Michael Chevinsky

Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

BACKGROUND Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. OBJECTIVE To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. DESIGN, SETTING, AND PARTICIPANTS Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. RESULTS AND LIMITATIONS Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. CONCLUSIONS PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. PATIENT SUMMARY Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Subcentimeter Pulmonary Nodules are Not Associated with Disease Progression in Patients with Renal Cell Carcinoma

PURPOSE Renal cell carcinoma most commonly metastasizes to the lung. Indeterminate pulmonary nodules develop preoperatively in half of the patients with localized renal cell carcinoma but clinical significance remains poorly defined. We determined whether the presence of indeterminate pulmonary nodules, or nodule size or number is associated with renal cell carcinoma outcomes. MATERIALS AND METHODS We reviewed data on 1,102 patients with renal cell carcinoma in whom chest computerized tomography was done within 6 months before nephrectomy from 2002 to 2012. Patients with metastatic disease at presentation, benign tumors, pulmonary nodules greater than 2 cm or concurrent pulmonary disease were excluded, leaving 748 available for analysis. Study outcomes included lung metastasis, any distant metastasis or death from renal cell carcinoma. Cox proportional hazards models were used to assess whether the presence of indeterminate pulmonary nodules, or nodule size or number was associated with outcomes. Models were evaluated by comparing discrimination using the Harrell c-index. RESULTS Indeterminate pulmonary nodules were present in 382 of 748 patients (51%). Median followup was 4.1 years (IQR 2.2-6.1). The presence of indeterminate pulmonary nodules was not associated with distant metastasis or death from kidney cancer. However, compared to subcm indeterminate pulmonary nodules the nodules greater than 1 cm were associated with metastatic disease after adjusting for tumor histology, stage and size (HR 2.48, 95% CI 1.08-5.68, p = 0.031). The outcome c-index increased slightly after adding nodule size to a predictive model adjusted for tumor characteristics. CONCLUSIONS No evidence in the current study suggested that indeterminate pulmonary nodules less than 1 cm are associated with renal cell carcinoma progression, although large nodules significantly predicted metastatic disease. Patients with subcm indeterminate pulmonary nodules would be unlikely to benefit from extensive postoperative chest imaging surveillance, which should be reserved for patients with nodules greater than 1 cm.

Impact of Ureteroscopy Before Nephroureterectomy for Upper Tract Urothelial Carcinoma on Oncologic Outcomes

OBJECTIVE To compare the oncologic outcomes of patients with upper tract urothelial carcinoma undergoing nephroureterectomy (NU) with and without prior ureteroscopy (URS). METHODS We reviewed records of all patients with no prior history of bladder cancer who underwent NU at our institution (n = 201). We compared patients who underwent URS before NU with patients who proceeded directly to NU based on imaging alone. After excluding patients undergoing URS with therapeutic intent, we used multivariable Cox proportional hazards models, adjusting for tumor characteristics with cancer-specific survival (CSS), intravesical recurrence-free survival, metastasis-free survival (MFS), and overall survival (OS) as end points. This study received institutional review board approval. RESULTS A total of 144 (72%) patients underwent URS before NU, and 57 (28%) patients proceeded directly to NU. The median follow-up time for survivors was 5.4 years from diagnosis. The performance of diagnostic URS before NU was significantly associated with IR (hazard ratio 2.58; 95% CI 1.47, 4.54; P = .001), although it was not associated with CSS, MFS, or OS. The adjusted intravesical recurrence-free survival probability 3 years after diagnosis is 71% and 42% for patients who did not and did receive URS before NU, respectively (adjusted risk difference 30%; 95% CI 13%, 47%). CONCLUSION We did not find evidence that URS adversely impacts disease progression and survival in patients with upper tract urothelial carcinoma. Although patients are at higher risk for IR after NU when they have undergone prior diagnostic URS, their CSS, MFS, and OS are not significantly affected.

Pathological Stage T3a Significantly Increases Disease Recurrence across All Tumor Sizes in Renal Cell Carcinoma

PURPOSE Tumor size and stage are important prognostic parameters in renal cell carcinoma. While pathological stage T1 and T2 are defined by size alone, the presence of certain intrinsic features can up stage a tumor to pathological stage T3a regardless of size. We investigate the effect of pathological tumor stage on the relationship between tumor size and risk of disease recurrence. MATERIALS AND METHODS Data were reviewed on patients who underwent nephrectomy at our institution between 2006 and 2013 to identify all those with pathological stage T1, T2 and T3a tumors. A proportional hazards Cox model was built with time to recurrence as outcome, and pathological stage and tumor size as covariates. An interaction term for stage and tumor size was included. RESULTS The final cohort included 1,809 patients. On multivariable analysis, when adjusted for tumor size, patients with pT3a tumors had a greater risk of tumor recurrence compared to those with pT1/T2 tumors (HR 3.70; 95% CI 2.31, 5.92; p <0.0001). The risk of disease recurrence increased more rapidly as tumor size increased only with the presence of perinephric fat invasion (p=0.006). CONCLUSIONS Using the AJCC 2010 staging criteria we validated pathological stage T3a as a poor prognostic factor in renal cell carcinoma regardless of tumor size. Our results also demonstrated an increased rate of risk of recurrence with perinephric fat invasion. Given this increased risk of recurrence, even in tumors less than 4 cm, closer surveillance is warranted in such cases and the role of perinephric involvement necessitates further investigation.

Partial and Radical Nephrectomy for Unilateral Synchronous Multifocal Renal Cortical Tumors.

