Presence Of Sarcomatoid Features Research Articles

Is there a minimum percentage of sarcomatoid component required to affect outcomes of localised renal cell carcinoma?

To evaluate and compare the outcomes of patients with localised renal cell carcinoma (RCC) with and without sarcomatoid features and the impact of this on cancer recurrence and survival. The Canadian Kidney Cancer information system database was used to identify patients diagnosed with localised RCC between January 2011 and December 2022. Patients with pT1-T3, n Nx-N0N1, M0 stage and documented sarcomatoid status were included. Patients with sarcomatoid RCC were categorised according to the sarcomatoid component percentage (%Sarc). Inverse probability of treatment weighting scores were used to balance the groups. Cox proportional hazards models were used to assess the impact of sarcomatoid status and %Sarc on recurrence-free and overall survival. A total of 6660 patients (201 with and 6459 without sarcomatoid features) with non-metastatic RCC were included. %Sarc data were available in 155 patients, and the median value was 10%. The weighted analysis revealed that the presence of sarcomatoid features was associated with an increased risk of developing metastasis and increased risk of mortality compared to absence of sarcomatoid features. A %Sarc value >10 was associated with an increased risk of developing metastasis and of mortality compared to a %Sarc value ≤10. Patients with a %Sarc >10 have an increased risk of recurrence and mortality. These patients may benefit from a more stringent follow-up and %Sarc could represent an important criterion in the risk assessment for adjuvant therapy.

Impact of immune checkpoint inhibitor-based combination therapy on palliative care utilization for patients with metastatic renal cell carcinoma.

e24086 Background: Palliative care (PC) is a vital tool in the treatment of patients with metastatic cancer, yet its role in metastatic renal cell cancer (mRCC) is poorly defined. These individuals are increasingly treated with immune checkpoint inhibitor-based combination therapies (ICT). While this approach confers a survival advantage, it comes with additional toxicity that may necessitate PC. Yet, little is known about how ICT impacts PC use for mRCC patients. Here we present real-world data from a single center with an embedded PC provider that evaluates the effect of ICT on PC utilization in mRCC and identifies predictors of PC use for these patients in the modern treatment era. Methods: A retrospective sample of patients who received systemic treatment for mRCC at the Jonsson Comprehensive Cancer Center from 2013 to 2023 was studied. With institutional approval, the electronic health record was queried for patient and disease characteristics. PC referral, engagement, and number of visits were compared between patients who did and did not receive ICT as first-line treatment using Pearson’s chi-squared and two-sample T tests. Predictors of PC utilization were identified using multivariable logistic modeling. Results: 146 patients were included. Mean age at mRCC diagnosis was 62.6 (SD 13.1) and 69.2% were male. The diverse patient sample was 6.4% non-Hispanic Black, 16.4% Hispanic, and 11.4% Asian. The majority (78.8%) had clear cell pathology and 20.5% had sarcomatoid features. More than 50% had more than 3 metastatic sites. More patients received ICT (45.2%) than tyrosine kinase inhibitor monotherapy (39.0%) or other single agents (15.7%). Patients travelled 53.2 (SD 98.0) miles for clinic visits. Overall, 48.6% had a PC referral and 43.8% completed a visit. Of the 46.6% of patients who died, 64.7% had a PC referral and 60.3% had a PC visit. There were no statistically significant differences in PC referral (55% vs. 44%, p = 0.19), PC engagement (50% vs. 39%, p = 0.17), or PC visits (mean 4.6 vs. 3.1, p = 0.19) for patients who received ICT compared to other treatments. Controlling for other variables, statistically significant predictors of PC referral were number of metastatic sites (OR 1.57, p = 0.01), distance from clinic (OR 0.99, p = 0.04), and presence of sarcomatoid features (OR 2.85, p = 0.02). Statistically significant predictors of PC engagement included number of metastatic sites (OR 1.61, p = 0.01). Conclusions: Using single institution real-world data, we found that PC referrals and engagement were driven by disease burden and adverse pathology, but not by treatment regimen. Patients receiving first-line ICT did not demonstrate increased need for PC, while patients who lived farther from clinic were slightly less likely to receive a PC referral. Further study of the role and timing of PC in the modern mRCC treatment era are warranted.

