High-risk Urothelial Carcinoma Research Articles

Commentary on “Impact of statin use on oncologic outcomes in patients with urothelial carcinoma ofthe bladder treated with radical cystectomy.” da Silva RD, Xylinas E, Kluth L, Crivelli JJ, Chrystal J, Chade D, Guglielmetti GB, Pycha A, Lotan Y, Karakiewicz PI, Sun M, Fajkovic H, Zerbib M, Scherr DS, Shariat SF, Department of Urology and Division of Medical Oncology, Weill

PurposeStatins are cholesterol lowering agents used to prevent cardiovascular disease. Evidence suggests a dichotomous effect of statins with cancer inhibiting and promoting properties. To our knowledge the effect of statins on the prognosis of muscle invasive urothelial carcinoma of the bladder remains uninvestigated to date. We tested the hypothesis that statin use impacts oncological outcomes in patients treated with radical cystectomy for urothelial carcinoma of the bladder. Materials and methodsWe retrospectively evaluated the records of 1,502 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant therapy at a total of 4 institutions. Cox regression models were used to determine the association of statins with disease recurrence and cancer specific mortality. ResultsA total of 642 patients (42.7%) were on statins. At a median followup of 34 months 509 patients (33.9%) experienced disease recurrence and 402 (26.8%) had died of urothelial carcinoma of the bladder. Statin users were older (p = 0.003), had a higher body mass index (median 32 vs 28 kg/m(2), p <0.001) and were more likely to have positive soft tissue surgical margins (9% vs 4%, p<0.001). On univariable Cox regression analysis statins, female gender, advanced age, higher body mass index, smoking status, tumor stage, tumor grade, soft tissue surgical margin status, lymphovascular invasion, lymph node metastasis and adjuvant chemotherapy were associated with disease recurrence (p≤0.05) and cancer specific mortality (p≤0.02). On multivariable Cox regression analysis statin use was not associated with either outcome. ConclusionsStatin users were at higher risk for disease recurrence and cancer specific mortality on univariable but not multivariable analysis. These data do not support modification of statin use in patients with high risk urothelial carcinoma of the bladder who will be treated with radical cystectomy.

Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro‐ureterectomy

What's known on the subject? and what does the study add?: Radical nephroureterectomy (RNU), the standard of care treatment for high-risk urothelial carcinoma of the upper tract (UTUC), results in loss of a renal unit. Loss of renal function decreases eligibility for systemic chemotherapies and results in decreased overall survival in various malignancies. The study shows that only a small proportion of patients had a preoperative renal function that would allow cisplatin-based chemotherapy. Moreover, eGFR significantly decreased after RNU, thereby lowering the rate of cisplatin eligibility to only 16 and 52% of patients based on the thresholds of 60 and 45 mL/min/1.73 m(2) , respectively. Taken together with the rest of the literature, the findings of the study support the use of cisplatin-based chemotherapy, when indicated, in the neoadjuvant rather than adjuvant setting. To report (i) the estimated glomerular filtration rate (eGFR) changes in patients undergoing radical nephro-ureterectomy (RNU) for upper tract urothelial carcinoma (UTUC); (ii) the rate of change in eGFR in patients eligible for cisplatin-based chemotherapy; and (iii) the association of preoperative, postoperative and rate of change of renal function variables with survival outcomes. We performed a retrospective analysis of 666 patients treated with RNU for UTUC at seven international institutions from 1994 to 2007. The eGFR was calculated at baseline and at 3-6 months (Modification of Diet in Renal Disease formula (MDRD) and Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EP) equations). The median (interquartile range) eGFR decreased by 18.2 (8-12)% after RNU. A total of 37% of patients had a preoperative eGFR ≥ 60 mL/min/1.73 m(2) , which decreased to 16% after RNU (P < 0.001); 72% of patients had a preoperative eGFR ≥ 45 mL/min/1.73 m(2) , which decreased to 52% after RNU (P < 0.001). The distributions were similar when analyses were restricted to patients with locally advanced disease (pT3-pT4) and/or lymph node metastasis. Patients older than the median age of 70 years were more likely to have a decrease in eGFR after RNU (P < 0.001). None of the renal function variables was associated with clinical outcomes such as disease recurrence, cancer-specific and overall mortality; however, when analyses were restricted to patients who had no adjuvant chemotherapy and did not experience disease recurrence (n = 431), a preoperative eGFR ≥ 60 mL/min/1.73 m(2) (P = 0.03) and a postoperative eGFR ≥ 45 mL/min/1.73 m(2) (P = 0.04) were associated with better overall survival in univariable analyses. In patients who had UTUC, eGFR was low and furthermore, it significantly decreased after RNU. Renal function did not affect cancer-specific outcomes after RNU.

