Abstract
Background
African American (AA) patients with renal cell cancer (RCC) have historically had inferior survival compared to Caucasian patients. Recent studies suggest the survival disparity between races may be worsening since the advent of targeted therapies for RCC. This study examines survival rates of AA and Caucasian patients with advanced RCC over time to determine if a disparity in survival persists in the targeted therapy era.
Methods
We identified patients with stage IV RCC in the National Cancer Data Base (NCDB) and compared survival between AA and Caucasian patients in the time periods before (1998-2004) and after (2006-2011) the advent of targeted therapy.
Results
48,846 patients were identified and 10% were AA. 3-year survival of both AA and Caucasian patients improved between the two time periods (p<0.01 for both) with no interaction of race on improvement in survival over time (p=0.15). The adjusted hazard ratio (HR) for death for AA compared with Caucasians was 1.13 (95% CI 1.08-1.19) in the post-targeted therapy era, which was unchanged from the pre-targeted therapy era (adjusted HR 1.10, 95% CI 1.04-1.15). The adjusted HR was similar when the analysis was restricted to those treated with systemic therapy.
Conclusions
Both AA and Caucasian patients have had a significant improvement in survival since the advent of targeted therapy. However, AA patients maintain a survival disadvantage compared to Caucasians independent of treatment received, potentially related to unmeasured comorbidities, disease burden, or tumor biology.
Keywords: Renal cell carcinoma, race, treatment outcomes, disparities, targeted therapy, delivery of health care
Introduction
Renal cell carcinoma (RCC) is the 8th most commonly diagnosed cancer in the United States with 61,000 new cases and 14,000 deaths estimated in the year 2015.1 Several analyses of the Surveillance, Epidemiology, and End Results (SEER) database suggest that African American (AA) patients with RCC have decreased overall survival compared to Caucasian patients regardless of age, sex, stage, and histologic subtype.2-4 Furthermore, the survival disadvantage of AA patients may be more prominent in the last decade compared with the 1990's,2,5 implying that AA patients have had less benefit from the introduction of targeted therapy than Caucasian patients. Some studies have suggested that the survival disparity seen in AA patients may be related to access to treatment and lower rates of nephrectomy, even among patients with metastatic RCC.3,6,7 However, the differential rates of nephrectomy and survival between races could be related to a number of factors including socioeconomic status, access to care, comorbidities, performance status, disease burden, and potentially tumor biology.
The survival rates for metastatic RCC were stable for many years but have improved since the advent of targeted therapies for RCC.5,8 In 2005, the FDA approved sorafenib, the first vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitor (TKI) for RCC. That approval was closely followed by the approval of several additional targeted agents for advanced RCC including other VEGFR-TKIs as well as mammalian target of rapamycin (mTOR) inhibitor therapies. It remains unclear how the availability of these novel agents has influenced the racial disparity in survival in advanced RCC, or if the survival of AA patients with advanced RCC has improved as much as that of Caucasian patients.
Our study utilizes a large national database to assess if the advent of targeted therapy has changed the disparity in survival between AA and Caucasian patients. To that end, we asked whether the survival of AA patients with advanced RCC has improved since the implementation of targeted therapy, and how any improvement in survival compares to that seen in Caucasian patients.
Methods
The National Cancer Data Base (NCDB) is a nationwide hospital-based oncology outcomes database that captures approximately 70% of all newly diagnosed cancer cases in the United States in over 1500 hospitals.9 The NCDB is a joint project of the American Cancer Society and the Commission on Cancer (CoC) of the American College of Surgeons. Available data in the NCDB include patient demographics, facility information, tumor characteristics, receipt of treatment, and outcomes. The data used in the study are derived from a de-identified NCDB file and therefore the study was approved for exempt status by the University of North Carolina Institutional Review Board. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators.
The NCDB was queried for all patients with stage IV RCC diagnosed between 1998 and 2011. All included patients had stage IV disease at the time of diagnosis. Patients were included in the analysis if race was designated as Caucasian or AA. Patients were categorized into two cohorts based on year of diagnosis. Patients diagnosed between 1998 and 2004 were defined as the “pre-targeted therapy” group since diagnosis occurred prior to the widespread use of targeted therapy in advanced RCC. Patients diagnosed between 2006 and 2011 were defined as the “post-targeted therapy” group. Patients diagnosed in 2005 were not included because the use of targeted therapy was more limited in this time period (Figure 1). Survival outcomes data was evaluated in 2014 in this dataset, and therefore maximum follow-up for the 2011 cohort was 3 years.
