Thompson, R. Houston

503 Background: We evaluated temporal patterns in the utilization of systemic therapy among patients undergoing cytoreductive nephrectomy (CN) for metastatic Renal Cell Carcinoma (mRCC) from a large national cancer registry and assessed patient characteristics associated with receipt of systemic treatment. Methods: We reviewed the National Cancer Database to identify patients with stage IV RCC who underwent CN between 1998-2010. Systemic therapy was defined as any treatment with immunotherapy and/or chemotherapy (including targeted agents). We evaluated the association between clinicopathologic features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations, and assessed the interaction of treatment with time, stratified as immunotherapy (1998-2004) versus targeted-therapy (2005-2010) eras. Results: Of 22,409 patients with mRCC undergoing CN, 8,830 (39%) received systemic therapy. Receipt of systemic therapy increased from 32% in 1998 to 49% in 2010 (p<0.001), largely due to increased utilization of chemotherapy (13.9% vs. 46.7%; p<0.001). Following adjustment, increasing patient age (51-60 years: OR 0.82 [CI 0.73-0.92]; 61-70 years: OR 0.67 [CI 0.59-0.76]; ≥71 years: OR 0.36 [CI 0.31-0.43]), as well as coverage with Medicaid (OR 0.61 [CI 0.5-0.74]), Medicare (OR 0.70 [CI 0.62-0.79]), or no insurance (OR 0.75 [CI 0.63-0.91]) were associated with decreased utilization of systemic therapy. Although use of systemic therapy in the elderly (≥71 years) and in patients with Medicare/Medicaid remained lower throughout the study period, each of these cohorts was significantly more likely to receive systemic treatment in the targeted versus immunotherapy era (all p values <0.05). Conclusions: Utilization of systemic therapy among patients undergoing CN has increased over time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology for lack of treatment is likely multifactorial, the potential health policy implications of continued disparities in care warrant further investigation.

498 Background: Surgery for RCC patients with IVC thrombus above the hepatic veins is complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with adverse surgical outcomes. The objective of this study is to determine the preoperative predictors of major complications and 90 day mortality after surgery in RCC patients with IVC thrombus above the hepatic veins. Methods: Records were reviewed of all RCC patients with IVC tumor thrombus above hepatic veins who had surgery from 1/2000 to 12/2012 at Mayo Clinic, MD Anderson, UT Southwestern and the University of Wisconsin. Major complications were recorded were defined as 3A or greater according to the Clavien- Dindo system within 90 days of surgery. Univariate and multivariate (MV) analyses were used to evaluate associations of preoperative clinical, pathological or laboratory variables with risk of major complications or 90-day mortality. Results: A total of 162 patients were identified for study (thrombus level 3,4 in 69 and 93 patients, respectively, according to Neves classification). Cardiopulmonary bypass was used in 60/162 (37.5%), while 40 (24.7%) patients underwent pre-operative angioembolization. Major complications were reported in 55 (34.0%) patients, with the most common being respiratory (12.4%), hematologic (9.2%) and cardiac (8.6%). On MV analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with an increased risk of major complications. Mortality was reported in 17 (10.5%) patients within 90 days after surgery. On MV analysis, ECOG performance status and low serum albumin were independently associated with increased risk of 90 day mortality. Conclusions: Contemporary perioperative mortality and major complication rates for RCC patients with upper level thrombus are 10 and 34%, respectively. ECOG PS >1 and low serum albumin are associated with an increased risk of perioperative mortality, and should be considered when selecting patients for neoadjuvant systemic therapy trials.

402 Background: The American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) are highly utilized sources for surveillance strategies following surgical treatment for renal cell carcinoma (RCC). However, the duration of follow-up may be inadequate to capture the majority of recurrences. Herein, we assess the ability of these guidelines to effectively capture recurrences of RCC following primary surgical resection. Methods: We reviewed our institutional database of 3,725 patients treated with radical or partial nephrectomy for M0 sporadic RCC between 1970-2008. For comparison to the AUA guidelines, patients were stratified into low risk following partial nephrectomy (LRp) or radical nephrectomy (LRr) = pT1N0, and moderate/high risk (M/HR) = pT2-4 N0-1. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods given for site-specific recurrence: AUA—LRp: 3yrs for all sites; LRr: 1yr for abdominal and 3yrs for chest/bone/other sites; M/HR: 5yrs for all sites; NCCN—6 months for abdominal/chest sites and 5yrs for bone/other sites. Results: Of the 3,725 patients, 2721 (73.1%) underwent radical nephrectomy, 2,210 (59.3%) were classified as pT1 NX-0 and 2,910 (78.1%) as clear cell RCC. Median postoperative follow-up was 8.9yrs (IQR 5.5-14.2) during which 1,114 (29.9%) patients developed recurrence. Of these recurrences, 760 (68.2%) would have been detected using the AUA guidelines and 432 (38.8%) by NCCN recommendations. Within AUA risk groups, 37.2% recurrences were captured in LRp, 31.4% in LRr and 80.2% in M/HR. Capture of 90% of recurrences in the abdomen and chest would require surveillance for 9yrs and 8 yrs, respectively in LRp, 15yrs and 12yrs in LRr and 11yrs and 10yrs in M/HR. Conclusions: Duration of follow-up recommended by current surveillance algorithms by the AUA and NCCN do not adequately capture many recurrences in RCC following radical or partial nephrectomy. Guidelines using risk stratification and site-specific recurrence parameters to assign length of surveillance may allow providers to better individualize surveillance regimens.

