mortality rate and the survival rate by life table method Results 1)One year lung metastasis was 28 6%(24/84) The average diseases free survival time was 16 4 months Life table showed that one year survival rate was 81 6%, two year 64 6%and three year 42 8% 2)Osteosarcoma cell line, HOS-8603, showed low level of p-gp expression, but OS-732 did not show low level of p-gp expression P-gp-positive and-negative cell lines showed correct control 3)The benign bone tumor did not express p-gp 4)Positive expression of p-gp in osteosarcoma was 55 1%(46/84) Most (30/46, 65 2%) of positive expression were low level 5)Rank correlation between the intensity of p-gp expression and one year lung metastasis rate was significant: rs=0 28,P 0 05; Rank correlation between percentage of p-gp staining and one-year lung metastasis rate was significant: rs=0 45, P 0 01; Rank correlation between percentage of p-gp staining and the intensity of p-gp expression was significant: rs=0 79, P 0 01 6)Logistic regression: the intensity and percentage of p-gp staining were risk factors of one year lung metastasis The odds ratio of intensity of p-gp expression was 3 24, 95%CI was 1 17～8 97; the odds ratio of the percentage of p-gp expression was 2 17, 95%CI was 1 35～3 51 The former was higher than the later Patients age and history were protecting factors Conclusions 1)MDR of osteosarcoma is mediated by p-gp 2)Expression of p-gp is a prognostical risk factor of one year lung metastasis 3)The intensity of p-gp is more correlative with one year lung metastasis of osteosarcoma than the positive percentage of p-gp 4)Immunohistochemical method is a sim ple, economic, efficient, repeatable and semiquantitative assay and can directly detect p-gp coded by mdr-1 It is suitable for clinic detection for expression of p-gp in osteosarcoma
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Objective To evaluate the prognostic significance of androgen receptor (AR)expression in patients with breast cancer. Methods The clinicopathological data of 184 consecutive female patients with primary breast cancer treated from January 9003 to June 2003 were analyzed retrospectively.The expression of estrogen receptor ( ER), progesterone receptor ( PR ), AR and c-erbB2 protein were assessed in breast cancer tissue before chemotherapy by using immunohistochemistry methods. The correlations between AR expression and lymph node status, c-erbB2 expression in patients who were classified as two subsets according to the lymph node status and c-erbB2 over-expression and the prognostic significance of AR expression were analyzed. Results All the 184 patients were followed up for more than 5 years. The lymph node involvement, 5-year metastasis and 5-year survival rate were 45. 1%, 16. 9% and 86. 4%, respectively. The 184 patients were classified as two subsets of node-negative and node-positive group. The Chi-square test showed an lowly inverse correlation between AR and lymph node status ( P ＜0. 05, r, = -0. 236), AR expression rate was lower in patients with positive nodes. The Kaplan-Meier test showed that AR expression had no influence on prognosis in lymph node-negative patients. In patients with positive nodes, the ones with AR-positive tumors had significantly better survival rate( P ＜0. 05 ), and the 5-year survival rate and the median survival time of patients with AR-positive tumors were significantly better than those of patients with AR-negative tumors(89. 3% vs. 67. 3% and 56 months vs. 37 months). When the patients were classified as two subsets: c-erbB2-negative and c-erbB2-positive, it indicated that AR expression had on impact on prognosis in c-erbB2-negative patients; and in c-erbB2-positive patients, the survival status was significantly better in patients with AR-positive breast cancer, the 5-year survival rate and the median survival time of patients with AR-positive tumors were significantly better than those of patients with AR-negative tumors(80. 0% vs. 57. 1% and 57 months vs. 37 months). Conclusions The patients with positive lymph nodes and positive c-erbB2 expression have a poorer prognosis in the female breast cancer patients, and the expression of AR has a prognostic significance in those patients. The patients with AR-positive tumors have a better prognosis than these with AR-negative tumors.
