bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic differences and survival in African Americans with metastatic clear cell renal cell carcinoma in the targeted therapy era.
Authors: Rose Tracy Lynn , Krishnan Bhavani , Kuykendal Adam Rea , Smith Angela , Milowsky Matthew I. , Kim William Y.
Published: February 2017

504

Background: African American (AA) patients with RCC have historically had inferior survival relative to Caucasians. There is little data on racial differences in tumor biology between AA and Caucasians to explain this disparity. In addition, it is not known if racial differences may result in differential response to targeted therapy and if the disparity has changed over time. Our study aims to define racial differences in tumor biology between AA and Caucasians with clear cell RCC (ccRCC) and to evaluate if observed differences in tumor biology are reflected in survival rates in the era of targeted therapy. Methods: We identified AA and Caucasian patients with stage IV clear cell RCC (ccRCC) in the National Cancer Data Base (NCDB) and analyzed survival of AA and Caucasians in the pre- and post-targeted therapy eras (1998-2004 and 2006-2011). We then analyzed The Cancer Genome Atlas (TCGA): Renal Clear Cell Carcinoma dataset to determine differences in somatic mutation rate, molecular subtype, and RNA expression between AA and Caucasians. Results: Overall survival (OS) is significantly longer in Caucasians than AA (9.2 vs 6.5 months, p < 0.01). The adjusted HR for death for AA compared with Caucasian patients was 1.08 (95% CI 1.01-1.14) in the post-targeted therapy era, which was unchanged from the pre-targeted therapy era (HR 1.07, 95% CI 1.01-1.14). AA patients were less likely than Caucasians to have VHL mutations (17% vs 50%, p = 0.04) and were enriched in the ccB molecular subtype (79% in AA vs 45% in Caucasians, p < 0.01). RNA expression revealed upregulation of several HIF-associated pathways in Caucasian compared with AA patients. Conclusions: ccRCC in AA have less frequent VHL mutations, are enriched in the ccB molecular subtype, and have less upregulation of HIF-associated pathways than Caucasians. These molecular features predict for decreased responsiveness to VEGF-targeted therapy and inferior survival in AA compared to Caucasians. Data from a large national database confirm that AA patients maintain inferior survival compared to Caucasians in the era of targeted therapy, potentially related to underlying tumor biology.
Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.
Authors: Bi Xiao , Zhao Siming , Adeniran Adebowale , Kluger Harriet M. , Xie Zuoquan , Nawaf Cayce , Merino Maria J , Valera Vladimir , Pantuck Allan J. , Said Jonathan W. , Belldegrun Arie S. , Lifton Richard P , Shuch Brian M.
Published: February 2017

509

Background: Sarcomatoid transformation in renal cell carcinoma (ccRCC) is one of the worst prognostic factors and outcome is extremely poor. We evaluate genetic alterations implicated in this process. Methods: Nephrectomy specimens from ccRCC with sarcomatoid transformation had DNA extracted from carcinoma, sarcomatoid, and normal kidney regions. Exome capture/Illumina sequencing was performed in 21 samples. Somatic mutation calling was accomplished by comparing sarcomatoid-normal and carcinoma-normal pairs. Results: Two tumors had evidence of hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining tumors, 42.6% of somatic mutations were shared. Sarcomatoid regions had a greater mutation burden (p = 4.0x10-4). A low percentage (57.9%) of tumors had mutations in VHL. Mutations in ccRCC driver genes, including PBRM1, PTEN, SETD2, ARID1A, and BAP1, were common. All mutations in ARID1A and BAP1 were specific to sarcomatoid regions. A high percentage (31.5%) of TP53 mutations were observed, all specific to sarcomatoid regions and occurring with loss of heterozygosity. Lastly, mutations in genes not previously described in ccRCC were observed, most sarcomatoid-specific. These include genes implicated in cell adhesion, polarity, motility, and WNT signaling (FAT1, FAT2, FAT3, PTK7), retinoic acid-regulated cell differentiation (RQCD1, LRIF1), and ubiquitinated protein trafficking and cytokinesis (TSG101). Conclusions: Sarcomatoid transformation in ccRCC results from clonal divergence from a common somatic cell of origin. The sarcomatoid region has significantly greater mutational burden of known cancer driver genes. TP53 mutations occurred at a high frequency and were exclusive to the sarcomatoid region. Hypermutation is a unique characteristic observed in a subset of tumors. Additional cohorts and mechanistic studies are critical to elucidate the role of candidate driver alterations.
The impact of contrast enhancement reduction on tumor response in patients with advanced renal cell carcinoma that treated with presurgical targeting therapy.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