Impact of smoking status (SS) on the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first line (1L) immuno-oncology (IO)-combination regimens: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

4555 Background: Active smoking is associated with decreased overall survival (OS) in patients (pts) with mRCC treated with VEGF targeted therapy (VEGF-TT) (Kroeger N. et al. 2019, IMDC investigators). Conversely, smoking history has been linked to improved OS in pts with advanced non-small cell lung carcinoma (NSCLC) receiving 1L pembrolizumab monotherapy (Popat S. et al., 2022). Herein, we assess the association between SS and outcomes in pts with mRCC treated with 1L standard of care (SOC) IO-based regimens. Methods: Real-world data from the IMDC were collected retrospectively. We included mRCC pts who received either dual IO therapy or IO + VEGF-TT in the 1L setting and known SS at disease diagnosis. Pts were categorized as current, former and non-smokers. The primary outcomes were OS, time to treatment failure (TTF) and objective response rate (ORR) on 1L IO-based regimens. OS and TTF were evaluated using Cox regression, adjusting for age at 1L treatment, IMDC risk groups, BMI, histological type and time from diagnosis to 1L treatment initiation. ORR was compared between the SS groups using a logistic regression, adjusting for the same confounders. Results: 989 pts were eligible and included. 438 (44.3%), 415 (42%), and 136 (13.7%) pts were non-smokers, former, and current smokers at diagnosis, respectively. Median time from diagnosis to initiation of 1L IO-based treatment was 0.47 years (IQR 0.13-2.15). At baseline, there were no significant differences in age at 1L, IMDC risk groups, KPS status, BMI, and presence of sarcomatoid features across the 3 groups (p>0.05). Median follow up was 21.2 months from 1L IO-based treatment initiation. On multivariable analysis, no significant differences in OS, TTF or ORR were seen between the SS groups (p>0.05). Conclusions: To our knowledge, this represents the first and largest effort to evaluate the impact of smoking on clinical outcomes in pts with mRCC treated with IO-based regimens. There was no association between SS at diagnosis and the clinical outcomes of patients with mRCC receiving current 1L SOC IO-based regimens. As opposed to other cancer types (i.e., NSCLC), current or past smoking history did not appear to be predictive of benefit from IO-based therapy. [Table: see text]

Impact of sarcomatoid features on treatment outcomes in metastatic clear cell renal cell carcinoma treated with first-line immunotherapy combinations.

687 Background: The presence of sarcomatoid features in clear cell renal cell carcinoma (cRCC) has historically been associated with poor response to tyrosine kinase inhibitor (TKI) monotherapy and poor overall survival; however, immunotherapy (IO) combination therapies have shown more promise in treating this variant. Front-line anti-PD-1 based IO combinations used in ccRCC include ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted TKI with a PD-1 inhibitor (TKI/IO). Here, we compare progression-free survival after therapeutic 1st-line (PFS) and 2nd-line (PFS-2) in patients who received IO/IO vs TKI/IO combinations as 1st line treatment for metastatic ccRCC, and test whether the treatment effects differ based on the presence or absence of sarcomatoid dedifferentiation. Methods: A retrospective analysis was performed on patients with ccRCC initiating 1st line combination IO at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020. Patient cohorts were defined by 1st line treatment type: IO/IO or TKI/IO. PFS and PFS-2 were estimated using the Kaplan-Meier method. Restricted mean survival time (RMST) was calculated for PFS and PFS-2 in each 1st line treatment group and modelled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of treatment effect among subgroups, sarcomatoid features (presence/absence) is included in the models and an interaction test is performed. Results: Ninety patients (28 sarcomatoid) received 1st line IO/IO and 83 (17 sarcomatoid) received 1st line TKI/IO. Median PFS time is 6.8 months (95% CI: 4.5, 12.2) for IO/IO and 21 months (95% CI: 15, 25) for TKI/IO, p=0.009. After adjusting for IMDC risk, and after 48 months of follow-up, RMST for PFS was 10 months for IO/IO and 24 months for TKI/IO (p=0.02) and RMST for PFS-2 was 20 months for IO/IO and 23 months for TKI/IO (p=0.24). In the RMST model, the interaction between treatment group and presence or absence of sarcomatoid features is not significant for PFS (0.95) or PFS-2 (0.29). Conclusions: For ccRCC patients treated with 1st line IO/IO or TKI/IO, adjusted RMST for PFS was significantly longer for the TKI/IO group, but there was no statistically significant difference in adjusted RMST for PFS-2. Anti-PD-1-based therapy is an effective approach to treating ccRCC with sarcomatoid features. [Table: see text]