Figure 1.
Rates of systemic therapy use from 1998-2011 in Caucasian and African American patients with advanced RCC
Demographic variables included age, gender, race, education, household income, insurance status, and comorbidity score. Per the NCDB, education was defined as the percentage of adults in the patient's zip code who did not graduate from high school and was categorized as ≥29%, 20-28.9%, 14-19.9%, and less than 14%. Household income was defined as median household income in each patient's zip code and was defined as $46,000 or more, $35,000-45,999 and less than $35,000. Insurance status was categorized as private, Medicare, managed care, Medicaid or other government, or uninsured. Comorbidities were estimated using the Charlson-Deyo comorbidity index with score of 0 (no comorbid conditions), 1, or ≥2 per the NCDB.10 The facility type in which each patient was treated was categorized into three categories: community-based practices, comprehensive community cancer centers, and academic or research programs.
Staging was defined by the American Joint Committee on Cancer (AJCC) TNM stage criteria based on pathologic stage, if available, or clinical stage if pathologic stage was unavailable. Histology was defined as clear cell, papillary, chromophobe, or unknown. Grade was defined as 1 (well-differentiated) through 4 (undifferentiated). Patients were defined as having received a nephrectomy if they had received a complete, total, simple, radical or any nephrectomy in the NCDB, as well as nephrectomy NOS. Targeted therapy, including receptor TKIs targeting the VEGF pathway and mTOR inhibitors, are categorized in the NCDB as chemotherapy. The NCDB does not annotate type of chemotherapy received, and therefore we defined receipt of systemic therapy as including both targeted therapy and cytotoxic chemotherapy with presumably low rates of cytotoxic chemotherapy use due to low efficacy in RCC. Receipt of systemic therapy does not include immunotherapy.
Statistical Analysis
Chi-square tests were used to analyze differences between races for categorical variables, and a t test was used to compare age. For each year between 1998 and 2011, rates of systemic therapy use were compared between races using chi-square tests. The Kaplan-Meier method was used to estimate survival times, including survival probabilities at 3 years and 5 years, and the Log-rank test was used to compare differences in survival between time periods, separately by race. Survival time was calculated from the date of diagnosis to date of last contact or death. Multivariable Cox regression models were used to compare differences in survival by race, separately for each time period, while controlling for potential confounders; hazard ratios for death are reported. Both receipt of nephrectomy and receipt of systemic therapy were treated as time-varying covariates in the models in order to control for time to initiation of systemic therapy and time to nephrectomy. All statistical tests were two-sided and a p-value of <0.05 was considered to be statistically significant. SAS v9.4 statistical software was used for all analyses (Cary, NC).
Results
48,846 patients with stage IV RCC were identified in the NCDB diagnosed from 1998-2004 and 2006-2011. 90% of these patients were Caucasian and 10% were AA. Demographics of the population by race are listed in Table 1. AA patients were younger than Caucasian patients (p<0.01). AA patients were more likely to be female, uninsured or Medicaid/other government insured, and treated in an academic or research facility (p<0.01 for all). AA patients were also more likely to have papillary histology and less likely to undergo a nephrectomy (p<0.01 for both). AA patients were more likely to have distant metastatic disease (p<0.01). The difference in comorbidity score between races was not significant (p=0.06).
Table 1.