310 Background: The European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) provide general guidelines for bladder cancer (BC) surveillance following radical cystectomy (RC). However, it is unclear how well these guidelines capture recurrences after surgery. Herein, we assess the ability of current guidelines to effectively capture BC recurrence following RC and propose a risk stratified and recurrence site-specific surveillance strategy. Methods: We reviewed our institutional database of 1,800 patients who underwent primary RC between 1980-2007. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods: EAU—5yrs; NCCN—2yrs. Patients were then stratified according to stage: < = pT1Nx-0, > = pT2Nx-0, pN+, and recurrence site: urothelium, abdomen, chest, other. Recurrence free survival estimates for stage groups and recurrence site were assessed with Kaplan Meier models. Results: Of the 1,800 patients, 634 (35.2%) were classified as > pT2Nx-0 and 234 (13%) as pN+ and overall 228 (12.7%) received perioperative chemotherapy. Median postoperative follow-up was 10.6yrs (IQR 6.8-15.2), during which 716 (39.8%) patients developed recurrence. Of these recurrences, 492 (68.7%) would have been detected using the NCCN guidelines and 644 (89.8%) by EAU recommendations. However, ending oncologic surveillance at 5 years would only capture 81.7% of all recurrences for < = pT1Nx-0 patients and 83% of urothelial specific recurrences across all stage groups. Capture of 90% of recurrences, by stage group, in the urothelium, abdomen and chest would require surveillance for 8yrs, 8yrs and 4yrs, respectively in < = pT1Nx-0, 6yrs, 4yrs and 3yrs in > = pT2Nx-0 and 3yrs, 3yrs and 2yrs for pN+ patients. Conclusions: Duration of surveillance recommended for BC following RC by the EAU and NCCN do not comprehensively capture recurrences seen, specifically, in low risk patients and in cases of urothelial recurrence. Guidelines using risk stratification and site-specific recurrence patterns to assign length of surveillance may allow providers to better individualize surveillance regimens.

36 Background: Following radical prostatectomy (RP), 30-40% of patients have adverse pathology and are deemed at high risk for metastatic progression. The objective of this study was to validate the ability of Decipher, a genomic classifier (GC), to improve prediction of metastatic disease progression compared with clinical variables in order to better identify candidates for therapy intensification. Methods: A previously developed 22-feature GC model was validated in a prospectively designed case-cohort study of a clinically high-risk population (i.e., with one or more adverse pathological features) of 1,010 RP patients treated at Mayo Clinic between 2000-2006. A random sample of 20% of the cohort was subjected to microarray analysis and GC scores were generated for 219 patients. The primary endpoint, the c-index for predicting metastatic disease progression (i.e., positive bone or CT scans) was evaluated in a blinded analysis. Cox modeling and decision curve analyses were used to compare the performance of GC to individual clinical variables and prediction models. Results: GC had a c-index 0.79 (95% CI 0.71-0.86) that was significantly better than any single clinical variable. Cumulative incidence curves in the cohort showed that 72% of patients had low GC scores with only 3% and 6% incidence of metastatic disease at 5 and 10 years post RP. In contrast, for the 28% of patients with high GC scores, the cumulative incidence was 17% and 25% at 5 and 10 years post RP. Decision curve analysis showed that the GC model had higher overall net benefit compared to clinical variables over a wide range of ‘decision-to-treat’ thresholds for risk of metastasis. In multivariable modeling with clinicopathologic variables, GC remained the only significant independent predictor of metastasis (HR=1.51, for each 0.1 unit increment, p<0.001). Conclusions: GC can better predict metastatic disease progression compared with clinical variables and may select among patients with adverse pathology a majority that is in fact at low risk for metastasis.

359 Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.