HER2 expression in patients (pts) with surgically resected urothelial cancer at high risk of recurrence screened for the phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy targeting HER2.

292 Background: HER2 overexpression has been suggested as a poor prognostic factor in pts with high-risk urothelial carcinoma (UC). Published data note a wide range of HER2 overexpression in UC, with some reports showing &lt;10% of cases and others exhibiting &gt;50% of cases with ≥2+ HER2 expression by immunohistochemistry (IHC). NeuACT (N10-1; NCT01353222) is a phase 2 trial to determine whether DN24-02, an autologous cellular immunotherapy targeting HER2 based on the same platform used for sipuleucel-T, given as adjuvant therapy following surgical resection can prolong survival (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples from this study. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest scoring system. Results: As of August 2012, tumor specimens from 61 pts have been screened for HER2 expression. Of these pts, 49 (80%; 95% CI: 68–89%) had a HER2 expression score of ≥1+ in the primary tumor, with 27 (44%) having ≥2+ score and 3 (5%) having a 3+ score. Twenty-three pts (38%) also had HER2 expression levels evaluated in tumor from involved lymph nodes. A total of 20 (87%; 95% CI: 66–97%) of these pts had a HER2 expression score of ≥1+ in the lymph nodes, with 12 (52%) having a ≥2+ score and 3 (15%) having a 3+ score. Two pts had primary tumor samples that expressed HER2 but were negative for HER2 expression in the lymph nodes submitted for analysis. Conclusions: Although preliminary, a high frequency (≥80%) of HER2 expression score of ≥1+ in primary tumor and lymph node samples was observed. These data highlight the prevalence of HER2 protein expression in high-risk UC. Furthermore, the HER2 expression data are consistent with previously published data in pts with invasive UC. Clinical trial information: NCT01353222.

Impact of Statin Use on Oncologic Outcomes in Patients with Urothelial Carcinoma of the Bladder Treated with Radical Cystectomy

Statins are cholesterol lowering agents used to prevent cardiovascular disease. Evidence suggests a dichotomous effect of statins with cancer inhibiting and promoting properties. To our knowledge the effect of statins on the prognosis of muscle invasive urothelial carcinoma of the bladder remains uninvestigated to date. We tested the hypothesis that statin use impacts oncological outcomes in patients treated with radical cystectomy for urothelial carcinoma of the bladder. We retrospectively evaluated the records of 1,502 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant therapy at a total of 4 institutions. Cox regression models were used to determine the association of statins with disease recurrence and cancer specific mortality. A total of 642 patients (42.7%) were on statins. At a median followup of 34 months 509 patients (33.9%) experienced disease recurrence and 402 (26.8%) had died of urothelial carcinoma of the bladder. Statin users were older (p = 0.003), had a higher body mass index (median 32 vs 28 kg/m(2), p <0.001) and were more likely to have positive soft tissue surgical margins (9% vs 4%, p <0.001). On univariable Cox regression analysis statins, female gender, advanced age, higher body mass index, smoking status, tumor stage, tumor grade, soft tissue surgical margin status, lymphovascular invasion, lymph node metastasis and adjuvant chemotherapy were associated with disease recurrence (p ≤ 0.05) and cancer specific mortality (p ≤ 0.02). On multivariable Cox regression analysis statin use was not associated with either outcome. Statin users were at higher risk for disease recurrence and cancer specific mortality on univariable but not multivariable analysis. These data do not support modification of statin use in patients with high risk urothelial carcinoma of the bladder who will be treated with radical cystectomy.