OBJECTIVE To evaluate clinicopathologic characteristics and treatment outcomes of patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN) for unilateral synchronous multifocal renal tumors. METHODS We retrospectively reviewed medical records for 128 patients with nonmetastatic, unilateral, synchronous, multifocal renal tumors who underwent surgical resection at our institution from 1995 to 2012. Five patients with hereditary renal cell carcinoma were excluded. Differences between patient and tumor characteristics from the 2 nephrectomy groups were evaluated. Outcomes in terms of recurrence-free survival, overall survival, and chronic kidney disease upstaging were estimated using Kaplan-Meier methods. The log-rank test was used for group comparisons. RESULTS The study cohort included 78 PN patients (63%) and 45 RN patients (37%); 17 of 95 planned PN (18%) were converted to RN. Tumor diameter and RENAL nephrometry scores were greater in RN patients (P <.0001 and P = .0002, respectively). Pathologic stage T3 was seen in 40% of RN patients and 10% of PN patients (P = .0002). Histologic concordance was apparent in 60 of 123 patients (49%). Median follow-up for patients alive without a recurrence was 4 years. Five-year recurrence-free survival was 98% for PN and 85% for RN. Five-year overall survival was 96% for PN and 86% for RN (P = .5). Five-year freedom from chronic kidney disease upstaging was 74% for PN and 55% for RN (P = .11). CONCLUSION Partial nephrectomy for the treatment of unilateral, synchronous, multifocal, renal tumors with favorable characteristics was associated with a low recurrence rate. These findings suggest PN is an appropriate management strategy for this group of carefully selected patients.

Surgical Treatment of Tumors Involving Kidneys With Fusion Anomalies: A Contemporary Series.

OBJECTIVE To report a contemporary series of surgically treated patients with tumors involving kidneys with fusion anomalies. MATERIALS AND METHODS We retrospectively reviewed the medical records of all 10 patients treated at a single tertiary care institution for tumors involving kidneys with fusion anomalies between the years 2000 and 2015. One patient, diagnosed with lymphoma, did not undergo surgical treatment and was therefore excluded. Data regarding patient, tumor, and treatment characteristics were collected and described. RESULTS The study cohort included 7 male and 2 female patients, at a median age of 52 years. Seven patients underwent open partial nephrectomy. Nephroureterectomy was performed on 2 patients; 1 open and 1 laparoscopic. All patients had localized disease at diagnosis. Tumor histologies were renal cell carcinoma in 5 patients, renal oncocytoma in 1 patient, urothelial carcinoma in 2 patients, and a well-differentiated liposarcoma involving the kidney in 1 patient. Accessory blood vessels were identified in 8 of 9 patients. Median estimated blood loss was 300 mL (interquartile range: 150-1000). Four patients had postoperative complications, including 3 major (Clavien grade ≥ 3) and 3 minor (Clavien grade ≤ 2) complications. During a median follow-up of 19.2 months (interquartile range: 3-34.8), 1 patient with urothelial carcinoma developed a bladder recurrence. None of the patients developed new-onset chronic kidney disease during the early postoperative period. CONCLUSION Localized renal cortical tumors in kidneys with fusion anomalies may be treated with partial nephrectomy; however, complication rates are relatively high. Preoperative imaging of the blood vessels is necessary, as most patients have an accessory blood supply.

Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection

The utility of cancer cell lines is affected by the similarity to endogenous tumour cells. Here we compare genomic data from 65 kidney-derived cell lines from the Cancer Cell Line Encyclopedia and the COSMIC Cell Lines Project to three renal cancer subtypes from The Cancer Genome Atlas: clear cell renal cell carcinoma (ccRCC, also known as kidney renal clear cell carcinoma), papillary (pRCC, also known as kidney papillary) and chromophobe (chRCC, also known as kidney chromophobe) renal cell carcinoma. Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC. Human ccRCC tumours clustering with cell lines display clinical and genomic features of more aggressive disease, suggesting that cell lines best represent aggressive tumours. We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes. Our results could aid investigators in analysing appropriate renal cancer cell lines.

Bilateral Testicular Germ Cell Tumors in the Era of Multimodal Therapy

OBJECTIVE To characterize the incidence, presentation, management, and relapse of a large population of bilateral testicular germ cell tumors (TGCT) from a single institution. PATIENTS AND METHODS We identified bilateral TGCT diagnosed between January 1989 and February 2014. We categorized synchronous and metachronous TGCT, noting time between first and second TGCT, histology (seminoma vs nonseminoma [NSGCT]), stage, and treatments. Kaplan-Meier survival estimates characterized relapse. RESULTS Of 5132 patients with TGCT, 128 (2.5%) had bilateral TGCT. Bilateral TGCT increased over time-1.7% in 1989-1994 up to 3.8% in 2010 to February 2014. The 35 (27%) synchronous cases of TGCT had 20 (57%) concordant seminoma, 5 (14%) concordant NSGCT, and 10 (29%) discordant NSGCT. The 93 (73%) metachronous cases had median time interval to second TGCT of 73 months (range: 5 months-28.6 years). Compared with first TGCT, 39 (42%) had discordant histology, 29 (31%) had concordant seminoma, and 25 (27%) had concordant NSGCT. Stage at first tumor was statistically similar to second TGCT (second stage I, II, II in 69%, 22%, 10%). Increasing duration between first and second TGCT was not associated with higher stage (II or III) at second TGCT (P = .09). Treatment at first tumor was not associated with stage at second tumor. Relapse following bilateral diagnosis was 16.8% (95% confidence interval 10.5%-26.2%) at 5 years. CONCLUSION Incidence of bilateral TGCT increased with >25% of metachronous TGCT presenting ≥10 years after first TGCT; possible causes include increased survivorship and referral bias. Stage was statistically similar at first and second tumor; stage at second tumor was not associated with time interval between tumors or prior treatment modality at first tumor.