Patient Survival Information Research Articles

P1-07-18: Expanding an Online Tool for Genome-Wide Validation of Survival-Associated Biomarkers in Breast and Ovarian Cancer Using Microarray Data of 3,862 Patients.

Abstract The pre-clinical validation of prognostic gene candidates in large independent patient cohorts is a pre-requisite for the development of robust biomarkers. We earlier implemented an online tool to assess the prognostic or predictive value of the expression levels of all microarray quantified genes in breast cancer patients. In present study, we further expanded our database, added additional analytical options and implemented the tool for ovarian cancer patients. The database was set up using gene expression data and survival information of breast and ovarian cancer patients downloaded from GEO and TCGA (Affymetrix HGU133A, HGU133A 2.0 and HGU133+2 microarrays). After quality control and normalization only probes present on all three Affymetrix platforms were retained (n=22,277). Patients can be stratified into the various robust subtypes either by histology or by various gene expression profiling based methods. To analyze the prognostic value of the selected gene in the various cohorts the patients are divided into two groups according to the median expression of the gene. A Kaplan-Meier survival plot is generated and significance is computed. All together 2,472 breast cancer patients and 1,390 ovarian cancer patients were entered into the database. These groups can be compared using relapse free survival (n=2,414 in breast cancer and 1,090 in ovarian cancer) or overall survival (n=463 and n=1,290). Follow-up threshold has been implemented to exclude long-term effects. The combination of several probe sets can be employed to assess the mean of their expression as a multigene predictor of survival and therapy efficiency. In summary, we expanded our global online biomarker validation platform to mine all available microarray data to assess the prognostic power of 22,277 genes in 2,472 breast and 1,390 ovarian cancer patients. The tool can be accessed online at: www.kmplot.com/breast and www.kmplot.com/dev/ovar. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-18.

398 EXPRESSION OF RICTOR IS ASSOCIATED WITH METASTASIS AND POOR PROGNOSIS OF RENAL CELL CARCINOMA

INTRODUCTION AND OBJECTIVES: Rictor is a key member of mTORC2, which is crucial to various carcinoma. We measured Rictor expression levels in tumor tissues and six RCC cell lines and evaluated its significance and prognostic use in renal cell carcinoma (RCC). Then we evaluated the change of cell migration, invation and adhesion in RCC cell with downregulation of Rictor. METHODS: Expression of Rictor was examined through immunohistochemistry in a tissue microarray constructed from 217 renal cancer patients to assess the correlation between Rictor expression level and RCC progression. We subsequently analyzed Rictor expression levels in several RCC cell lines through western blotting. Rictor expression in ACHN cell line was down-regulated by SiRNA and the change of cell migration, invision and adhesion wan examined. RESULTS: Rictor positive staining was noted in 74% of RCC patients with 86% in CCRCC and 62 % in PRCC respectively, whereas staining of Rictor expression was remarkably weak in most normal tubules.(FigA). Further statistical analysis showed that Rictor expression was detected in 24 out of 31 long metastasis cases (p 0.000) and in 10 out of 14 lymph node metastasis cases (p 0.003) (Table1). Rictor expression is significantly higher in RCC cell lines with high metastatic potential (ACHN°¢SN12C°¢HTB47) than in primary RCC cell lines(786-O and 769-P )(Fig2A). The Rictor expression level was significantly higher in cases with a symptomatic presentation,as well as in higher TNM stage and higher Furhman grade compared with those with lower stage and lower grade. (Table1) Patients with positive Rictor expression showed lower probability of disease-free survival compared with patients with negative Rictor expression. Knockdown of Rictor by small interference RNA inhibits cancer cell migration and invision and impaired EGF-induced cell adhesion. CONCLUSIONS: The Rictor expression may correlate with cancer migration and metastasis, and the detection of expression levels provides useful prognostic information for cancer-specific survival in patients with RCC. Down-regulation of Rictor inhibits cancer cell migration and invision impaired EGF-induced cell adhesion,so Rictor is a potential target for the treatment of RCC metastasis.

