Association of topoisomerase II expression and cancer-specific death in patients with surgically resected clear cell renal cell carcinoma.

e15539 Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 1,380 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/16/1990 and 4/14/2009. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features we employed Kruskal-Wallis tests and for associations with cancer-specific survival we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher MayoSSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001), and this association remained strong after after multivariate adjustment for well-known predictors of RCC aggressiveness. Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.62 95% CI 1.95-3.54; p<0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.48 95% CI 1.56-7.76; p =0.002). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.

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Association of topoisomerase II expression and cancer-specific death in patients with surgically resected clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.446 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 446-446 ◽

Cited By ~ 1

Author(s):

Faithlore Patrice Gardner ◽

Richard Wayne Joseph ◽

Daniel Serie ◽

Tracy W. Hilton ◽

Mansi Parasramka ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Cancer Specific Survival ◽

Risk Of Death ◽

Pathologic Features ◽

Increased Risk ◽

Risk Of Cancer

446 Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 947 patients who underwent nephrectomy to treat clinically localized ccRCC between January 16, 1990, and September 27, 2006. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features, we employed Kruskal-Wallis tests and for associations with cancer-specific survival, we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher Mayo SSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001). Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.31 95% CI 1.64-3.25; p < 0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.09 95% CI 1.29-7.40; p = 0.01). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.

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Loss of BAP1 and PBRM1 protein expression and its association with clear cell renal cell carcinoma-specific survival.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.414 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 414-414 ◽

Cited By ~ 3

Author(s):

Richard Wayne Joseph ◽

Payal Kapur ◽

Daniel Serie ◽

Jeanette Eckel-Passow ◽

Thai Huu Ho ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Protein Expression ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Cancer Specific Survival ◽

Pathologic Features ◽

The Impact

414 Background: While mutations in PBRM1 (~40%) and BAP1(~10%) are associated with clinical outcomes and pathologic features in clear cell renal cell carcinoma (ccRCC), the impact of protein expression of these genes remains unknown. Herein, we quantify PBRM1/BAP1 protein expression in a large cohort of patients with localized ccRCC and associate expression with cancer-specific survival (CSS) and pathologic features. Methods: We utilized the Mayo Clinic Renal Registry and identified 1,416 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/3/1990 and 4/14/2009. We used immunohistochemistry (IHC) to detect PBRM1/BAP1 expression, and a central pathologist blinded to the outcomes scored tumors as either positive or negative. Tumors with heterogeneous or equivocal staining were excluded from this analysis. We generated Cox proportional hazard regression models for associations with ccRCC-SS, and we employed Mann-Whitney U tests for associations with pathologic features. Results: Of the 1,416 samples, 1,232 (87%) were PBRM1/BAP1 positive or negative, 163 (11%) had heterogeneous staining, and 21 (1%) could not be assessed. The distribution and association of PBRM1/BAP1 phenotypes with clinical outcomes are listed in the table below. PBRM1+/BAP1+ tumors have the best CSS, and PBRM1-/BAP1- have the worst. In addition, PBRM1/BAP1 expression strongly associated with the tumor size, stage, grade, and tumor necrosis (p<0.0001). Conclusions: This study is the first and largest to quantify PRBM1/BAP1 protein expression in ccRCC tumors. We were able to quantify PBRM1/BAP1 through IHC in the vast majority of tumors (87%), and PRBM1/BAP1 expression strongly associates with both CSS and pathologic tumor characteristics. Our data confirms our previous findings of the importance of PRBM1/BAP1 in the molecular pathogenesis of ccRCC. [Table: see text]

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MP54-12 DIABETES MELLITUS IS ASSOCIATED WITH AN INCREASED RISK OF CANCER-SPECIFIC MORTALITY AMONG PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA UNDERGOING NEPHRECTOMY

The Journal of Urology ◽

10.1016/j.juro.2014.02.1601 ◽

2014 ◽

Vol 191 (4S) ◽

Author(s):

Sarah Psutka ◽

Christine Lohse ◽

Suzanne Stewart ◽

Matthew Tollefson ◽

Stephen Boorjian ◽

...

Keyword(s):

Diabetes Mellitus ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Increased Risk ◽

Specific Mortality ◽

Cancer Specific Mortality ◽

Risk Of Cancer

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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

European Urology ◽

10.1016/j.eururo.2013.12.017 ◽

2014 ◽

Vol 66 (5) ◽

pp. 929-935 ◽

Cited By ~ 22

Author(s):

Alexander S. Parker ◽

Jeanette E. Eckel-Passow ◽

Daniel Serie ◽

Tracy Hilton ◽

Mansi Parasramka ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Topoisomerase Ii ◽

Clear Cell ◽

Topoisomerase Ii Alpha ◽

Cell Renal Cell Carcinoma ◽

Increased Risk ◽

Independent Marker ◽

Risk Of Cancer

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Diabetes mellitus and risk of cancer-specific mortality among patients with clear cell renal cell carcinoma undergoing nephrectomy.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.516 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 516-516

Author(s):

Sarah P. Psutka ◽

Suzanne B. Stewart ◽

Christine M. Lohse ◽

Matthew K. Tollefson ◽

Stephen A. Boorjian ◽

...