External validation of somatic copy number alteration (SCNA) at chromosome 1q23.3 in advanced urothelial carcinoma (UC).

4585 Background: Advanced UC is associated with multiple SNCAs. To identify SCNA predictors of poor survival in advanced UC, we evaluated SCNAs in two cohorts of high-risk urothelial carcinoma of the bladder. Methods: We obtained DNA copy number data from bladder cancer patients in two independent cohorts [Spanish cohort (n= 93, Agilent aCGH 180k array) and Brigham and Women’s/Dana-Farber (BW/DF) cohort (n = 48, Affymetrix OncoScan FFPE Express 2.0)]. For the BW/DF cohort, we acquired copy number information from 30 primary tumors and 33 metastases. For 12 patients, both primary and matched metastases were available. The GISTIC method was used on GLAD segmented data to identify driver copy number lesions, and the NBC algorithm to identify recurrent breakpoints. Cox proportional hazards models were used to estimate the effect of the identified SCNAs on overall survival, defined as time from start of chemotherapy for metastatic disease (Spanish) or from metastatic recurrence (BW/DF). Copy numbers were incorporated in the Cox models as continuous measures. Statistical significance of optimal cutpoints was estimated with permutation tests. Copy number profiles of primary tumors and metastases were compared with hierarchical clustering. Results: Amplification of 1q23.3 was independently associated with overall survival in both cohorts (Spanish cohort: HR 3.98; 95% 1.64-9.67; p &lt; 0.03; C-statistic 0.54, 95% 0.45-0.65. BW/DF cohort: HR 6.28; 95% 1.84-21.4; p &lt; 0.042; C-statistic 0.62, 95% 0.48-0.76). Amplifications at 22q12.2 were enriched in patients who developed metastasis (p &lt; 0.05). A breakpoint analysis identified possible truncations of ITPR1 (Spanish: 15%; BW/DF: 25%) and PRIM2 (Spanish: 31% BW/DF: 12.5%) in large numbers of samples. For primary tumors with matched metastases, we observed that metastases clustered together with their primary tumors. Conclusions: External validation of the 1q23.3 amplification demonstrates the association of this SCNA with poor outcomes in advanced UC; the identification of the target of this copy number gain is ongoing. Gene truncations and their biological significance require further experimental investigation.

Combination of a Novel Gene Expression Signature with a Clinical Nomogram Improves the Prediction of Survival in High-Risk Bladder Cancer

We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder. We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence. Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean ΔC-statistic: 0.14; 95% confidence interval (CI), 0.01-0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (ΔC-statistic: 0.08, 95% CI, -0.04-0.20; P < 0.005). Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting.

Outcomes after adjuvant chemotherapy in the treatment of high‐risk urothelial carcinoma of the upper urinary tract (UUT‐UC)

Urothelial carcinoma of the upper urinary tract (UUT-UC) was a rare, aggressive urologic cancer with a propensity for multifocality, local recurrence, and metastasis. High-risk patients had poor outcomes. Because of the rarity of these tumors, randomized clinical trials and data regarding adjuvant chemotherapy in locally advanced tumors are currently unavailable. Our objective was to assess the effect of adjuvant chemotherapy and the impact of potential prognostic factors on survival in high-risk, postsurgical UUT-UC patients. Using a multi-institutional, international retrospective database, identified were 627 patients with high risk UUT-UCs (pT3N0, pT4N0 and/or N+ and/or M+) who underwent surgical removal. Only patients who received adjuvant chemotherapy were included. Overall, 140 patients (22.6%) with a median age of 67 years were included. The median follow-up was 22.5 months. The 5-year, overall survival for the entire cohort was 43%, the 5-year recurrence-free survival was 54%, and metastasis-free survival was 53% at 5 years. Positive surgical margins were an independent prognostic factor for recurrence (P = .06), cancer-specific mortality (P = .05), and overall mortality (P = .02) of any cause. Adjuvant chemotherapy was not linked with overall or cancer-specific survival in patients with high risk disease (adjuvant chemotherapy [n = 140] vs no treatment [n = 487]) (P >.5). Adjuvant postoperative chemotherapy did not offer any significant benefit to overall survival in our population. Additional data were necessary, and studies enrolling patients at high risk in clinical trials investigating neoadjuvant chemotherapy in conjunction with chemotherapy should have been highly encouraged.

