Mazyar Ghanaat

Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations

INTRODUCTION Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

Prognostic value of lymph node yield during nephroureterectomy for upper tract urothelial carcinoma

INTRODUCTION Lymph node dissection (LND) performed during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) remains controversial and difficult to evaluate. The aim of this study was to investigate whether removal of more lymph nodes during RNU is safe and improves oncologic outcomes. METHODS We evaluated 422 patients who underwent RNU with concomitant LND for upper tract urothelial carcinoma between 1976 and 2015, assessing for an association between total nodes removed, recurrence-free survival, and cancer-specific survival using Cox proportional hazards models. We also investigated the relationship between nodal yield and perioperative metrics and intersurgeon variability using linear regression. RESULTS In our cohort of 442 patients, 239 developed recurrences and 94 patients died of disease. Median follow-up among survivors was 3.7 years (interquartile range: 1.2, 7.4). The median nodal yield was 9 (interquartile range: 4, 16). Among patients with node-positive disease (pN1), we observed a significant improvement in recurrence-free survival (hazard ratio = 0.84 per 5 nodes removed, P = 0.039) and a nonsignificant improvement in cancer-specific survival with an increase in the nodal yield (hazard ratio = 0.90 per 5 nodes removed, P = 0.2). There was no evidence of an association between node yield and operative time, estimated blood loss, or 30-day complications on multivariable analysis. There was significant heterogeneity among surgeons regarding the extent of LND (P<0.0001). CONCLUSIONS We found that a more extensive node dissection may improve oncologic outcomes in a subset of high-risk patients without significantly increasing operative time or serious complications. Additionally, we identified considerable intersurgeon heterogeneity regarding the extent of LND furthering the notion of surgeon variability as a nonstandardized factor.

Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma

BACKGROUND Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. RESULTS AND LIMITATIONS Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088). CONCLUSIONS Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. PATIENT SUMMARY In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma

BACKGROUND Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. OBJECTIVE To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non-clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. DESIGN, SETTING, AND PARTICIPANTS DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Differences in patient characteristics and mutational status were tested using Fishers exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. RESULTS AND LIMITATIONS TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1-18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19-6.01; p=0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. CONCLUSIONS Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. PATIENT SUMMARY We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Cystic renal cell carcinoma: a report on outcomes of surgery and active surveillance in patients retrospectively identified on pretreatment imaging

Purpose: We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic. Materials and Methods: We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma. Results: Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1‐2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma. Conclusions: Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.

Comparison of Post-Radical Cystectomy Ileus Rates Using GIA-80 versus GIA-60 Intestinal Stapler Device

OBJECTIVE To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer. METHODS We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition. RESULTS Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance. CONCLUSION The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD.

The association of renal cell carcinoma with gastrointestinal stromal tumors

Prior small studies have reported a possible association between renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). In the largest known series, our objective was to describe the prevalence of RCC among patients with GISTs over 26 years at Memorial Sloan Kettering Cancer Center (MSKCC).

MP39-02 COMPARATIVE GENOMIC PROFILING OF MATCHED PRIMARY AND METASTATIC TUMORS IN RENAL CELL CARCINOMA

were found to be significantly more common in those who had recurrence or died of their disease (24% vs. 4%; adjusted p1⁄40.02). Survival analysis showed patients with KDM5C having statistically significant inferior cancer-specific survival (adjusted p1⁄4<0.01) and a trend for inferior survival in those with SETD2 mutations (adjusted p1⁄40.11) (Figure 1). CONCLUSIONS: We identified mutations in SRMs that are associated with recurrence and lethality. The strongest association was seen with KDM5Cmutations. Use of these potential genomic biomarkers may improve risk stratification of patients with SRMs and for those who may be appropriate for AS. Prospective evaluation of these markers is needed.