A STAT3 Gene Expression Signature in Gliomas is Associated with a Poor Prognosis

Gliomas frequently display constitutive activation of the transcription factor STAT3, a protein that is known to be able to mediate neoplastic transformation. STAT3 regulates genes that play a central role in cellular survival, proliferation, self-renewal, and invasion, and a cohort of STAT3 target genes have been found that are commonly coexpressed in human cancers. Thus, these genes likely subserve the transforming ability of constitutively activated STAT3. To determine whether the coordinated expression of STAT3 target genes is present in a subset of human gliomas, and whether this changes the biology of these tumors in patients, gene expression analysis was performed in four distinct human glioma data sets for which patient survival information was available. Coordinate expression of STAT3 targets was significantly associated with poor patient outcome in each data set. Specifically, patients with tumors displaying high expression of STAT3 targets had a shorter median survival time compared to patients whose tumors had low expression of STAT3 targets. These data suggest that constitutively activated STAT3 in gliomas can alter the biology of these tumors, and that development of targeted STAT3 inhibitors would likely be of particular benefit in treatment of this disease.

Expression of Adipose Differentiation-Related Protein: A Predictor of Cancer-Specific Survival in Clear Cell Renal Carcinoma

We recently found that adipose differentiation-related protein (ADFP) is a potential diagnostic and prognostic biomarker for clear cell subtype renal cell carcinoma (RCC). To further evaluate the correlation between ADFP expression levels and clinicopathologic characteristics and patient outcome, we retrospectively examined patients with clear cell RCC. A series of 432 consecutive patients with sporadic clear cell RCC who underwent nephrectomy between March 1986 and June 2004 were enrolled in the study. ADFP expression levels in the primary tumors and in 18 metastases were measured by real-time quantitative PCR. The clinicopathologic and prognostic data were collected, as well as the von Hippel-Lindau disease (VHL) gene alteration status in selected cases. ADFP expression was apparently high in cases without a symptomatic presentation, as well as in cases of low-stage, low-grade, or VHL alteration-positive clear cell RCC, whereas it was down-regulated in undifferentiated tumors with a spindle/pleomorphic component or metastatic lesions. Univariate analyses showed that high ADFP expression was associated with better cancer-specific survival and cancer-free survival. Further Cox multivariate analyses combined with the split-sample validation method showed that ADFP expression still remains an independent predictor for cancer-specific survival in all tumor stages and in advanced metastatic cases, whereas the predictive value of ADFP expression for cancer recurrence is rather weak. The ADFP expression may represent the tumor differentiation status, and the detection of the expression levels provides useful prognostic information for cancer-specific survival in patients with clear cell RCC.

Angiotensinogen M235T and T174M Gene Polymorphisms in Combination Doubles the Risk of Mortality in Heart Failure

Angiotensinogen M235T and T174M polymorphisms have individually been associated with elevated levels of plasma angiotensinogen, hypertension, and left ventricular hypertrophy. In this study, heart failure patients (n=451) were genotyped for the angiotensinogen M235T and T174M polymorphisms to investigate association with survival (recorded over 4 years of follow-up) and prognostic hormone markers. Patients carrying the 235TT genotype (n=86) were 3 years younger at admission (P=0.011), and, in those with hypertension, diagnosis was made approximately 10 years earlier than other patients. Patients carrying >or=1 174M allele (n=94) were more likely to have a previous history of heart failure (P=0.044) and increased mortality during follow-up (risk ratio: 1.69, 95% CI: 1.03 to 2.79; P=0.038) compared with 174TT homozygotes (n=355), despite having a higher left ventricular ejection fraction (P=0.009). "High-risk" genotype combinations (defined a priori as 235TT and/or >or=1 174M allele; n=144; 32%) were independently predictive of mortality, conferring a 2-fold greater risk of dying during the follow-up period (odds ratio: 2.0; 95% CI: 1.3 to 3.0; P=0.001). This study suggested that angiotensinogen gene variants M235T and T174M may provide prognostic information for long-term survival in heart failure patients.

Overall and Progression-Free Survival in Metastatic Melanoma: Analysis of a Single-Institution Database

Many new agents are currently in trial in melanoma. It remains unclear, however, what the benefit of a given therapy may be since information on progression-free and overall survival of untreated patients is limited. Since few trials in melanoma have had a non-treated cohort, it remains unclear what survival can be expected in patients who are not treated with chemotherapy. To help develop parameters for future trials, we analyzed treatment history and survival in 212 patients with metastatic melanoma seen at our institution between January 1998 and September 2003. A retrospective analysis was done using a database created for melanoma patients at our center. Patient survival information was determined from this database, tumor registry, Social Security index, and direct patient calls. Patient staging information was determined according to the 2001 guidelines. Non-chemotherapy-treated patients with M1c disease were used as "controls." The median survival of stage M1c melanoma was 6.0 months. Survival was longer for stage M1a and M1b and shorter in older patients. No significant differences were found in survival based on gender. Among chemotherapy-treated patients, those with progressive disease on treatment or with increased lactate dehydrogenase (LDH) fared worse than those with a clinical response or normal LDH, respectively. Patients treated with either biochemotherapy or temozolomide and thalidomide survived longer than those who received no chemotherapy treatment. Dacarbazine (DTIC) treatment did not prolong survival. In this retrospective review of patients treated at a single institution, those treated with multiagent chemotherapy but not with single-agent DTIC appeared to have had a survival benefit.

Positron-emission tomography as a prognostic tool for early-stage lung cancer

Background Positron-emission tomography (PET) shows tissue metabolic activity in the form of the standard uptake value (SUV). This study examines the prognostic value of the SUV for early-stage lung cancer. Methods A retrospective review of 187 patients undergoing PET for potential lung cancer. Data collected included patient demographics, tumor pathology, and survival information. Data were correlated with PET results to determine if a prognostic relationship exists. Results The sensitivity and specificity of PET for detecting malignant lesions were 98% and 24%. Malignant lesions had a higher SUV than benign lesions (5.9 ± 6.2 versus 2.2 ± 1.8, P < .0001). The average SUV of well-differentiated tumors was 2.6 ± 3.1 versus 5.9 ± 5.5 for other tumors ( P = .010). There was a strong correlation between tumor stage and SUV (analysis of variance, P < .0001). There was no difference in tumor SUV for survivors versus nonsurvivors. Conclusions The SUV correlates with prognostic indicators, such as tumor stage and grade. The SUV alone was not an independent predictor of survival.

Stage and mRNA expression of survivin in lymph node as prognostic indicators in patients with oral squamous cell carcinoma

Squamous cell carcinoma (SCC) is the most common malignant head and neck tumor and is responsible for more than 90% of head and neck cancers and accounts for 4.5% of all malignant tumors in males and 3.5% in females in South Korea. The purpose of this study was to investigate the correlation of suggested clinico-pathological prognostic factors such as gender, age, T score ( T number in TNM), clinical stage, proliferation, invasion index, and lymph node metastasis to the survival of SCC patients in Korea. Furthermore, cytokeratin (CK), carcinoembryonic antigen (CEA), and recently documented apoptosis related protein, survivin, were analyzed by RT-PCR. In 113 patients, survival curves were estimated by the Kaplan–Meier method and nominal or numeric variable influence on survival was studied by Univariate and Multivariate Regression analysis (Cox proportional hazards model). Univariate analysis demonstrated that gender and age factor had no significant effect on survival rate. T score, on the other hand, significantly influenced survival and univariate analysis demonstrated that Stage 4 group had a significantly lower survival rate than the other stage groups but differentiation and invasion index factors had no significant effect on survival rate. Using a 50% cut-off point, patients with lower PCNA scores showed no survival advantages over those with higher PCNA scores but lymph node metastasis was a significant survival predictor in univariate analysis. In addition, lymph node CK and survivin mRNA expression have significant effects on OSCC patient survival rate. This means that prognostic value can be amplified by coincident analysis of T score, pathologically confirmed lymph node metastasis, and lymph node CK or survivin mRNA expression. Multivariate analysis using Cox's proportional hazards model, clinical TNM stage and lymph node survivin mRNA expression were independent OSCC prognostic factors, which support cancer staging based on the TNM as a powerful prognostic variable and lymph node survivin expression might provide predictive information for OSCC patient survival.

Prediction of survival with squamous cell carcinoma antigen in patients with resectable esophageal squamous cell carcinoma

Background. Increased preoperative serum squamous cell carcinoma antigen (SCC-Ag) concentrations have been found to be associated with advanced stage and poor prognosis in lung and cervical cancers. Because little was known about the significance of SCC-Ag concentration in patients with esophageal cancer, the aim of this study was to analyze the clinicopathologic significance of SCC-Ag in patients with esophageal SCC. Patients and Methods. Preoperative SCC-Ag concentration was measured with enzyme-linked immunosorbent assay in 309 patients with primary esophageal SCC. All patients underwent curative radical surgery without any preoperative therapy. In 215 of 309 patients, carcinoembryonic antigen (CEA) was also measured to compare clinical significance of CEA with that of SCC-Ag. The prognostic significance for survival of SCC-Ag concentrations was studied with multivariate analysis with Cox proportional hazards model. Results. The SCC-Ag concentration and the positivity rate of SCC-Ag were significantly elevated in patients associated with tumor progression. Statistically significant differences in SCC-Ag concentrations and SCC-Ag positivity rates were observed depending on tumor size, tumor depth, lymph node status, and distant metastasis. Although CEA was not a prognostic factor (P =.21), a high SCC-Ag concentration was a significant prognostic factor (P <.01). Multivariate analyses indicated that T factor had the best predictive power, but SCC-Ag concentration contained additional, independent prognostic information. Conclusion. Our findings suggest that preoperative serum SCC-Ag concentrations might provide a predictive information for tumor progression and survival in patients with esophageal SCC. (Surgery 2003;133:486-94.)

Original Articles

In an attempt to define the relationship among tumor size, stage and survival, the Cancer Incidence and End Results Committee of the American Cancer Society, Illinois Division, Inc. reviewed the records of 2,473 patients with a histological diagnosis of renal cell carcinoma. Tumor size was related to stage and survival. Larger tumors were generally associated with an increased stage (p < or = 0.0005) as well as poorer survival (p < or = 0.005). For Robson stages II, III and IV, tumor size may contribute additional prognostic information for patient survival.

Original Articles: Kidney Cancer: Renal Cell Carcinoma: Tumor Size, Stage and Survival

ABSTRACTIn an attempt to define the relationship among tumor size, stage and survival, the Cancer Incidence and End Results Committee of the American Cancer Society, Illinois Division, Inc.reviewed the records of 2,473 patients with a histological diagnosis of renal cell carcinoma. Tumor size was related to stage and survival. Larger tumors were generally associated with an increased stage (p <=0.0005) as well as poorer survival (p <=0.005). For Robson stages II, III and IV, tumor size may contribute additional prognostic information for patient survival.

Primary Mesenchymal (Nonangiomatous/Nonlymphomatous) Neoplasms Occurring in the Canine Spleen: Anatomic Classification, Immunohistochemistry, and Mitotic Activity Correlated with Patient Survival