510

Background: RECIST is a standard tool for tumor response assessment. However, evaluation for targeted therapy by RECIST is insensitive because tumors often showed a modest change in size despite of significant necrosis. Therefore, we investigated an impact of contrast enhancement reduction for tumor shrinkage in RCC patients with presurgical targeting therapy. Methods: From March 2011 to July 2015, 17 patients (18 tumors) with RCC who underwent presurgical targeting therapy were included. Indications for presurgical targeting therapy were cT3-4, bilateral tumors, poor performance status, or small distant metastasis. Contrast enhancement reduction was evaluated by contrast medium enhanced area (CMEA) before and after targeting therapy. CMEA measurements were performed by OsiriX and Adobe Photoshop. Eighteen tumors were evaluated by RECIST and CMEA. Differences between two methods were compared. Results: Median age and followup after initiation of targeted therapy were 68 years old and 15.3 months. IVC thrombus and small distant metastasis existed in seven (41%) and five (29%) patents, respectively. Fifteen patients (88%) received TKI based (sunitinib and/or axitinib), and three patients (12%) received mTOR inhibitor based (everolimus or temsirolimus) presurgical therapy. The median treatment period of presurgical targeted therapy was 3.3 months. Median tumor responses in RECIST and CMEA were 10.5% and 49.0%, that was significantly correlated by liner regression analysis (P = 0.002). TKI based presurgical therapy showed significant tumor reduction in CMEA than RECIST (P = 0.0062). In addition, tumor reduction rate was significantly higher in TKI based presurgical therapy than mTOR inhibitor (P = 0.014). No patient experienced tumor recurrence. Conclusions: Contrast enhancement reduction might be useful tool for tumor shrinkage in patients with RCC who underwent presurgical targeting therapy.
Durability of responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2 (HD IL-2).
Authors: Clark Joseph , Morse Michael A. , Wong Michael K.K. , McDermott David F. , Kaufman Howard , Daniels Gregory A. , Perritt Jessica C , Hua Hong , Aung Sandra
Published: February 2017

511

Background: HD IL-2 is FDA approved for advanced renal cell carcinoma (mRCC), however, the data supporting its use is 23 years old. In 2011, a HD IL-2 patient database was established called PROCLAIMSM, and comprises the largest active prospective collection of data from mRCC and metastatic melanoma (MM) patients receiving HD IL-2 treatment and provides longitudinal real-time insights into the clinical impact of sequencing drug treatments. These data report on the outcomes and interactions with prior targeted therapies in mRCC patients in the current era. Methods: Inclusion criteria require patients to receive at least one dose of HD IL-2. Patients who received HD IL-2 and had already undergone a post-treatment scan were not eligible. Survival analysis was performed by the method of Kaplan and Meier using datasets as of July 27, 2015. Results: The overall response rate (ORR) and median overall survival (mOS) are described in Table 1. The mOS was not reached (NR) for 364 patients. The 1, 2 and 3 year survival rates were 79%, 63%, and 51%, respectively. For patients with stable disease (SD), the mOS was not reached and the 1, 2 and 3 year survival rates were 96%, 80%, and 60% respectively. There was a significant difference in mOS between SD and progressive disease (PD) patients, NR vs 15.5 months, P<.0001. The mOS was not reached for patients regardless of whether or not they received targeted therapy (TT) prior to HD IL-2. There were 4 reported treatment-related deaths in 364 patients (1.1%), none of these patients had prior TT. Conclusions: PROCLAIM data demonstrate that SD, previously grouped with the non-responders, is associated with extended survival rates. HD IL-2 is an active 2ndline treatment option for patients who have failed TT. These data support that HD IL-2 has a favorable safety profile and remains an effective therapy for eligible patients with mRCC. Clinical trial information: NCT01415167. [Table: see text]
Real world chart review of adverse event management in patients taking tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) by line of therapy (LoT).
Authors: Srinivas Sandhya , Stein Dara , Teltsch Dana Y , Tao Sunning , Ramaswamy Krishnan
Published: February 2017

