Bladder Ca Markers Tied to More Fatal Outcomes (CME/CE)

FG_AUTHORS: MedPage Today

Alterations in a nine-biomarker panel plus smoking intensity predicted survival in patients with bladder cancer, a tissue-based study showed.

The protein panel, combined with the duration of a smoking habit and the volume of daily cigarette use, provided a more accurate prognostic forecast than did clinicopathologic features with (P<0.001) or without (P=0.018) smoking intensity, reported Richard Cote, MD, of the University of Miami, and colleagues in Cancer online.

Three individual biomarkers -- apoptotic protease activating factor 1 (Apaf-1), E-cadherin, and p53 -- also predicted bladder cancer survival, but only E-cadherin remained prognostic after multivariable analysis, they said, adding that increasing smoking intensity was an independent predictor of worse outcome (P<0.001).

"Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually," they explained. "These findings can potentially affect [bladder cancer] management across all stages."

They added that the documenting tobacco-use history is important as "increasing smoking intensity was identified as a unique independent variable that may be associated with poor prognosis. Furthermore, the nine-biomarker panel can be employed as a tool to identify patients in need of more aggressive treatment, independent of routine clinicopathological parameters or smoking history."

Urothelial carcinoma of the bladder arises from alterations in several cellular processes. Efforts to identify alterations in biomarkers associated with urothelial cancer have focused on individual markers or multiple markers within the same cellular process, according to the authors.

More recently, several groups, including Cote and colleagues, have employed biomarker-panel approaches to develop alteration profiles across several signaling pathways involved in bladder cancer. Most of the studies have not accounted for common risk factors' influence on outcome.

Cote's group reported findings from a study that combined the prognostic value of molecular alterations involved in bladder cancer and smoking intensity in a multicenter cohort. The study involved 212 patients with primary bladder cancer diagnosed from 1987 to 1996 and with available archived tissue.

Investigators performed immunohistochemical analysis of tissue specimens from each patient to assess expression of Bax (a tumor antigen), caspase-3, Apaf-1, Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin.

The patients were separated into three categories of smoking intensity:

  • Nonsmokers and patients who smoked ≤20 cigarettes a day for ≤30 years
  • Patients who smoked for 31 to 40 years or >20 cigarettes a day for ≤30 years
  • Patients who smoked for >40 years

Analysis of clinical and histopathologic data showed that age, pathologic stage, surgical modality, and adjuvant therapy had significant associations with survival (P=0.050 to P<0.001).

Increasing pathologic stage was associated with increased frequency of alterations in p53 (P<0.001), E-cadherin (P=0.002), p21 (P=0.022), and Apaf-1 (P=0.047).

Expression of p53, E-cadherin, and p21 was associated with surgery (P=0.046 to P<0.001). The majority of the patients (93%) with nonmuscle invasive tumors had transurethral resection, while 74% of patients with muscle-invasive or nodal metastasized disease underwent radical cystectomy.

Increased smoking intensity was associated with poor outcome (P<0.001). Additionally, a smoking history greater than 30 years was associated with an increased risk of COX-2 alterations (P=0.020) and number of cigarettes smoked daily with Bax expression (P=0.008). Smoking intensity had no associations with the types of alterations in markers.

Alterations in three of the nine biomarkers had significant associations with poor prognosis:

  • Apaf-1 (P=0.005)
  • E-cadherin (P=0.014)
  • p53 (P=0.032)

By multivariate analysis, pathologic stage (P=0.003) and smoking intensity (P<0.001) retained statistically significant associations with outcome, as did E-cadherin (P=0.040).

The patients were grouped according to number of biomarkers with alterations (≤3, 4 or 5, and 6 to 9). Increasing number of biomarkers with alterations was associated with poor prognosis in the overall population (P<0.001) and in separate analyses of patients with muscle-invasive (P=0.001) and nonmuscle-invasive disease (P=0.022).

A survival model based on age, pathologic stage, surgical modality, and adjuvant therapy resulted in an area under the receiver operating characteristic (ROC) curve of 75.6%. Adding smoking intensity to the model significantly improved performance (ROC 80.9%, P=0.012).

The addition of individual biomarkers to the curve increased the model's predictive accuracy, regardless of the biomarker's association with survival. The final model that included clinical-histopathologic factors, smoking intensity, and all nine biomarkers had an ROC of 85.4% (P<0.001 versus base model). The final model also was superior to a model consisting of baseline covariates and smoking intensity (P=0.018).

"Although validation of this panel is needed, this study clearly demonstrates that a multipathway-based approach to constructing rational marker panels holds potential for future [bladder cancer] management," the authors said.

The study was supported by the National Cancer Institute.

The authors reported no conflicts of interest.

Primary source: Cancer
Source reference:
Mitra AP, et al "Combination of molecular alterations and smoking intensity predicts bladder cancer outcome. A report from the Los Aneles Cancer Surveillance Program" Cancer 2013.

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