Baseline characteristics of patients with advanced RCC by race (n=48,846)
| Characteristic | Caucasians (n=43,928) | African Americans (n=4,918) | p value |
|---|---|---|---|
| Age, mean (SD) | 65 (12) | 60 (14) | <0.01 |
| Sex, male | 64.3% | 61.8% | <0.01 |
| Median household income | |||
| >= 46K | 37.4% | 18.1% | |
| 36K-45,999 | 30.2 | 22.1 | <0.01 |
| <35K | 32.3 | 59.9 | |
| Primary payer | |||
| Private insurance | 42.3% | 35.7% | <0.01 |
| Medicare | 47.0 | 41.9 | |
| Managed Care | 1.0 | 1.4 | |
| Medicaid/federal | 5.5 | 12.9 | |
| Not insured | 4.2 | 8.1 | |
| Facility Type | |||
| Community practice | 10.8% | 8.3% | <0.01 |
| Comprehensive community cancer center | 51.6 | 41.6 | |
| Academic/research program | 37.4 | 50.1 | |
| Charlson Comorbidity Score | |||
| 0 | 71.9% | 70.4% | |
| 1 | 20.1 | 20.5 | 0.06 |
| 2 | 8.0 | 9.1 | |
| Pathologic grade | |||
| 1 (well-differentiated) | 1.9% | 2.0% | <0.01 |
| 2 (moderately differentiated) | 9.7 | 8.1 | |
| 3 (poorly differentiated) | 25.5 | 24.1 | |
| 4 (undifferentiated) | 12.3 | 9.0 | |
| Unknown | 50.6 | 56.7 | |
| Histology | |||
| Clear cell | 72.3% | 69.0% | <0.01 |
| Chromophobe | 0.5 | 0.5 | |
| Papillary | 2.4 | 5.9 | |
| Unknown | 24.8 | 24.6 | |
| Distant metastatic disease (M1) | 70.4% | 74.6% | <0.01 |
| Nephrectomy Performed | 43.1 | 33.2 | <0.01 |
| Systemic therapy received | 31.6 | 31.6 | 0.97 |
Abbreviations: SD, standard deviation
Patients in the post-targeted therapy period were much more likely to receive systemic therapy than patients in the pre-targeted therapy period (47% vs 17%, p<0.01). Systemic treatment increased dramatically with time but rates of implementation did not differ by race (p≥ 0.08 for each year) (figure 1). A similar percentage of Caucasian and AA patients received systemic therapy overall (p=0.97). However, AA patients were slightly less likely than Caucasian patients to receive systemic therapy in the post-targeted therapy period (46% vs 48%, p=0.04).
The 3-year and 5-year survival of all patients with advanced RCC improved significantly between the pre-targeted therapy period and the post-targeted therapy period with an improvement of 1.4 months for Caucasians and 0.8 months for AA patients (p<0.01 for both)(table 2). Median follow-up was 7.0 years for the pre-targeted therapy period and 2.6 years for the post-targeted therapy period. There was no significant interaction between race and time period on survival (p=0.15). In order to control for access to care which has been postulated as a reason for disparate survival rates in the past, we then restricted the survival analysis to patients that actually received systemic therapy. Among these patients, survival rates were higher than in the total population, and there remained a statistically significant improvement in survival over time for both Caucasians and AA. When the survival analysis was further restricted to only those that received systemic therapy and had clear cell histology, the improvement in survival over time in AA patients lost statistical significance for AA (p=0.06), although the sample size was drastically reduced in this subset. The magnitude of the benefit was roughly similar between the two groups with Caucasians having a 1.9 month (or 19.2%) improvement in OS between the two time periods and AA having a 1.6 month (or 20.5%) improvement. In those with papillary histology, there was no statistically significant change in survival across time in either race.
Table 2.
Median OS and OS at 3 and 5 years for Caucasian and African American patients with advanced RCC in the pre- and post-targeted therapy eras
| Caucasians | African Americans | |||||
|---|---|---|---|---|---|---|
| All Patients | ||||||
| 1998-2004 (n=22,583) | 2006-2011 (n=21,345) | p value | 1998-2004 (n=2,440) | 2006-2011 (n=2,478) | p value | |
| Median OS (95% CI) | 6.9 mos (6.8-7.1) | 8.3 mos (8.1-8.5) | <0.01 | 5.6 mos (5.1-6.0) | 6.4 mos (6.1-6.9) | <0.01 |
| OS at 3 years (95% CI) | 13.7% (13.3-14.2) | 17.7% (17.2-18.3) | 11.3% (10.1-12.7) | 13.2% (11.8-14.7) | ||
| OS at 5 years (95% CI) | 8.4% (8.0-8.7) | 10.3% (9.8-10.9) | 7.5% (6.5-8.7) | 8.5% (7.1-9.9) | ||
| Patients treated with systemic therapy | ||||||
|---|---|---|---|---|---|---|
| 1998-2004 (n=3,596) | 2006-2011 (n=9.895) | p value | 1998-2004 (n=413) | 2006-2011 (n=1,092) | p value | |
| Median OS (95% CI) | 9.7 mos (9.3-10.1) | 11.0 mos (10.6-11.4) | <0.01 | 8.1 mos (7.0-9.5) | 8.9 mos (8.3-9.8) | 0.04 |
| OS at 3 years (95% CI) | 12.4% (11.3-13.6) | 17.4% (16.5-18.2) | 10.8% (8.0-14.1) | 13.1% (11.0-15.4) | ||