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. The panel considered peer-reviewed reports published in English. The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Abstract 6473: Outcomes of advanced renal cell carcinoma with sarcomatoid features post-cytoreductive nephrectomy in clear cell and non-clear cell disease

Abstract Background: Cytoreductive nephrectomy in the setting of treatment of advanced renal cell carcinoma with sarcomatoid features (sRCC) has been highly contested in terms of added benefit for survival. Patients with sRCC are known to have a poor prognosis and more aggressive tumor biology. Methods: Pts with clear cell RCC and non-clear cell RCC underwent cytoreductive nephrectomy in efforts to improve overall survival. Patients were stratified by presence or absence of histologic presence of sarcomatoid features within the tumor samples. Results: Of 167 patients who underwent cytoreductive nephrectomy, 127 had clear cell, of which 14 had sarcomatoid features and 40 had non-clear cell RCC of which 13 had sarcomatoid features. Median age in the cohort was 62 (range, 56.5-69). The cohort included 119 male (71.3%) and 48 (28.7%) female patients. There were 121 patients with >T3 disease, 24 (14.4%) with T2a/b disease, and 22 (13.2%) with T1a/b disease. In all patients with advanced RCC having sRCC had a significant impact on survival post-cytoreductive nephrectomy (30 vs. 8 mos; HR 2.88; p <0.0001). Additionally, good-risk patients had significantly longer OS compared to intermediate- or poor-risk patients (56 vs 30 vs 10 mos; HR 0.21; p = 0.00016). For patients with clear cell RCC, having sRCC present conferred a poorer significant survival (30 vs 9 mos; HR 2.82; p = 0.0035). Patients with non-clear cell sRCC also had significantly worse outcomes compared to those without sarcomatoid features (30 vs 6.5 mos; HR 3; p = 0.009). When sRCC patients were stratified by whether there was >10% or ≤10% present within the sample, there was no significant difference in overall survival (8 vs 8.5; p = 0.32). Conclusions: Sarcomatoid features within tumor histology confers significantly poor prognosis. Patients with sRCC regardless of clear cell vs non-clear cell histology have significantly shorter overall survival. Even among patients with 10% or less sarcomatoid features there was no overall survival benefit to cytoreductive nephrectomy. Based on our findings, there appears to be a limited to no role of cytoreductive nephrectomy, if sRCC is identified on pre-treatment biopsy. Citation Format: Jacob J. Adashek, Alyssa Bilotta, Jad Chahoud, Jiannong Li, Philippe E. Spiess. Outcomes of advanced renal cell carcinoma with sarcomatoid features post-cytoreductive nephrectomy in clear cell and non-clear cell disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6473.

Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC): An international mRCC database consortium (IMDC) analysis.

5068 Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P < 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p < 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p < 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.

MP14-07 PERFORMANCE OF A NEW RISK ASSESSMENT TOOL FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA UNDERGOING CYTOREDUCTIVE NEPHRECTOMY IN THE TARGETED THERAPY ERA: REMARCC SCORE

MP14-07 PERFORMANCE OF A NEW RISK ASSESSMENT TOOL FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA UNDERGOING CYTOREDUCTIVE NEPHRECTOMY IN THE TARGETED THERAPY ERA: REMARCC SCORE

Evolving Paradigms in the Management and Outcomes of Sarcomatoid Renal Cell Carcinoma in the Era of Immune Checkpoint Inhibitors.

Renal cell carcinoma (RCC) is a common cancer that affects a significant number of patients every year around the world. The presence of sarcomatoid features in these tumors is considered a poor prognostic feature. Patients with RCC with sarcomatoid features had significantly worse outcomes when treated with sunitinib, the previous first-line standard of care therapy when compared to patients without such features. Multiple immune checkpoint inhibitors have recently been approved for the treatment of RCC. In this article, we review the literature available on the outcomes of patients with sarcomatoid RCC treated with immune checkpoint inhibitors.

CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features.

4513 Background: Patients (pts) with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognosis and suboptimal outcomes with anti-VEGF targeted therapy. Nivolumab plus ipilimumab (N+I) demonstrated superior objective response rate (ORR) and overall survival (OS) vs sunitinib (S) in previously untreated pts with International Metastatic RCC Database Consortium (IMDC) intermediate/poor (I/P)-risk, clear-cell, advanced RCC in the phase 3 CheckMate 214 trial. Methods: We performed a post-hoc exploratory analysis of N+I vs S in CheckMate 214 sRCC pts. The presence of sarcomatoid features was assessed by keyword search for “sarcomatoid” in pts with available local pathology reports accompanying pretreatment tumor samples. Results: 842 (77%) of 1096 intention-to-treat pts had local pathology reports available, including 112 randomized pts with I/P-risk sRCC (N+I, n = 60; S, n = 52). Baseline characteristics of sRCC pts were balanced between arms. Notably, 47% vs 53% of I/P-risk sRCC pts in the N+I and S arms had tumor PD-L1 expression ≥1% at baseline, which was higher than in all I/P-risk pts (N+I, 26% vs S, 29%). In descriptive analyses performed at a minimum follow-up of 30 months, confirmed ORR and complete response rate per investigator (RECIST v1.1), OS, and progression-free survival (PFS) per investigator were improved with N+I vs S in I/P-risk pts with sRCC (Table). No new safety signals were seen in sRCC pts. Conclusions: In this post-hoc descriptive subgroup analysis of CheckMate 214, N+I demonstrated promising efficacy and prolonged survival vs S, with consistent safety, in previously untreated, I/P-risk, advanced clear-cell RCC with sarcomatoid features. Prospective studies of N+I that include pts with sRCC are ongoing. Clinical trial information: NCT02231749. [Table: see text]

The UCLA Histo-Genetic Risk Classification (U-HGRC) to predict outcomes of localized clear cell renal cell carcinoma.