521

Background: This is the first real world study to describe adverse events of special interest (AESI) management for all available TKIs by LoT. A better understanding of optimal AE management can positively impact patient care. Methods: A chart review was conducted largely in community oncology practices in Canada and the US. Patients with mRCC were eligible if they started TKI monotherapy between Nov 15, 2010-Nov 15, 2013 and had ≥ 1 of 5 AESI onset ≤ 3 months post TKI start. AESI included fatigue, hypertension, diarrhea, hand-foot syndrome and stomatitis/mucositis. Data on patient demographics, medical history, drug regimen, and AESI management were collected. Results: 220 patients from 27 centers were included. 63% of patients received TKI in 1st, 22% in 2nd and 15% in 3rd LoT. TKIs included axitinib (9%), pazopanib (27%), sorafenib (8%) and sunitinib (55%). 376 AESI occurred in 220 patients; 87% were non-serious. Fatigue (62%), hypertension (37%), diarrhea (31%), stomatitis/mucositis (29%), and hand-foot syndrome (12%) were reported. 55% of AESI resolved/were resolving within 3.5 months of onset. 8% of patients received AESI prophylaxis (Px) and 59% received treatment (Tx). Incidence of stomatitis/mucositis declined as LoT progressed (37%, 16%, 12%). More patients in 1st vs. ≥ 2nd LoT had AESI related TKI discontinuation (17% vs. 12%), interruptions (17% vs. 12%) and reductions (43% vs. 32%). Fewer patients missed doses as LoT progressed (38%, 25%, 18%). Fatigue was the commonest AESI across LoT, and fatigue as a reason for therapy delay/interruption increased across LoT (7%, 14%, 50%). The rates of Tx or Px for fatigue remained low across LoT. Rates of AESI Px were low across the LoT (10%, 0.4%, 0.3%). More patients in 1st (61%) received AESI Tx vs. 2nd (47%) LoT. Conclusions: Most AESI were non-serious, and over half of patients received some form of AESI Tx. Fatigue was the most common yet least frequently Tx AESI. Very few patients received Px across LoT. More patients in 1st versus 2nd LoT experienced dose modifications/discontinuation and received AESI Tx. More emphasis on Px/Tx options for non-serious bothersome AEs is warranted.
Angiogenic markers during bevacizumab-based treatment in metastatic renal cell carcinoma (RCC).
Authors: Dorff Tanya B. , Longmate Jeff , Groshen Susan G. , Stadler Walter Michael , Fishman Mayer N. , Vaishampayan Ulka N. , Pinski Jacek K. , Pal Sumanta K. , Hu James , Quinn David I. , Lara Primo
Published: February 2017

