Higher expression of topoisomerase II alpha is an independent marker of increased risk of cancer-specific death in patients with clear cell renal cell carcinoma

Abstract

Background: Tumor-based biomarkers of outcome for patients with clear cell renal cell carcinoma (ccRCC) remain limited, especially for those with low-risk disease. Type IIa topoisomerase (TOPOIIa) is a well-known biomarker of DNA replication and a target for antineoplastic agents, but it has not been evaluated as a biomarker of ccRCC outcome.

Objective: To evaluate the association of TOPOIIa expression in ccRCC and risk of cancer-specific death following surgery.

Design, setting, and participants: Two independent cohort studies were studied in tertiary referral urology practices in the United States. We identified cohorts of 1378 (analytic) and 279 (validation) patients who underwent nephrectomy for clinically localized ccRCC and had paraffin tumor tissue available. TOPOIIa expression was assessed using immunohistochemistry and scored as the number of positive cells per square millimeter.

Outcome measurements and statistical analysis: Our primary end point was cancer-specific survival (CSS). We evaluated TOPOIIa expression as a continuous variable and dichotomized as low versus high. For associations with CSS, we used Kaplan-Meier curves and Cox regression models.

Results and limitations: In both cohorts, patients who had high TOPOIIa expression were approximately three times more likely to experience ccRCC death than those with low expression (hazard ratio [HR]: 2.75; 95% confidence interval [CI], 2.12-3.56; p=1.79E-14 and HR: 3.45; 95% CI, 1.34-8.88; p=0.0104, respectively). Multivariable adjustment for pathologic features of aggressiveness did not explain these associations, and stratified analysis suggests that the association is more pronounced among patients with low-risk disease as defined by the Mayo Clinic SSIGN (stage, size, grade, and necrosis) score.

Conclusions: Higher TOPOIIa expression is independently associated with increased risk of cancer death among patients undergoing surgery for ccRCC, and the prognostic value is pronounced among patients with low-risk disease. Evaluation of TOPOIIa in ccRCC provides the opportunity to help guide postsurgical surveillance for ccRCC patients as well as inform the design of more targeted clinical trials and novel treatment strategies.

Keywords: Biologic; Carcinoma, renal cell; Kidney neoplasms; Survival; Tumor biomarkers.

Fig. 1

Estimated cancer-specific survival following surgery by dichotomized type IIa topoisomerase expression for 1378 patients with clear cell renal cell carcinoma (analytic cohort). RCC = renal cell carcinoma; TOPOIIa = type IIa topoisomerase.

Fig. 2

Estimated cancer-specific survival following surgery by dichotomized type IIa topoisomerase expression among patients with (a) low, (b) intermediate, and (c) high Mayo Clinic stage, size, grade, and necrosis scores. RCC = renal cell carcinoma; SSIGN = stage, size, grade, and necrosis; TOPOIIa = type IIa topoisomerase.