627 Background: Thirty percent of patients with localized clear cell renal cell carcinoma (ccRCC) will ultimately develop recurrence (local or metastatic) after nephrectomy. Current risk stratification systems still misclassify patients. We have developed a novel classification integrating cytogenetic findings to better stratify the risk of recurrence and overall survival (OS) after surgery for localized ccRCC. Methods: A total of 646 patients from UCLA with ccRCC and tumor cytogenetic analysis, were included in this study. After a selection of histologic parameters using logistic regression and cytogenetic parameters using principal component analysis a CHAID decision tree and Kaplan Meier analysis were used to build the UCLA Histo-Genetic Risk Classification (U-HGRC). Survival analyses of the model were validated on two random samples of 323 patients. Recurrence was defined as any local recurrence or development of new metastasis after surgery. Results: The T-stage, tumor size, presence of sarcomatoid features, gain of chromosome 5q, loss 10q, or loss X/Y were used to stratify the risk of recurrence of ccRCC into three U-HGRC groups of low (1), intermediate (2) or high-risk (3). After a mean follow-up of 55 months, risk of recurrence (HR = 2.44, p = .001 for U-HGRC 2; HR = 9.90, p < .0001 for U-HGRC 3), disease-free survival (DFS) (Log-rank p < .0001), risk of death (HR = 1.72, p = .033 for U-HGRC 2; HR = 4.74, p < .0001 for U-HGRC 3) and OS (Log-rank p < .0001) were significantly different between groups. These findings were validated on two random samples. For high-risk group, median DFS and OS were 2.7 and 6.3 years, respectively. The 5-year risks of recurrence for U-HGRC group 1, 2 and 3 were 9%, 25% and 62%, respectively. The AUC of the model was significantly improved comparing to the current UISS system (0.72 for U-HGRC vs 0.65 for UISS, p = .008) with an accuracy of 82.8% for the U-HGRC high-risk group. Conclusions: The U-HGRC, which integrates genomic alterations with clinical and pathologic features, allowed a better stratification of recurrence risk and overall survival that could help to select appropriate patients for surveillance and adjuvant therapy protocols.

Categorization of gene expression subtypes in clear cell renal cell carcinoma with sarcomatoid features.

519 Background: Presence of sarcomatoid features in Renal Cell Carcinoma (sRCC) tumors signals aggressive clinical behavior and poor prognosis compared to Clear Cell Renal Cell Carcinoma (ccRCC). However, the underlying gene expression patterns of sRCC are poorly understood. We sought to categorize ccRCC and sRCC gene expression subtypes and compare survival outcomes, as well as evaluate whether sRCC gene expression patterns are similar to non-renal sarcomas. Methods: We identified 511 ccRCC cases, of which 36 had a sarcomatoid component from The Cancer Genome Atlas. Enrichment analysis was used to measure associations between gene expression signatures for soft tissue sarcomas and expression profiles of sRCC and ccRCC cases measured by RNA-Seq. The resulting scores were used to identify distinct patient groups using K-means clustering. Overall survival (OS) was evaluated by Kaplan-Meier, log rank, and Cox regression methods. Results: Our analysis identified 4 distinct clusters that differ in enrichment for soft-tissue sarcoma gene expression profiles. The clusters showed significantly different OS distributions (p-value<0.001 log rank). Most sRCC cases (69%) segregated into a single cluster with the worst prognosis. Among ccRCC cases, 57% of patients with higher levels of sarcoma signature enrichment were associated with a shorter OS, which is independent of tumor stage. 5-year/median OS survival estimates for ccRCC cases in the 4 clusters, by increasing levels of sarcoma profile enrichment, were 83%/NR, 75%/NR, 67%/90.9 mo, and 49%/56.7 mo. We also validated existence of these clusters in another sRCC cohort (Sircar 2015). Conclusions: We identified strong associations between sarcoma expression signatures and gene expression profiles of sRCC. We also found that 57% of morphologically non-sRCC cases demonstrate enrichment for sarcoma expression signatures, and these patients have worse OS than their non-sarcoma enriched ccRCC counterparts. The presence of sarcoma expression signatures has not been previously evaluated in RCC. These signatures portend poor survival and may be clinically actionable, as they describe unique subtypes of RCC that may not correspond to histologic characterization.

Outcomes of patients (pts) with renal cell carcinoma and sarcomatoid dedifferentiation (sRCC) treated with nephrectomy (Nx) and systemic therapies (T) over three decades: The MD Anderson Cancer Center (MDACC) experience.

534 Background: Pts with sRCC historically have had a poor prognosis. We determined the overall survival (OS) and prognostic factors of pts treated with Nx and T in the cytokine and targeted therapy eras. Methods: This is a retrospective study of pts with sRCC who had Nx and received T at MDACC in the cytokine era (1987-2005) or the targeted therapy era (2006-2015). OS was measured from time of diagnosis until death of any cause or last follow-up. OS times were estimated by Kaplan-Meier plots and were compared using the log-rank test. Cox regression models were used to determine the association of covariables with OS. Results: Among 199 pts with sRCC (80.9% clear-cell) identified, 167 pts (83.9%) have died at a median follow-up of 8.8 years (median OS 16.5 months; 95% CI: 15.2, 20.9). The 1-year, 2-year, and 5-year OS rates were 67%, 38%, and 14%, respectively. There was no significant difference in OS between pts with clear-cell vs. those with non-clear cell histology. Pts with metastatic disease at initial diagnosis had a significantly shorter OS compared with pts with localized disease (median 12.1 months vs. 23.3 months; p=0.0064). Biopsy of the primary tumor or a metastatic site was able to detect the presence of sarcomatoid features in only 7% of cases. The % of sarcomatoid component (<10%, 10-40%, >40%) in the primary tumor did not impact OS. For first-line (1L) therapy, 77 pts (39%) received targeted agents, and 122 pts (61%) received chemotherapy or cytokines. Although a significant improvement in OS rate was observed at 1 year for pts treated in the targeted therapy era (p = 0.011), this effect was attenuated at year 2 and disappeared at years 3-5 after diagnosis. Conclusions: Pts with sRCC still have poor prognosis with no clear long-term benefit of targeted therapy, underscoring the need to develop more effective systemic therapies for these patients.

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Outcomes and prognosticators in patients with pathologic T4 renal cell carcinoma.

514 Background: The 2010 American Joint Committee on Cancer (AJCC) TNM staging system defines pathological T4 renal cell carcinoma (RCC) as extension of tumor beyond Gerota’s fascia and/or invading contiguously into the adrenal gland. This subset of patients with the highest stage and locally advanced disease demonstrate poor outcomes with an estimated 5 year-survival rate of 20-30%. For this high-risk population, patient selection is imperative for proper patient counseling and to identify patients who would benefit from surgical intervention. Our objective was to study patient outcomes and determine prognostic variables predicting survival in pT4 RCC. Methods: From July 1992 to January 2012, we identified 64 patients at our institution who underwent radical nephrectomy and were found to have pT4 disease. The clinical and pathological variables were studied using univariate analysis to identify prognostic variables predicting survival using the Cox proportional hazards model. Survival plots were estimated using Kaplan-Meier method and survival analysis was performed using log-rank test. Results: Median patient age was 56 years (35-82), and 46 (68.7%) were male. Fifty-two (83%) patients had ECOG Performance Status 0 or 1. At diagnosis, 20 (32%) patients were M0 and 42 (68%) were M1. Median tumor size was 13 cm (5.5-25). Forty-nine (76%) patients had clear cell RCC and 26 (40%) had sarcomatoid features. Forty-seven (73.4%) patients had Fuhrman grade 3 or 4. Twenty-eight (44%) patients were pN0, 16 (25%) were pN1, and 20 (31%) were pNx. On multivariate analysis, the significant predictors of survival (p &lt; 0.05) were M stage at time of nephrectomy, pN stage, performing LN dissection, Fuhrman grade, and presence of sarcomatoid features. Conclusions: Survival in patients with pT4 remains poor. Predictors of survival in pT4 RCC patients include M stage, N stage, LN dissection, Fuhrman grade, and sarcomatoid features. Preoperative identification of patients with pT4 needs refinement, and could help improve patient management and selection for inclusion in neoadjuvant trials.

Outcomes in a Multi-institutional Cohort of Patients Treated With Intraoperative Radiation Therapy for Advanced or Recurrent Renal Cell Carcinoma

This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.

Prognostic Factors Associated with the Response to Sunitinib in Patients with Metastatic Renal Cell Carcinoma

We investigated the prognostic clinicopathologic factors associated with overall survival (os) and progression-free survival (pfs) in the once-daily continuous administration of first-line sunitinib in a consecutive cohort of Turkish patients with metastatic renal cell carcinoma (rcc). The study enrolled 77 Turkish patients with metastatic rcc who received sunitinib in a continuous once-daily dosing regimen between April 2006 and April 2011. Univariate analyses were performed using the log-rank test. Median follow-up was 18.5 months. In univariate analyses, poor pfs and os were associated with 4 of the 5 factors in the Memorial Sloan-Kettering Cancer Center (mskcc) score: Eastern Cooperative Oncology Group performance status of 2 or higher, low hemoglobin, high corrected serum calcium, and high lactate dehydrogenase. In addition to those factors, hypoalbuminemia, more than 2 metastatic sites, liver metastasis, non-clear cell histology, and the presence of sarcomatoid features on pathology were also associated with poor pfs; and male sex, hypoalbuminemia, prior radiotherapy, more than 2 metastatic sites, lung metastasis, nuclear grade of 3 or 4 for the primary tumour, and the presence of sarcomatoid features were also associated with poorer os. The application of the mskcc model distinctly separated the pfs and os curves (p < 0.001). Our study identified prognostic factors for pfs and os with the use sunitinib as first-line metastatic rcc therapy and confirmed that the mskcc model still appears to be valid for predicting survival in metastatic rcc in the era of molecular targeted therapy.

Improved survival in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy in the era of targeted therapy

We aimed to review our clinical experience of cytoreductive nephrectomy for patients with metastatic renal cell carcinoma (mRCC) and to identify factors associated with postoperative prognosis in these patients. This study included a total of 164 Japanese patients with mRCC who underwent cytoreductive nephrectomy and subsequently received immunotherapy and/or molecular-targeted therapy between 2000 and 2010. Baseline characteristics of the 164 patients were as follows: median age was 66 years; metastatic sites included the lung in 133 (81.1 %), bone in 44 (26.8 %), and other in 37 (22.6 %); and 34 (20.7 %), 106 (64.7 %), and 24 (14.6 %) patients were classified into favorable, intermediate-risk, and poor-risk groups, respectively, according to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model. As postoperative systemic therapy, 80 patients (48.8 %) were treated with immunotherapy alone; the remaining 84 (51.2 %) received molecular-targeted agents irrespective of previous treatment with immunotherapy. Median overall survival of these 164 patients was 25.8 months. Univariate analysis identified the MSKCC risk classification, preoperative C-reactive protein (CRP) level, metastatic site, nodal involvement, presence of sarcomatoid features, histological subtype, and introduction of molecular-targeted agents as significant predictors of overall survival, among which only the preoperative CRP level and introduction of molecular-targeted agents appeared to be independently associated with overall survival. Treatment with molecular-targeted agents following cytoreductive nephrectomy may contribute to improve the survival of patients with mRCC compared with immunotherapy alone, and it may be important to employ an aggressive systemic treatment for patients with an increased preoperative value of CRP.

Outcomes for a multi-institutional cohort of patients treated with intra-operative radiation therapy for advanced or recurrent renal cell carcinoma.

442 Background: For patients with advanced or locally recurrent (LR) renal cell carcinoma (RCC), the role of intra-operative radiation therapy (IORT) remains controversial. We analyzed outcomes in a multi-institutional cohort of patients with RCC who received IORT. Methods: Between 1985 and 2010, 98 patients were treated with IORT for advanced or LR RCC at 9 institutions. We collected demographic, clinical, treatment, and outcomes data for all patients. Overall (OS), disease specific (DSS), and disease-free survival (DFS) was estimated using the Kaplan-Meier method. A multivariate Cox hazards regression was used to test significance. Results: IORT was delivered at nephrectomy for advanced disease (28%) or during resection of LR RCC in the renal fossa (72%). 69% of patients were male and mean age at RCC diagnosis was 57. At initial nephrectomy, primary T-stage was 17% T1, 12% T2, 55% T3, and 16% T4. Prior to IORT, 87% had visibly complete surgical resection of tumor. Mean IORT dose delivered was 14.7Gy (range 9-20Gy). Average post-op hospitalization was 10.7 days. Median follow-up after IORT was 1.6 years. OS at 1 and 5 years after IORT was 69% and 37% for advanced patients and 94% and 55% for LR patients, respectively. DFS at 1 and 5 years was 72% and 39% for advanced patients and 96% and 52% for LR patients, respectively. DSS at 1 and 5 years was 72% and 41% for advanced patients and 96% and 60% for LR patients, respectively. For the entire cohort, higher IORT dose (HR 1.3, p &lt; 0.001), positive initial node status (HR 2.9-3.6, p &lt; 0.01), and presence of sarcomatoid features (HR 3.7-6.9, p &lt; 0.05) had a significant association with decreased OS, DFS and DSS. Patients who received adjuvant systemic therapy after IORT showed decreased DSS (HR 2.4, p = 0.03). When analyzing LR tumors alone, positive margin (HR 2.6, p = 0.01) was associated with decreased OS. Conclusions: We report on the largest known cohort of patients with RCC managed with IORT and we have identified factors associated with survival. Outcomes in our cohort with LR RCC treated with local resection and IORT compare favorably to similar groups treated with resection alone suggesting improved DSS may be possible with IORT.

A SEER Database Analysis of Urethral Cancer Management

Chained multiple imputation was performed to account for missing data and a multivariate Cox hazards regression was used for testing significance. Results: IORT was delivered during nephrectomy for advanced disease (28% of patients) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of patients were male and the mean age at RCC diagnosis was 57. At initial nephrectomy, primary T-stage was 17% T1, 12% T2, 55% T3, and 16% T4. Prior to IORT, 87% had a visibly complete surgical resection of tumor. Mean IORT dose delivered was 14.7 Gy (range, 9-20 Gy). Average length of post-op hospitalization was 10.7 days. Pre-operative or post-operative external beam radiation therapy (EBRT) was administered to 27% and 35% of patients, respectively (2% received both pre and post-operative EBRT). Median follow-up after IORT was 1.6 years. OS at 1 and 5 years after IORT was 69% and 37% for advanced patients and 94% and 55% for locally recurrent patients, respectively. DFS at 1 and 5 years was 72% and 39% for advanced patients and 96% and 52% for locally recurrent patients, respectively. DSS at 1 and 5 years was 72% and 41% for advanced patients and 96% and 60% for locally recurrent patients, respectively. For the entire cohort, higher IORT dose (HR 1.3, p < 0.001), positive initial nodal status (HR 2.9-3.6, p < 0.01), and presence of sarcomatoid features (HR 3.7-6.9, p < 0.05) had a statistically significant association with decreased OS, DFS and DSS. Patients who received adjuvant systemic therapy after IORT showed decreased DSS (HR 2.4, p Z 0.03). When analyzing locally recurrent tumors alone, positive margin status (HR 2.6, p Z 0.01) was associated with decreased OS. Conclusion: We report on the largest known cohort of patients with RCC managed with IORT and we have identified several factors associated with survival. Outcomes in our cohort of patients with locally recurrent RCC treated with local resection and IORT compare favorably to similar groups treated with local resection alone suggesting improved DSS may be possible with IORT. Author Disclosure: J.J. Paly: None. C.L. Hallemeier: None. P.J. Biggs: None. A. Niemierko: None. F. Roeder: None. R. Martinez-Monge: None. J.M. Whitson: None. F.A. Calvo: None. G. Fastner: None. J.A. Efstathiou: None.