522

Background: Targeting the vascular endothelial growth factor (VEGF) pathway delays progression in mRCC, however innate and acquired resistance limit success. CD105 (endoglin) is a TGFb family receptor which is upregulated after VEGF inhibition, possibly mediating resistance. We studied serum CD105 and TGFb at baseline and after treatment, and tissue levels of TGFbR1 & 2 plus AVCRL, to discover biomarkers for treatment response as part of a randomized trial of bevacizumab (Bev) +/- the anti-endoglin antibody TRC105. Clinical data from the trial were presented at ASCO 2015 (Dorff et al, abstr 4542). Methods: Serum was collected at baseline and before cycles 2&4. ELISA was performed using kits from Abcam. Changes from baseline were evaluated and compared overall and between arms using a general linear mixed effects model. Immunohistochemistry was performed on paraffin embedded tissue samples using antibodies from R&D systems; tissue and baseline ELISA data were evaluated for association with PFS using Kaplan-Meier analysis and the logrank test. Results: 54 subjects (24 on Bev and 28 on Bev+TRC105) had at least one analyzed serum sample; 14 and 19 respectively had both baseline and cycle 2 samples. Mean CD105 was 82.8 (95%CI 64.6, 106.2) at baseline and 59.0 (95%CI 43.2, 80.7) at cycle 2; for 16 patients with cycle 4 data the mean was 39.8, significantly lower than baseline (p = 0.024), but not different between treatment arms. Cycle 2 TGFb levels were not different from baseline (p = 0.66) or between arms (p = 0.17). Baseline serum TGFb below the median ( < 10.6) was associated with higher likelihood of PFS at 12 and 24 weeks; (0.78 vs 0.3 and 0.49 vs 0.19, respectively, p = 0.022); baseline CD105 was not (p = 0.83). Tissue was available for 29 subjects. No tissue markers (TGFbR1 &2 or AVCRL) were associated with longer PFS except, in exploratory analysis, higher TGFbR2 staining in patients treated with TRC105 (p = 0.017). Conclusions: No pharmacodynamics markers for TRC105 therapy were identified. Lower baseline serum TGFb levels may be prognostic of PFS during Bev therapy, supporting the notion that this pathway contributes to resistance. Better PFS in TRC105-treated patients with higher tissue TGFbR2 expression warrants further study. Clinical trial information: NCT01727089.
Identification and validation of an 8-gene expression signature for predicting high-Fuhrman grade renal cell carcinoma.
Authors: Wan Fangning , Zhu Yao , Han Chengtao , Xu Qinghua , Dai Bo , Zhang Hailiang , Shi Guohai , Gu Weijie , Ye Dingwei
Published: February 2017

526

Background: Clear cell renal cell carcinoma (ccRCC) is a malignancy with heterogeneous outcomes. Currently, renal mass biopsies are commonly employed to extract disease characteristics and aid prognosis. Although the pathological diagnosis of malignant disease is accurate in contemporary reports, the classification of Fuhrman grade using biopsy specimens is still far from promising. Our aim is to generate a signature biomarker to distinguish high grade ccRCC that could be readily applied to clinical biopsy samples. Methods: Using the Cancer Genome Atlas (TCGA) database, a gene expression signature was developed to distinguish high-grade (G3/4) from low-grade (G1/2) disease. The expression profile was further validated for performance and clinical usage in 283 frozen renal cancer samples and 127 ex-vivo renal mass biopsy samples, respectively. The area under curve (AUC) was used to quantify discriminative ability and was compared using the De-long test. Results: Using the development dataset, we identified a 24-gene signature for high-grade disease with an AUC of 0.884. After applied to the replication dataset, an eight-gene profile was defined and achieved an AUC of 0.823. The accuracy of 8-gene panel was maintained in the RMB samples (AUC = 0.821). Conclusions: Using a two-stage replication design, we validated an eight-gene expression signature for predicting high Fuhrman grade of ccRCC. This tool may help to reveal the characteristics of ccRCC biopsy specimens.
A novel preoperative inflammatory marker prognostic score in patients with clear cell and non-clear cell renal cell carcinoma.
Authors: Sekar Rishi Robert , Patil Dattatraya , Pearl Jeff , Baum Yoram , Kucuk Omer , Harris Wayne B. , Carthon Bradley , Alemozaffar Mehrdad , Filson Christopher Paul , Ogan Kenneth , Master Viraj A.
Published: February 2017

530

Background: Several inflammatory markers have been studied as potential biomarkers in clear cell renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of preoperative C-Reactive Protein (CRP), albumin, Erythrocyte Sedimentation Rate (ESR), corrected calcium, and AST/ALT ratio into a RCC Inflammatory Score (RISC) could serve as a rigorous prognostic indicator in patients with clear cell and non-clear cell RCC. Methods: Patients that underwent nephrectomy for localized RCC were queried from our nephrectomy database. The optimal threshold for individual biomarkers was determined using grid search methodology, receiver operating characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. The final score, RISC, was the sum of points accrued from each biomarker (Table). ROC and chi-square analysis was performed to compare the prognostic ability of RISC to SSIGN and UISS. Impact on overall survival was analyzed with multivariate logistic regression analysis. Results: 391 patients were included in the study. Area under the curve (AUC) for RISC, SSIGN, and UISS was 0.78, 0.78, and 0.81, respectively. Chi-square analysis of AUCs revealed no statistically significant difference between RISC, SSIGN, and UISS (p= 0.820, and p =0.317, respectively). On multivariate analysis, after adjusting for confounding variables, each unit increase in RISC was associated with a 32% increase in mortality (HR=1.32, 95%CI 1.17-1.49, p<0.001). Conclusions: RISC is an independent and significant predictor of overall survival in clear cell and non-clear cell RCC with accuracy at least as good as other established prognostic tools. Notably, RISC is composed of standardized preoperative laboratory markers, allowing crucial prognostic information to be integrated into medical decision making prior to surgery. [Table: see text]
The effect of stereotactic ablative radiotherapy on time to change of systemic therapy in extra-cranial renal cell carcinoma metastases.
Authors: Wang Chiachien Jake , Cai Xin , Kim Dong W. , Huelsmann Lorel , Meyer Jeffrey John , Pedrosa Ivan , Brugarolas James , Margulis Vitaly , Timmerman Robert D. , Hannan Raquibul
Published: February 2017