The Effectiveness of Off-Protocol Adjuvant Chemotherapy for Patients with Urothelial Carcinoma of the Urinary Bladder

The role of adjuvant chemotherapy for patients with high-risk urothelial carcinoma of the bladder (UCB) is not well defined. Here we address the value of adjuvant chemotherapy in patients undergoing radical cystectomy for UCB in an off-protocol routine clinical setting. We collected and analyzed data from 11 centers contributing retrospective cohorts of patients with UCB treated with radical cystectomy without neoadjuvant chemotherapy. Patients were grouped into quintiles based on their risk of disease progression using estimates from a fitted multivariable Cox proportional hazards model. The association of adjuvant chemotherapy with survival was explored across separate quintiles. The cohort consisted of 3,947 patients, 932 (23.6%) of whom received adjuvant chemotherapy. Adjuvant chemotherapy was independently associated with improved survival (hazard ratio, 0.83; 95% confidence interval, 0.72-0.97%, P = 0.017). However, the effect of adjuvant chemotherapy was significantly modified by the individual's risk of disease progression such that an increasing benefit from adjuvant chemotherapy was seen across higher-risk subgroups (P < 0.001). There was a significant improvement in survival between the treated and nontreated patients in the highest-risk quintile (hazard ratio, 0.75; 95% confidence interval, 0.62-0.90; P = 0.002). This group was characterized by an estimated 32.8% 5-year probability of cancer-specific survival, with 86.6% of patients having both advanced pathologic stage (> or =T(3)) and nodal involvement. Adjuvant chemotherapy is associated with a significant improvement in survival for patients treated in an off-protocol clinical setting. Selective administration in patients at the highest risk for disease progression, such as those with advanced pathologic stage and nodal involvement, may optimize the therapeutic benefit of adjuvant chemotherapy.

Sequential adjuvant chemotherapy after surgical resection of high‐risk urothelial carcinoma

Despite definitive surgery, the survival of patients with high-risk urothelial carcinoma (UC) is poor. Adjuvant cisplatin-based chemotherapy may be beneficial, but it is restricted by the need for normal renal function (RF). Sequential administration of adjuvant chemotherapy facilitates drug delivery and improves survival in patients with breast cancer. The objective of this study was to evaluate the feasibility and survival impact of adjuvant, sequential chemotherapy in patients with high-risk UC. Fifty patients were treated on 2 simultaneous protocols between 1997 and 2004. The patients on Protocol A (normal RF) received doxorubicin and gemcitabine (AG) followed by paclitaxel and cisplatin. The patients on Protocol B (impaired RF) received AG followed by paclitaxel plus carboplatin. Overall survival (OS) and disease-specific survival (DSS) were compared with a group of 203 contemporary control patients who had similar pathology and RF and who underwent surgery alone. The median follow-up of protocol patients was 6.5 years (range, 0.9-8.6 years), and 25 patients remained alive. The median follow-up of the control group was 4.7 years (0.0-9.2), and 68 patients remained alive. The median OS for patients on Protocol A was greater than that for controls who had good RF (4.6 years vs 2.5 years; P = .03). The median OS for patients on Protocol B was greater than that for controls who had impaired RF (3.4 years vs 2 years; P = .04). DSS for the protocol and matched control groups was similar (good RF: 4.6 years vs 3 years; P = .24; impaired RF: 3.4 years vs 3.3 years; P = .40). In this nonrandomized study, adjuvant, sequential chemotherapy for patients with high-risk UC did not improve DSS over that observed with surgery alone.

PD‐L1 (B7‐H1) expression by urothelial carcinoma of the bladder and BCG‐induced granulomata

PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder. Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment. PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment. Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature.