Using Protein Expressions to Predict Survival in Clear Cell Renal Carcinoma

Abstract

Purpose: An accurate system for predicting survival for patients with solid tumors will allow for better patient selection for both established and novel therapies. We propose a staging system for clear cell variants of renal cell carcinoma (RCC) that includes molecular predictors and standard clinical predictors such as tumor-node-metastasis (TNM) stage, histological grade, and performance status (PS).Experimental Design: A custom tissue array was constructed using clear cell RCC from 318 patients, representing all stages of localized and metastatic RCC, and immunohistochemically stained for molecular markers Ki67, p53, gelsolin, CA9, CA12, PTEN, EpCAM, and vimentin. We present a strategy for evaluating individual candidate markers for prognostic information and integrating informative markers into a multivariate prognostic system.Results: The overall median follow-up and the median follow-up for surviving patients were 28 and 55 months, respectively. A prognostic model based primarily on molecular markers included metastasis status, p53, CA9, gelsolin, and vimentin as predictors and had high discriminatory power: its statistically validated concordance index (Cindex) was found to be 0.75. A prognostic model based on a combination of clinical and molecular predictors included metastasis status, T stage, Eastern Cooperative Oncology Group PS, p53, CA9, and vimentin as predictors and had a C-index of 0.79, which was significantly higher (P < 0.05) than that of prognostic models based on grade alone (C ‫؍‬ 0.65), TNM stage alone (C ‫؍‬ 0.73), or the University of California Los Angeles integrated staging system (C ‫؍‬ 0.76).Conclusions: Protein expressions obtained using widely available technology can complement standard clinical predictors such as TNM stage, histological grade, and PS.

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

“…In breast and gall bladder cancer, patients with high Ep-CAMexpressing primary tumours indeed showed a decreased survival (Gastl et al, 2000;Spizzo et al, 2002;Spizzo et al, 2004;Varga et al, 2004). In clear cell renal cell carcinoma, Ep-CAM expression is infrequent, but patients with Ep-CAM overexpressing tumours show a trend to better survival (Kim et al, 2004;Seligson et al, 2004;Went et al, 2005). A similar correlation was reported for gastric cancers (Songun et al, 2005).…”

“…Epithelial cell adhesion molecule upregulation was an independent marker for poor survival in lymph node positive breast cancers , and gall bladder cancers (Varga et al, 2004). In contrast, improved survival was found associated with Ep-CAM upregulation in clear cell renal cell carcinoma (Kim et al, 2004;Seligson et al, 2004;Went et al, 2005), and gastric cancers (Songun et al, 2005). Here, we observed that survival of patients in the subgroup of moderately differentiated colon cancers also showed a significant positive correlation with Ep-CAM expression.…”

“…Although Ep-CAM is also expressed on normal epithelia, a lower expression there compared to tumour cells (Kim et al, 2004;Osta et al, 2004) and a possible sequestration of Ep-CAM between epithelial cells (McLaughlin et al, 2001) appears to open a therapeutic window. This is supported by the benign safety profile of certain Ep-CAM targeted therapies such as edrecolomab, adecatumumab and vaccination approaches with the autoantigen.…”

Genomics of renal cell cancer — Does it provide breakthrough?

“…5,6 Another TMA study on clear cell RCC from 318 patients suggested, upon a multivariate analysis, that only metastatic status (M=1, or n>0), gelsolin, p53 and metastatic status/CAIX remained significant predictors of survival. 19 In a similar analysis CAIX, vimentin and p53 were statistically significant predictors of survival independent of the clinical variables. 22 A model using comparative genomic hybridization (CGH), a molecular screening method permitting the detection of all DNA losses and gains in a tumor, suggested that there may be at least two subclasses of clear cell RCC: one marked by the events -6q, +17q, +17p, and the other by -9p, -13q, -18q.…”

Proteomic Identification of Interleukin-2 Therapy Response in Metastatic Renal Cell Cancer

“…Although the administration of IL-2 offers the possibility of durable CRs, it is associated with considerable toxicity, while only a small subset of patients respond to therapy 3 . Possible biomarkers for RCC such as carbonic anhydrase-IX (CA IX), Ki67 or PTEN have been published 6,7 . However, there is no reliable single marker available to identify those patients that are more likely to respond to IL-2 therapy, although factors such as regional lymphadenopathy, expression of CA-IX 8,9 , and selective pathologic subtypes have been proposed 10 .…”