| OS at 5 years (95% CI) | 7.1% (6.2-7.9) | 8.7% (8.0-9.5) | 6.2% (4.1-8.9) | 7.4% (5.6-9.5) | ||
| Patients treated with systemic therapy with clear cell histology | ||||||
|---|---|---|---|---|---|---|
| 1998-2004 (n=2,231) | 2006-2011 (n=6,938) | p value | 1998-2004 (n=263) | 2006-2011 (n=702) | p value | |
| Median OS (95% CI) | 9.9 mos (9.3-10.4) | 11.8 mos (11.4-12.2) | <0.01 | 7.8 mos (6.4-9.6) | 9.4 mos (8.3-10.3) | 0.06 |
| OS at 3 years (95% CI) | 13.7% (12.3-15.2) | 18.8% (17.8-19.8) | 12.2% (8.5-16.5) | 14.6% (11.9-17.5) | ||
| OS at 5 years (95% CI) | 7.8% (6.7-9.0) | 9.2% (8.3-10.1) | 7.4% (4.6-11.0) | 7.9% (5.6-10.8) | ||
Abbreviations: mos, months
p value from the Log rank test comparing survival between time periods, separately for each race
AA patients had decreased overall survival compared to Caucasian patients and the disparity remained relatively stable over time with an unadjusted HR for death of 1.13 (95% CI 1.08-1.18) in the pre-targeted therapy era and HR of 1.18 (95%CI 1.13-1.23) in the post-targeted therapy era (Figure 2). After adjusting for age, sex, income, insurance, type of facility, comorbidity score, grade, histology, presence of distant metastatic disease, nephrectomy status and receipt of systemic therapy, the HR for death in AA compared to Caucasians was 1.10 (95% 1.04-1.15) in the pre-targeted therapy period and 1.13 (95% CI 1.08-1.19) in the post-targeted therapy period. A substantial number of patients in the pre-targeted era had missing comorbidity information and when those patients were excluded from the analysis, the HR remained unchanged (1.08 in pre-targeted therapy era, 1.13 in post-targeted therapy era). In the post-targeted therapy time period, the HR for death remained significant when adjusting for baseline T and N stage (HR 1.14, 95% CI 1.06-1.21). Other factors associated with survival are listed in Table 3.
Figure 2.
Kaplan Meier plot for OS in AA vs Caucasian NCDB patients with advanced RCC in the a) pre-targeted therapy era (1998-2004) and b) post-targeted therapy era (2006-2011)
Table 3.
Adjusted HR for death for factors associated with mortality in the pre- and post-targeted therapy eras in advanced RCC
| 1998-2004 Adjusted* HR | 2006-2011 Adjusted* HR | |
|---|---|---|
| Race | ||
| Caucasians | 1.00 | 1.00 |
| African Americans | 1.10 (1.04-1.15) | 1.13 (1.08-1.19) |
| Age | ||
| <70 | 1.00 | 1.00 |
| >= 70 | 1.26 (1.22-1.31) | 1.29 (1.24-1.34) |
| Sex | ||
| Male | 1.00 | 1.00 |
| Female | 1.05 (1.02-1.08) | 1.04 (1.01-1.08) |
| Median household income | ||
| >= $46K | 1.00 | 1.00 |
| $36K-$45,999 | 1.05 (1.02-1.09) | 1.06 (1.03-1.10) |
| <$35K | 1.07 (1.03-1.11) | 1.12 (1.08-1.16) |
| Primary payer | ||
| Private insurance | 1.00 | 1.00 |
| Medicare | 1.16 (1.12-1.20) | 1.16 (1.11-1.20) |
| Managed Care | 1.00 (0.87-1.16) | 1.19 (1.05-1.36) |
| Medicaid/federal | 1.13 (1.06-1.20) | 1.20 (1.13-1.27) |
| Not insured | 1.27 (1.19-1.37) | 1.18 (1.10-1.27) |
| Facility Type | ||
| Community practice | 1.00 | 1.00 |
| Comprehensive community cancer center | 1.05 (1.01-1.10) | 1.11 (1.05-1.16) |
| Academic/research program | 0.88 (0.86-0.91) | 0.85 (0.82-0.87) |
| Charlson Comorbidity Score | ||
| 0 | 1.00 | 1.00 |
| 1 | 1.12 (1.05-1.19) | 1.12 (1.08-1.16) |
| 2 | 1.24 (1.12-1.38) | 1.29 (1.22-1.36) |
| Pathologic grade | ||
| 1 (well-differentiated) | 1.00 | 1.00 |
| 2 (moderately differentiated) | 0.94 (0.85-1.05) | 0.93 (0.82-1.06) |
| 3 (poorly differentiated) | 1.36 (1.23-1.50) | 1.35 (1.20-1.52) |
| 4 (undifferentiated) | 1.44 (1.29-1.60) | 1.49 (1.32-1.69) |
| Unknown | 1.51 (1.37-1.67) | 2.0 (1.78-2.25) |
| Histology | ||
| Clear cell | 1.00 | 1.00 |
| Chromophobe | 0.76 (0.61-0.96) | 0.77 (0.62-0.94) |
| Papillary | 0.94 (0.84-1.04) | 0.95 (0.87-1.03) |
| Other/Unknown | 1.34 (1.29-1.38) | 1.48 (1.43-1.53) |
| Distant metastatic disease (M stage) | ||
| 0 | 1.00 | 1.00 |
| 1 | 1.56 (1.51-.161) | 1.40 (1.34-1.45) |
| Nephrectomy Performed | ||
| No | 1.00 | 1.00 |
| Yes | 0.83 (0.79-0.86) | 0.76 (0.73-0.80) |
| Systemic therapy received | ||
| No | 1.00 | 1.00 |
| Yes | 0.90 (0.67-1.22) | 0.93 (0.70-1.24) |
Adjusted for all listed covariates, including nephrectomy status and receipt of systemic therapy as time-varying covariates
Discussion
Our study shows that both AA and Caucasian patients with advanced RCC have had a significant increase in rates of systemic treatment with an accompanying improvement in survival since the advent of targeted therapy. However, a disparity in survival persists between races even after controlling for treatment differences such as nephrectomy status and receipt of systemic therapy. This suggests that the racial disparity in survival may be related to factors unaffected by the implementation of targeted therapy and that treatment bias does not explain the survival disparity.