Key words:
Breast neoplasms; Prognosis; Androgen receptor; Estrogen receptor; Progesterone receptor
Progesterone receptor
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Adjuvant Therapy
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The aim of this article was to investigate the correlation between expression of O(6)-methylguanine-DNA methyltransferase (MGMT) in osteosarcoma and the curative effect of alkylating agent (Cis-diaminodichloroplatinum, CDDP). 42 male patients and 34 female patients with a median age of 17 years (9 to 43 years) were eligible for this study. According to histopathological types, there were 3 cases of telangiectatic osteogenic sarcoma, 22 cases of osteoblastic, 11 cases of chondroblastic and 16 cases of fibroblastic sarcoma. Immunohistochemical method was used to detect the expression of MGMT protein. The correlations between MGMT expression and the curative effect of CDDP on osteosarcoma have been investigated. It was shown by immunohistochemical staining that among 76 osteosarcoma biopsy specimens, 52 (68%) cases were positive, 27 (35%) cases were weak positive, 18 (24%), cases were moderate positive, and 7 (9%) cases were strong positive. There were no significant differences in MGMT expression among different pathological types of tumors (p>0.5). After CDDP chemotherapy, among pathologic specimens in which MGMT expression was positive, necrosis rates were as follows: grade I, 5 cases (38%); grade II, 7 cases (25%); grade III, 15 cases (21%); grade IV, 2 cases (23%). Osteosarcoma necrosis rate was low when the expression of MGMT protein was positive, whereas necrosis rate was high when there was a low level of MGMT expression (p<0.01). There was a significant negative correlation between the level of MGMT expression in osteosarcoma tissue and osteosarcoma necrosis rate after cisplatin chemotherapy.
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Objective To investigate the expression of p53,c-erbB2 and MRP and its clinicopathological significance in non-small-cell lung cancer(NSCLC).Methods The expressions of p53,c-erbB2 and MRP protein were detected in 152 tumor samples of primary NSCLC by immunohistochemical staining using a polyclonal antibody.The correlation of protein expression with clinicopathologic parameters was analyzed.Results The positive rates of p53,c-erbB2 and MRP expression were 53.9%(82/152),44.1%(67/152) and 43.4%(66/152),respectively.There was significantly correlation of p53expression with gender,tumor differentiation,TNM stage and lymph metastasis(P0.05),but there was no correlation of c-erbB2 expression with clinicopathologic parameters in NSCLCs.MRP positive rate in adenocarcinoma was significantly higher than that in squamous-cell carcinomas(67.6% vs 33.0%,P0.05).Overall survival was significantly correlated with the co-overexpression of p53,c-erbB2 and MRP proteins.The 1-,2-,3-year survival rates in patients with co-positive p53,c-erbB2 and MRP were 72.6%,54.8% and 32.2%,respectively,which were lower than those in patients with co-negative expression(92.1%,78.5% and 63.4%;P=0.02,0.01 and 0.00).The survival rate in patients who received surgery alone with co-positive expression was lower than that in patients with co-negative expression(P0.05);and the survival rate of patients who had surgery plus chemotherapy with co-positive c-erbB2 and MRP was lower than that with co-negative(P=0.01).Cox′s model analysis showed that c-erbB2 expression and cell differentiation were independent prognostic factors in patients with completely resected NSCLC.Conclusion p53,c-erbB2 and MRP may be useful indicators in prognosis of NSCLC.
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Negative correlation
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Potential values of microRNA152 (miR-152) as a serum diagnostic and prognostic biomarker have not been determined in human osteosarcoma. By detecting the expression of miR-152 among 80 osteosarcoma patients, 20 periostitis patients and 20 healthy individuals using qRT-PCR, we aimed to explore the clinical significance of miR-152 in osteosarcoma patients. The expression of miR-152 was significantly decreased in patients with osteosarcoma compared to patients with periostitis (P<0.01) and healthy controls (P<0.01). The relationship between clinicopathologic characteristics and miR-152 was analyzed by chi-square test. The outcome indicated that miR-152 might be linked with the development of osteosarcoma. Moreover, the receiver operating characteristic (ROC) curve was performed to estimate the diagnostic value of miR-152. The result demonstrated that miR-152 might be a promising diagnostic marker of osteosarcoma with an AUC of 0.956, combing with 92.5% specificity and 96.2% sensitivity. The relationship between miR-152 and overall survival of osteosarcoma patients was analyzed by Kaplan-Meier curve and log rank test. As a result, the survival time of patients with low miR-152 expression was significantly shorter than those with high miR-152 expression (P<0.001). Then Cox regression analysis was used to estimate the prognostic value of miR-152 in osteosarcoma. The outcomes showed that low miR-152 expression (P=0.004) might be a potential independent prognostic marker for osteosarcoma patients. These findings suggested that down-regulation of miR-152 could be considered as a predictor for diagnosis and prognosis of osteosarcoma patients.