Keyword(s):

Diabetes Mellitus ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Pathologic Features ◽

Increased Risk ◽

Ckd Stage ◽

Risk Of Cancer ◽

The Impact

516 Background: The impact of diabetes mellitus (DM) on outcomes in patients with renal cell carcinoma (RCC) is controversial. Herein, we evaluated the association of DM with survival among patients with RCC. Methods: We reviewed 2,589 patients treated with nephrectomy for sporadic, unilateral, M0 RCC between 1990 and 2008 and compared demographic and tumor characteristics in patients with and without DM (nonDM). Patients with DM (n=313) were matched 1:2 to nonDM patients according to date of surgery, age, smoking status, obesity, ECOG performance status (PS), CKD stage, histological subtype, and nuclear grade. Cancer-specific (CSS) and overall survival (OS) were compared by Kaplan-Meier analysis. The association of DM with outcomes was evaluated with Cox proportional hazards regression models. Results: A total of 313 (12%) patients had DM. DM patients were significantly older at RCC diagnosis, more likely to be obese, and had higher Charlson scores, CKD class, rates of smoking, and worse PS at surgery (p<0.001). Patients with DM were also more likely to have ccRCC (83% vs. 76%, p=0.02) and to undergo nephron-sparing surgery (42% vs. 35%, p=0.01), while other pathologic features were similar in DM and nonDM. Among the 939 matched cases and controls, 463 patients died within a median of 5.5 years after nephrectomy. Median follow-up for survivors was 8.6 years. Five-year CSS was not significantly different among DM patients 84% vs. nonDM patients 87% (p=0.11), although 5-year OS was significantly worse among DM patients (66% vs. 75%; p<0.001). Indeed, even after adjusting for Charlson score, DM patients were noted to have a significantly increased risk of all-cause mortality (HR 1.33; p=0.004). In a subanalysis of patients with clear cell RCC, DM patients were more likely to die from RCC compared with nonDM patients after adjusting for the SSIGN (Stage, Size, Grade, Necrosis) score (HR 1.44; p=0.034). Conclusions: In this surgical cohort, DM was independently associated with decreased CSS among patients with ccRCC and with decreased OS in all RCC subtypes. Further studies to determine the potential biologic mechanism for this interaction are warranted.

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Survival trends of men and women with metastatic clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4566 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4566-4566

Author(s):

Claud Grigg ◽

Sally Trufan ◽

Peter E Clark ◽

Stephen Boyd Riggs ◽

Jason Zhu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Clinical Stage ◽

Tumor Biology ◽

Cell Renal Cell Carcinoma ◽

Risk Of Death ◽

Increased Risk

4566 Background: Clear cell renal cell carcinoma (ccRCC) is nearly twice as common in men as in women, and women with non-metastatic RCC have a better prognosis than men. The etiology for these disparities is not known, though sex-specific differences in risk factor prevalence and tumor biology have been reported. The differential impact of systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), on prognosis in women and men with metastatic ccRCC is not defined. Methods: Clinicopathologic features and survival of patients with clinical stage IV ccRCC were obtained from the National Cancer Database (NCDB). Patients were grouped by date of metastatic diagnosis into three eras that correspond to major advances in systemic therapy: 2004-2005 (pre-TKI), 2006-2014 (TKI), and 2015-2016 (ICI). Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: 15,025 male and 7,100 female patients with metastatic ccRCC were identified. Demographic features were similar between cohorts though females were slightly older (median 64.8 vs 62.7 mo, p < 0.0001), more likely to be black (6.5% vs 6.0%, p = 0.0119) or receiving Medicare benefits (46.4% vs 39.9%, p < 0.0001). In the combined cohort, median overall survival (OS) was higher in patients diagnosed in the ICI vs TKI (23.0 vs 16.5 mo) and pre-TKI eras (14.4 mo, log-rank p < 0.0001). Compared with men of the same age groups, OS was inferior for women age 50-64 yr (median 18.4 vs 21.1mo, p = 0.0084) and > 64 yr (15.3 vs 12.6mo, p = 0.0001), but not < 50 yr (20.3 vs 21.7mo, p = 0.6290). In the ICI era, median OS improved by a lesser absolute but similar relative amount for women compared to men (+5.6mo [+39%] and +7.2mo [+41%]), respectively). After controlling for age, race, Charlson-Deyo score, initial treatment modality, and insurance and socioeconomic status, women remained at increased risk of death in both the ICI era (HR 1.12 [95% CI 1.04-1.22], p = 0.004) and the TKI era (HR 1.08 [1.04-1.12], p < 0.001). Conclusions: Women with metastatic ccRCC have a worse prognosis than men which is not explained by demographic differences. This disparity is observed in both the TKI and ICI eras. This finding contrasts with previous studies suggesting women with localized RCC have a favorable prognosis compared with men. Further investigation into the sex-specific biology of metastatic ccRCC is warranted.

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