TY - JOUR
T1 - 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
AU - Parker, Alexander S.
AU - Eckel-Passow, Jeanette E.
AU - Serie, Daniel
AU - Hilton, Tracy
AU - Parasramka, Mansi
AU - Joseph, Richard W.
AU - Wu, Kevin J.
AU - Cheville, John C.
AU - Leibovich, Bradley C.
N1 - Funding Information:
Funding/Support and role of the sponsor: This research was funded by a grant from the National Institutes of Health (NIH) and National Cancer Institute (NCI) [R01CA134466-4]. NIH and NCI participated in the collection, management, analysis, and interpretation of the data in this study.
Publisher Copyright:
© 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - Objective: To evaluate the association of TOPOIIa expression in ccRCC and risk of cancer-specific death following surgery.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.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.
AB - Objective: To evaluate the association of TOPOIIa expression in ccRCC and risk of cancer-specific death following surgery.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.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.
KW - Biologic
KW - Carcinoma, renal cell
KW - Kidney neoplasms
KW - Survival
KW - Tumor biomarkers
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U2 - 10.1016/j.eururo.2013.12.017
DO - 10.1016/j.eururo.2013.12.017
M3 - Article
C2 - 24388441
AN - SCOPUS:84907578775
SN - 0302-2838
VL - 66
SP - 929
EP - 935
JO - European Urology
JF - European Urology
IS - 5
ER -