533

Background: Renal cell carcinoma (RCC) has traditionally been refractory to radiotherapy with conventional fractionation, although recent evidence suggests a response to higher doses per fraction. We evaluated local control of extra-cranial metastases from RCC treated with stereotactic ablative radiotherapy (SABR). Methods: RCC patients with extra-cranial metastases treated with SABR were retrospectively enrolled from a single institution between 2005 and 2015. A total of 188 lesions were identified from 91 patients. Radiation (8-60Gy) was delivered in 1-5 fractions (fx) using stereotactic guidance. Local control (LC) was determined by imaging according to RECIST 1.1. Results: Median age at the time of treatment was 62.4 years. Metastases were detected in bone (39.9%), lung (14.9%), liver (9.6%), lymph nodes (11.7%) and other sites (23.9%). Ninety-seven (51.6%) lesions reached curative intent while 91 (48.4%) only reached palliative intent. The most common radiation regimens were 20Gy/1fx, 30Gy/3fx, and 40Gy/5fx. One-year overall survival was 76.5% with a median follow up of 10.7 months. Patients treated with curative SABR showed a 2-fold median survival as compared to those treated with palliative therapy (3.97 year vs 1.43 year, p<0.05). LC rates at 1 and 2 years were 91.4% and 89.7%, respectively. For the patients that failed, median time to local failure was 6.6 months. LC at 1 year significantly improved when treatment was curative (96.1% vs 84.9%, p<0.05), while it decreased in a re-irradiation setting (94.8% vs 46.7%, p<0.05). The median biological equivalent dose (BED) for the lesions that failed was 103Gy, corresponding to 6Gy x 5fx, and was significantly lowered compared to controlled lesions (BED 134Gy). Although 79% of patients developed new lesions within 1 year following SABR, 34.8% did not switch systemic therapy. Switching systemic therapy was delayed in patients treated with curative as compared to palliative SABR (13.4 vs 2.5 months, p<0.05). Conclusions: SABR improved LC of extra-cranial RCC metastases and delayed change to systemic therapy. SABR may complement systemic therapy to improve outcome in the present patient population.
Variation in national use of long-term ADT by disease aggressiveness among men with unfavorable-risk prostate cancer.
Authors: Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Reznor Gally , Choueiri Toni K. , Sweeney Christopher , Martin Neil E. , Orio Peter F. , Chen Yu-Wei , Nezolosky Michelle Daniel , Hoffman Karen E. , Feng Felix Yi-Chung , Trinh Quoc-Dien , Nguyen Paul L.
Published: February 2017