494 Background: Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both rhabdoid and sarcomatoid differentiation are classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We sought to determine the prognostic value of rhabdoid differentiation in comparison to RCC with sarcomatoid differentiation, grade 4 RCC without rhabdoid or sarcomatoid differentiation, and grade 3 RCC. Methods: Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1,758 patients with grade 3 RCC. A urologic pathologist reviewed all specimens to determine the presence of both rhabdoid and sarcomatoid differentiation. Associations of clinical and pathologic features with death from RCC were evaluated using Cox models. Results: Among the 406 grade 4 RCC tumors, 111 (27%) had rhabdoid differentiation and 189 (47%) had sarcomatoid differentiation, although only 28 (7%) demonstrated both rhabdoid and sarcomatoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (HR 0.95, p=0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR 1.63, p<0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than patients with grade 3 RCC (HR 2.45, p<0.001) and grade 3 RCC with necrosis (HR 1.62; p<0.001). Conclusions: This study confirms that RCC with rhabdoid differentiation is appropriately classified as grade 4. However, unlike sarcomatoid differentiation, the presence of rhabdoid differentiation in grade 4 RCC is not associated with an increased risk of death from RCC. Therefore, rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC.

447 Background: Components of the peripheral blood counts (PBC) are associated with poor prognosis in patients diagnosed with non-metastatic clear cell renal cell carcinoma (ccRCC). Related to this, higher tumor expression of programmed death ligand one (PDL1) is also associated with poor ccRCC prognosis. Herein, we utilize a large cohort of patients undergoing nephrectomy for localized ccRCC to evaluate the association of PBC with tumor expression of PDL1. Secondarily, we examine the association of PBC and relapse free survival (RFS) after adjusting for age and PDL1 expression. Methods: Through chart review, we obtained PBC values at time of nephrectomy for patients enrolled in the Mayo Clinic Renal Registry from 1990-2009 who were treated for localized (M0) ccRCC including the following: hemoglobin (HGB), white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophil count (AEC), absolute monocyte count (AMC), and platelets (PLT). We determined tumor PDL1 expression as a continuous variable (% of positive PDL1 tumor cells) using the 5H1 antibody on archived tissues. We analyzed the correlation of PBC values with PDL1 expression as a continuous variable using a linear estimate. To evaluate the association of PBC values with RFS after adjusting for PDL1 expression, we employed multivariate Cox regression models. Results: A total of 706 ccRCC patients had available PDL1 expression and PBC. PDL1 expression was inversely associated with HGB (linear estimate of -0.02, p<0.001) and positively associated with platelets (linear estimate 1.73, p<0.001) whereas there was no association with PDL1 with WBC, ANC, AEC, or AMC. After adjusting for age and PDL1 expression, a higher HGB (HR=0.87, p<0.001), higher ALC (HR 0.68, p=0.003), and higher AEC (HR 0.12, p=0.002) were all associated with improved relapse free survival. Conversely, higher PLT was associated with decreased RFS (HR 1.002, p<0.001). Conclusions: PDL1 expression is associated with decreased HGB and increased PLT at the time of nephrectomy. After adjusting for PDL1 expression and age, higher HGB, ALC, and AEC are associated with improved RFS, while higher platelets are associated with decreased RFS.

420 Background: Cytoreductive nephrectomy (CN) has been associated with significant morbidity, but there is little data identifying patients at increased risk. We evaluated the association of clinicopathologic features with early post-operative complications and prolonged length of stay (pLOS) among CN patients. Methods: We identified 294 patients treated with radical nephrectomy for M1 renal cell carcinoma between 1990 and 2009 at the Mayo Clinic. All complications within 30 days of surgery were reported using standardized methodology according to the Clavien classification. Associations with the presence of any early complication and pLOS (defined as ≥8 days, the top 25th percentile) were evaluated using logistic regression models. Results: Thirty-five (12%) patients experienced at least one early complication and 15 (5%) patients experienced at least one Clavien grade ≥3 early complication. The median LOS was 6 days (IQR 5-7), and 68 (23%) patients had a pLOS. On univariate analysis, liver metastases, symptomatic presentation, intraoperative transfusion, and pathologic nodal stage were significantly associated with both early complications and pLOS (Table). Two multivariate models were constructed. In Model 1 (limited to pre-operative features), only liver metastases (p<0.01) were associated with early complications while liver metastases (p=0.01) and open approach (p=0.02) were associated with pLOS. In Model 2 (all variables included), liver metastases (p=0.01), intraoperative transfusion (p<0.01), and high nuclear grade (p<0.01) were associated with early complications while intraoperative transfusion (p<0.01) and positive nodes (p=0.05) were associated with pLOS. Conclusions: CN was associated with a low incidence of early post-operative complications, particularly Clavien ≥3 complications. Presence of liver metastases and intraoperative transfusion were independently associated with increased risk of both complications and pLOS. [Table: see text]

513 Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.