MP67-14 CHARACTERIZATION OF RENAL CELL CARCINOMA IN PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS COMPARED TO OTHER SOFT TISSUE SARCOMAS

patterns in renal cell carcinoma (RCC) in patients with end stage renal disease (ESRD), such as acquired cystic disease (ACD)-associated and clear cell papillary RCC. In this study, a central pathologist reanalyzed the pathological findings of RCC in patients with ESRD from multiple institutions, based on the new classification. METHODS: This study included 315 patients who underwent radical nephrectomy in 3 Japanese institutes from 1987 to 2015. A central pathologist reviewed sections from all patients according to the 2016 WHO classification. RESULTS: Based on the new classification, clear cell was diagnosed in 144 patients (46%), ACD-associated in 100 (31%), papillary in 41 (13%), chromophobe in 10 (3%), clear cell papillary in 3 (1%), MiT family translocation in 2 (1%), and unclassified in 15 (5%). We next compared clinicopathological findings of ACD-associated RCC with those of non-ACD-associated RCC. Multivariate analysis showed that independent prognostic clinical factors for occurrence of ACDassociated RCC were the presence of acquired cystic disease of the kidney (ACDK) (hazard ratio [HR]: 2 D710, p<0.01), age (HR: 0.97, p1⁄40.03), and duration of dialysis (HR: 1.06, p<0.01). We further compared pathological features in ACD-associated and other RCCs. ACD-associated included more Furman grade 3/4 (90 vs. 47%, p<0.01). In contrast, other unfavorable findings was less frequent in ACD-associated RCC, including the presence of sarcomatoid features (2 vs. 7%, p1⁄40.04), lymphovascular invasion (3 vs. 11%, p<0.01), and necrosis (7 vs. 13%, p1⁄40.18). CONCLUSIONS: ACD-associated RCC accounts for 31% of RCC in patients with ESRD, and prognostic clinical factors for occurrence include young age, long dialysis duration, and presence of ACDK. In addition, ACD-associated RCC showed higher Furman grade, but fewer cases with other unfavorable pathological features, suggesting the need for an independent nuclear grading system for ACD-associated RCC.

MP55-01 MIXED EPITHELIAL AND STROMAL TUMOR FAMILY: A SINGLE INSTITUTIONAL EXPERIENCE WITH THIS RARE RENAL ENTITY

INTRODUCTION AND OBJECTIVES: In 2016 the World Health Organization coined the term mixed epithelial and stromal tumor family (MESTF) to encompass adult cystic nephroma (ACN) within the classification of mixed epithelial and stromal tumors (MESTs) on the basis of overlapping clinical and pathologic profiles. MESTs have traditionally been regarded as benign, with only a few reports of malignant transformation or recurrence in the literature. Diagnosis requires histopathological evaluation, as radiologic imaging cannot accurately determine whether such tumors are benign or malignant. We aim to characterize our institutional experience with this rare neoplasm. METHODS: We identified all patients with a pathological diagnosis of MEST or ACN from our prospectively collected institutional database between Jan 1995 Dec 2015. Available imaging was rereviewed by a single expert radiologist (AH). Demographic, radiologic, and clinical characteristics were recorded. RESULTS: Data was available for 40 patients. The median age at diagnosis was 48.8 years (31.5-73.4). Thirty-seven (92.5%) patients were female and three (7.5%) were male. Imaging was available for rereview for 29 (72.5%) patients. The mean diameter of the tumor on preoperative imaging was 5.8 cm (1.9-16.1). Patients presenting with symptoms at diagnosis had a mean diameter of 7.4 cm (4-16.1). On imaging, 25 (86.2%) tumors where characterized as Bosniak 3 lesions and four (13.8%) were described as Bosniak 4 lesions. All patients underwent surgical resection, with partial nephrectomy performed in 72.5% of cases. Mean pathological tumor size was 5.9 cm (1.5-15). Median follow-up was 71.6 months (1-217). Two (4.9%) patients died from non-tumor related causes. At last follow-up, all patients showed no evidence of disease. CONCLUSIONS: MESTF are indolent tumors with a female predominance. They are usually detected incidentally as Bosniak 3 or 4 lesions. Partial nephrectomy should be performed whenever possible to resect the tumor and preserve renal function. Given the low likelihood of recurrence following excision, we believe that, once pathologically identified, patients have an excellent long-term prognosis and require minimal surveillance imaging on follow-up. Genomic characterization is currently underway. Source of Funding: Funded in part by the Sidney Kimmel Center for Prostate and Urologic Cancers and the National Cancer Institute Training Grant T32 CA082088 (BM, MG)