Our survival analysis is in agreement with other recently published studies in advanced RCC. Pal et al published a SEER analysis of patients with metastatic RCC and found an improvement in median disease-specific survival (DSS) between 1992 and 2009, with shorter survival of AA patients compared with Caucasian patients.6 Vaishampayan et al also showed an improvement in overall survival over time, although the change in survival of AA patients over the same time period was not significant.5 Therefore to our knowledge, our study is the first to show an overall survival improvement of AA patients since the advent of targeted therapy. The proportion of patients receiving systemic therapy for advanced RCC did not approach the most recent levels until 2007, suggesting that the Vaishampayan paper post-targeted therapy group from 2005-2008 may have analyzed survival too early in the history of targeted therapy to see an effect. The difference in improvement of AA patients between our study and the prior study could also be potentially explained by differential rates of implementation between AA and Caucasians, but we did not see evidence of this in our analysis. We believe that the lack of statistical significance of the improvement in survival of African Americans who received systemic treatment and with clear cell histology is related to the drastically reduced sample size of this population, given the overall similar magnitude of benefit across time in this population.
It should also be noted that the survival rates in our study are lower than expected based on clinical trials of targeted therapy in RCC. Our population had a large proportion of patients with distant metastases at diagnosis compared to the cohort of patients in the Vaishampayan et al analysis (70.8% vs 52.7%, respectively). These findings emphasize the poor survival associated with stage IV RCC in the general population.5,11-13 Among patients who actually received systemic therapy in our analysis, survival rates are similar to those seen in poor risk metastatic RCC trials.14
The cause of the persistent disparity in survival among AA patients compared with Caucasians has not been defined. Several studies have suggested access to care and nephrectomy rates as potential explanations.3,6,7 In order to control for this possibility, we designed our study using the NCDB which is annotated for treatment received. Unlike prior studies, we were able to account for receipt of systemic therapy in our analysis, and found a persistent survival disparity in patients who were treated with systemic therapy. We did find that AA patients were more likely to have distant metastatic disease (M1), which may contribute to the survival disparity and may also suggest a delay in diagnosis in AA patients. While it was not possible to control for timeliness of diagnosis, we did control for presence of distant metastatic disease, as well as time to initiation of systemic therapy and time to nephrectomy. Therefore, our analyses suggest that racial differences in socioeconomic status or access to care are unlikely to explain the findings. Supporting this conclusion is a study by Tripathi et al that retrospectively examined racial disparities in patients with RCC enrolled in clinical trials in an effort to eliminate socioeconomic status and treatment choice as potential confounders. They also found that OS remained statistically shorter for AAs than Caucasians in this setting.4
Therefore, when taken together with prior studies, our study supports that differences in tumor biology other than standard histology could potentially explain these findings. As has been shown in prior reports, we found that AA patients were more likely to have papillary histology than Caucasian patients.15,16 Patients with non-clear cell histology are associated with inferior survival in advanced RCC,17 and we therefore controlled for histology in our analysis. Our rates of non-clear cell histology are slightly lower than expected rates from prior literature, which may be related to the high rate of “unknown” histology designations in our study and could potentially confound our results.18 However, a survival disparity between races exists even within each subtype and this would not fully explain our findings.2
Based on data from The Cancer Genome Atlas, our group recently demonstrated that tumors of AA patients with clear cell RCC are less likely to harbor VHL mutations, have lower RNA expression of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF) associated pathways, and more likely to have the more aggressive clear cell B subtype.19 These differences suggest that AA with clear cell RCC may be less likely to respond to VEGF-targeted therapy and that differences in tumor biology may drive some of the observed survival disparity. Our current study supports the potential role of tumor biology in the racial disparity in survival given that after adjustment for clinical factors, the survival disparity persists between races. It does not, however, support that African Americans have had inferior response to VEGF-targeted therapy. There could be several reasons for this finding. The NCDB does not differentiate between types of systemic therapy received so it may be that the use of mTOR inhibitors or other non-VEGF targeted therapies are driving the survival improvement seen in AA patients. Alternatively, it may be that despite lower rates of VHL mutations and downstream gene expression differences, AA may retain sensitivity to VEGF-targeted therapy. In fact, VHL status and VEGF expression are not reliable predictors of response to VEGF pathway inhibition and VHL loss may be influencing survival rates through a VEGF-independent manner.20,21
There are several limitations to our current analysis. Inherent to any study utilizing the NCDB, the data presented here are not truly population-based, as patients are drawn from certain designated Commission on Cancer hospitals. Despite this, we feel this analysis is likely reflective of the true trends in outcomes because these data encompass the majority of diagnosed cases in the US over this time period and come from a wide array of settings. A strength of this study is the ability to restrict the analysis to patients who actually received systemic therapy. However, we were unable to confirm that the systemic therapy received was in fact targeted therapy or which agent was used. We were also unable to confirm actual usage, as it is possible that tolerability could differ between races. The NCDB also does not collect data on performance status and the Charlson Comorbidity Index is a validated, but not comprehensive, tool to assess comorbidities. We also could not account for all the variables in the commonly used prognostic scoring systems in metastatic RCC due to inherent NCDB limitations such as lack of reporting on laboratory values. Therefore, unmeasured confounders could influence our results, although we attempted to minimize this possibility by restricting our analysis to the treated patients who were more likely to have similar performance status and comorbidities.
We conclude that targeted therapy has been effective in improving survival in both AA and Caucasian patients with advanced RCC. However, there remains a survival disparity between races that is independent of other prognostic factors and nephrectomy status, and exists even within patients who were actually treated with systemic therapy. Further studies should focus on the differences in tumor biology between races, which may be independent of the VEGF pathway given the lack of differential survival improvement between races on a population-level.
Acknowledgments
Funding:
This work has no specific funding source, although author research funding is as follows: B.K. was supported through the Department of Defense (Grant No. CA120297). M.E.N. was supported in part by the American Cancer Society (Grant No. MRSG-13-154-01-CPPB) and the Urology Care Foundation/Astellas. A.B.S. was supported in part by the National Center for Research Resources, the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant No. KL2TR000084, and PCORI. W.Y.K. was supported in part by the AACR Kure It and is a Damon Runyon Merck Clinical Investigator. M.I.M. has received research funding from Pfizer, BIND Therapeutics, Dendreon, Exelixis, Johnson & Johnson, Astellas Pharma, Mirati Therapeutics, Merck, and Cerulean Pharma, Inc.
Footnotes
Author Contributions: T.L.R., W.Y.K., and M.I.M. were involved in conception and design, analysis and interpretation of data, drafting and revising the manuscript, and final approval of the manuscript. A.M.D., B.K., and M.E.N. were involved in analysis and interpretation of data, drafting and revising the manuscript, and final approval of the manuscript. A.B.S. was involved in conception and design, drafting and revising the manuscript, and final approval of the manuscript.
Conflict of Interest: The authors have no other conflicts of interest to disclose.
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