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Elevated ErbB2 expression and gene amplification have been shown to be associated with poor prognosis in many cancers. Recently, it has been demonstrated that overexpression of ErbB2 protein in osteosarcoma is associated with the presence of pulmonary metastasis and decreased survival. By contrast, a previous study showed that the expression of ErbB2 declines in individual osteosarcomas as they become metastatic. In the current study, the authors determined the relation between ErbB2 status and outcome in a large number of selected patients with high-grade osteosarcoma.ErbB2 status was determined immunohistochemically in biopsy specimens of osteosarcoma of the extremities from 81 patients who were treated with surgery and chemotherapy. None of the patients had metastatic disease at presentation (Stage II), and all were followed-up for at least five years. The ErbB2 status was analyzed in relation to the lengths of event-free and overall survival.Of the 81 tumors examined, 51 (61%) demonstrated high levels of ErbB2 expression. The presence of increased levels of ErbB2 in osteosarcoma was significantly associated with the increased probability of event-free (72.2% v. 45.6% at 5 years, P = 0.03) and overall survival (79.7% v. 58.2% at 5 years, P = 0.03). Cox multivariate analysis showed that the risk of adverse events and death was increased substantially (rate ratio: 2.24 and 2.54; 95% confidence interval, 1.07-4.72 and 1.09-5.67, respectively) among patients with decreased levels of ErbB2 protein in tumor cells, as compared with patients who had increased levels of ErbB2 in tumor cells.In patients with high-grade osteosarcoma without metastatic disease at presentation and treated with surgery and chemotherapy, the presence of increased levels of ErbB2 in tumor cells is associated with a significantly increased probability of event-free and overall survival. Further data are needed before this marker can be used in making clinical decisions.
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Abstract Objective. To test if hormone or growth factor receptor expression is associated with survival among patients with high grade serous ovarian cancer (HGS OvCa) we analyzed tumor mRNA expression microarray and clinical data from The Cancer Genome Atlas (TCGA). Methods. HGS OvCa patients were surgically staged prior to treatment with IP (n = 90) or IV-only (n = 398) chemotherapy. Multivariate Cox proportional-hazards regression tested associations of expression of 9 hormone or growth factor receptors with progression free survival (PFS) and overall survival (OS). Hazard ratios are hazard per each one standard deviation increase in gene expression. Expression was analyzed as a continuous variable by restricted mean survival analysis. Mean PFS or OS were compared between IP and IV groups by permutation testing stratified by expression. P-values were two-tailed. Results. Expression of ESR1, PGR, FSHR, LHCGR, MET, and EGFR were not associated with PFS or OS. TSHR expression was associated with decreased OS (HR 1.22 (1.06-1.41), p = 0.005) and PFS (HR 1.18 (1.05-1.33), p = 0.006) among IV-only treated patients. ERBB2 expression was associated with decreased OS (HR 1.48 (1.05-2.10), p = 0.027) among patients who received IP chemotherapy. Using multigene (ESR2, PGR, TSHR, and ERBB2) analysis, among the IP group, ERBB2 (HR 1.76 (1.11-2.79), p = 0.015) and ESR2 (HR 0.28 (0.08-0.93), p = 0.037) were associated with OS. Only TSHR expression was associated with decreased OS (HR 1.22 (1.06-1.41), p = 0.005) and decreased PFS (HR 1.18 (1.05-1.33), p = 0.007) on multigene analysis of IV-only treated patients. OS and PFS decreased steeply at high expression of TSHR and ERBB2. Among patients with upper 10th percentile TSHR expression, no significant difference in mean OS or PFS was observed between patients treated with IP versus IV-only chemotherapy. Patients with lower TSHR expression (< 90% percentile) experienced a mean 13.7-month increased OS and 16.4-month increased PFS associated with IP chemotherapy (p < 0.0001). Conclusions. Among HGS OvCa patients treated with IV-only chemotherapy, increased tumor TSHR expression was associated with decreased OS and PFS. High TSHR expression characterized patients who did not benefit from IP chemotherapy. Citation Format: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi. Overexpression of TSH and ERBB2 (HER2) receptors is associated with sharply decreased survival in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4754.
Tissue microarray
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Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer.The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients.Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis.The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages 50 years old.
Univariate analysis
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Objective To discuss the correlation between Bcl-2 and apoptosis and its role in the growth and development of pediatric osteosarcoma.Methods Forty-one children of osteosarcoma were selected who had been pathologically confirmed and treated in the affiliated hospital of Taishan medical university and Tai'an maternal and child health hospital from January 1998 to March 2010.Thirty-six children were enrolled into this study who were about to receive standard treatment including surgery,preoperative and postoperative chemotherapy.Immunohistochemical method was used to detect the expression of Bcl-2 in specimens from 36 cases of pediatric osteosarcoma and 20 cases of pediatric osteochondroma.Univariate analysis was conducted on the correlation between Bcl-2 and gender,age,primary tumor site,tumor size,pathologic type,Enneking stage.Cell apoptosis in pediatric osteosarcoma and osteochondroma was detected by TUNEL.Apoptotic index(AI) was calculate and analyzed for its correlation with Survivin and Bcl-2 expression,which was further discussed for clinical significance.Results For expression of Bcl-2,the positive rate was 47.2% in the 36 cases of pediatric osteosarcoma(17/36) and no positive case was found in the controls(P0.05);the positive expression of Bcl-2 was not significantly correlated to gender,age,tumor site,tumor size,and pathologic type(P0.05),but correlated to Enneking staging(P﹤0.05);the positive rate was 30%(6/20)in patients of Enneking's stage Ⅰ-Ⅱ and 62.5% in patients of Enneking's stage Ⅲ,significance was found between them(P0.05).It showed that the expression of Bcl-2 was positively correlated to pathologic stage.AI values ranged from 3.6%-16.4%,with an average of 7.3%.Cell AI was(6.66 ± 1.87)% in children with osteosarcoma upon test and(12.28 ± 3.29) % in control group,the difference was statistically significant between the two groups(P﹤0.05),which indicated that there was a reduced apoptosis in osteosarcoma.AI value was(4.68±0.57)% and(6.53±1.65)% respectively in Bcl-2 positive group and Bcl-2 negative group,which showed significant difference(P0.05).The expression of Bcl-2 was negatively correlated with AI.The survival curves made by Kaplan-Meier method indicated that the life span in Bcl-2 positive group was significantly shorter than that in Bcl-2 negative group(P﹤0.01).Multivariate survival analysis using Cox regression model showed that Enneking staging and the level of Bcl-2 expression in osteosarcoma were important and independent factors for the prognosis of pediatric osteosarcoma.Conclusions Positive expression of Bcl-2 is not obviously correlated with gender,age,tumor location,tumor size,pathologic type in children with osteosarcoma,but correlated with Enneking stage.Positive expression of Bcl-2 can shorten the life span and the expression of Bcl-2 is negatively correlated with AI,all of which indicate that Survivin and Bcl-2 protein may inhibit cell apoptosis and promote the proliferation of tumor cells in pediatric osteosarcoma.Multivariate analysis indicates that Enneking staging and the level of Bcl-2 expression in osteosarcoma are important factors for the prognosis of osteosarcoma.In conclusion,the indicators mentioned above are of great value to the prognosis of osteosarcoma in children.
Survivin
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Univariate analysis
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