Surgical submissions from canine splenectomy cases spanning a 3-year period (1988-1990) were evaluated. Eighty seven neoplasms of the spleen considered to be of nonangiomatous and nonlymphomatous origin were selected for morphologic classification, mitotic index determination, immunohistochemical analysis, and patient survival determination. In 76/87 cases, patient survival information was available, and the mitotic index was determined in 83/87 cases. Immunohistochemistry for selected antigens (vimentin, desmin, smooth muscle actin, myosin, and factor VIII-related antigen) was performed in 58/87 of the cases. Morphologic classification of these lesions in standard HE preparations yielded the following neoplastic groups: fibrosarcoma (19/87), undifferentiated sarcoma (19/87), leiomyosarcoma (14/87), osteosarcoma (8/87), mesenchymoma (7/87), myxosarcoma (6/87), histiocytic sarcoma (6/87), leiomyoma (3/87), lipoma-myelolipoma (2/87), liposarcoma (2/87), and malignant fibrous histiocytoma (1/87). A lack of distinct morphologic characteristics among many of the neoplasms that were classified as either fibrosarcoma, leiomyosarcoma, or undifferentiated sarcoma contrasted these groups with the relatively unambiguous features that distinguished the other sarcoma groups. Using immunohistochemical staining for muscle-specific antigens (desmin, smooth muscle actin, and myosin), specific staining often overlapped extensively within the neoplastic groups of fibrosarcomas, leiomyosarcomas, and undifferentiated sarcomas, suggesting either ambiguous morphologic findings or the possibility of a common histogenesis from smooth muscle trabeculae or a distinct population of splenic myofibroblasts. The biological behavior of all tumors examined could be placed into three categories of patient survival: (1) benign, noninvasive tumors (leiomyoma, lipoma) with prolonged survival intervals; (2) malignant tumors (fibrosarcoma, undifferentiated sarcoma, leiomyosarcoma, osteosarcoma, myxosarcoma, histiocytic sarcoma, and liposarcoma), showing severely truncated survival (median 4 months with 80-100% mortality after 12 months; and (3) intermediate survival periods (median 12 months with 50% 1 year survival) attributed to a single group of neoplasm, the mesenchymomas. The biological behavior of primary splenic nonangiomatous, nonlymphomatous sarcomas was most closely correlated with observed mitotic index. Splenic neoplasms of this type with a mitotic index < 9 showed significantly (P < 0.0001) longer survival intervals than those with an index > 9. With the exception of osteosarcoma, all anatomically defined tumor groups contained one or more specimens with a mitotic index < 9. The clinical prognosis given for splenic sarcomas should be modified according to the mitotic index as a predictive value for patient survival.

Immunohistochemical expression of sialyl Lex antigen in relation to survival of patients with colorectal carcinoma.

The alterations of carbohydrate chains in cancer cell membrane can be related, not only to the formation of tumor-associated antigens, but also to cell biologic significance. There is, furthermore, a possibility of their relationship to tumor metastatic behavior and subsequent survival of patients with cancer. Recent clinical studies elucidated that a carbohydrate antigen, sialyl Lex, is a useful tumor marker in colorectal cancer. However, the sialyl Lex antigen immunoreactivity in colorectal carcinoma in relation to patient survival is unknown. The aim of the study was to elucidate whether sialyl Lex expression in tumors was correlated with patient survival. Immunohistochemical expression of sialyl Lex antigen, as detected by monoclonal antibody CSLEX1, was studied in 175 specimens of primary colorectal carcinoma from 120 patients who received radical surgery. The positive expression of sialyl Lex was observed in 87 of 120 patients (72.5%). There was no statistically significant association between the negative or positive of sialyl Lex and clinicopathologic factors, excluding Dukes stage and histologic type. The difference between overall 5-year survival of patients with sialyl Lex-negative tumors and that of patients with sialyl Lex-positive tumors (81.2% versus 60.6%) was statistically significant (P = 0.0263). In proportion to staining intensity that was expressed as a score based on the percentage of the total field stained positive with CSLEX1, 5-year survival of patients indicated a worse outcome (P = 0.0113). The prognostic value was then studied in a Cox regression model. Dukes stage had the strongest association with patient survival, whereas sialyl Lex expression was found to be the second-ranking parameter. When examining the expression of sialyl Lex antigen, as detected by monoclonal antibody CSLEX1, clinically useful information for patient survival after radical resection of colorectal cancer is given.

Prostate cancer. Magnitude of the problem. American College of Surgeons database and epidemiologic study.

The third American College of Surgeons pattern of care survey for cancer of the prostate is underway to document the current methods and means of presentation, diagnosis, and clinical management of patients in the United States. Questions about the geographic distribution and methods of treatment by stage and grade together with patient mix and survival information will be answered from the data collected from more than 950 hospitals across the United States for the period 1984-1990. May 1992 was the final date for submission of data for this survey. Prostate cancer continues to be the most common cancer in men, excluding skin cancer. The annual number of patients with this disease reported in the National Cancer Database for 1988 was 26,957, an increase of 9427 cases yearly since the end of the second American College of Surgeons' survey in 1983.