54

Background: Current National Comprehensive Cancer Network (NCCN) guidelines uniformly recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer. We sought to determine whether the use of long-term ADT varied by the subcategory of disease, including the recently-defined subcategories of high-risk disease (favorable, other, and very-high) versus intermediate-risk disease. Methods: We identified 5,836 patients with NCCN intermediate-, high-, or very high-risk prostate cancer diagnosed between 2004 and 2007 and managed with external beam radiation therapy (EBRT) using the Surveillance, Epidemiology, and End Results database linked to Medicare claims data. Patients were stratified by risk group: intermediate-risk, favorable high-risk (previously defined and validated as T1c, Gleason 4+4=8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL), other high-risk, or very high-risk. We used competing risks regression to estimate the rates of long-term (≥ 2 years) ADT in each of these groups. Differences were compared using multivariable regression modeling, adjusting for year of diagnosis, race, marital status, income level, age, and comorbidity. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive 2 years of ADT than others with high-risk disease (21.9% vs. 29.3%, adjusted hazard ratio [AHR] 0.78, 95% confidence interval [CI] 0.67-0.90, p = 0.001), and similarly likely as those with intermediate-risk disease (AHR 1.08, 95% CI 0.94-1.25, p = 0.288). Others with high-risk disease were less likely to receive 2 years of ADT than those with very high-risk cancer (29.3% vs 36.4%, AHR 0.84, 95% CI 0.74-0.96, p = 0.010). Conclusions: Patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Despite NCCN guidelines recommending long-term ADT for all high-risk or very high-risk prostate cancer, our results might reflect the view that these patients represent a heterogeneous group, with favorable high-risk cancer possibly warranting less aggressive therapy than other high-risk or very high-risk disease.
Gene-expression profiling of collecting duct carcinoma of the kidney.
Authors: Tessari Anna , Testa Isabella , Verzoni Elena , Nigita Giovanni , Colecchia Maurizio , Palmieri Dario , Grassi Paolo , Maggi Claudia , Martinetti Antonia , De Braud Filippo G. , Croce Carlo M , Procopio Giuseppe
Published: February 2017

540

Background: Collecting duct carcinoma (CDC) of the kidney is a rare tumor, originating from renal medulla, characterized by younger age at diagnosis and poor prognosis. Since targeted therapies are currently not available for CDC, we aimed to identify the most deregulated pathways in this type of cancer to gain insights into new molecular targets. Methods: Total RNA was extracted from FFPE samples of primary CDC (n=9), clear cell carcinoma (CCC, n=7) and healthy normal (n=7) adjacent renal tissues (23 total samples). Gene expression profile was performed by GeneChip Human Transcriptome Array 2.0 (HTA 2.0 -Affymetrix). The One-Way between-subject ANOVA algorithm was used to calculate statistical significances of pairwise comparisons. Transcripts with a linear fold change (f.c.) of <-2/>2 (p-value<0.05) were included in the study. Functional enrichment analysis identified the most deregulated pathways in CDC. Results: A total of 1,079 genes (827 coding, 252 non-coding) were significantly deregulated comparing CDC, CCC and normal kidney (p<0.05). In CDC vs normal tissue comparison, 484 genes (339 coding, 145 non-coding) are significantly up-regulated, and 49 (40 coding, 9 non-coding) down regulated in tumors (p<0.05). The 4 most highly expressed transcripts in CDC are currently unknown, requiring further studies. Among the most altered known transcripts, we identified FN1 (f.c. 6.33), miR-21 (f.c. 4.01), KNG1 (f.c. -9.4) and AQP2 (f.c. -6.03), whose deregulation was previously associated with advanced disease and lower survival in renal cancer, supporting the quality of our analysis. Functional enrichment analysis indicated a strong downregulation of transcripts associated with histone modifications, function of cytoplasmic ribosomal proteins, senescence, autophagy and focal adhesion in CDC vs both CCC and normal tissues. Conclusions: Our analysis identifies several coding and non-coding transcripts differentially expressed in CDC vs CCC and normal kidney, resulting in alteration of a number of cellular pathways associated with cancer pathogenesis, progression and prognosis. These results pave the way to a deeper understanding of a rare tumor as CDC, driving the development of new, targeted therapies for this aggressive disease.
Very late relapse metastatic renal cell carcinoma: Characteristics and outcomes of patients with a disease-free interval of greater than 10 years.
Authors: Kucharczyk John Ross , Matrana Marc Ryan
Published: February 2017

541

Background: Late relapse of renal cell carcinoma (RCC), or presentation with metastatic disease after a disease free interval of >5 years, is a known behavior of RCC. Recent studies have concluded that late relapse RCC is associated with favorable patient and tumor characteristics as well as an improved response to targeted therapy (TT) when compared to early relapse patients. Less studied are patients who relapse very late, with a disease free interval >10 years. We evaluated the clinical characteristics, response to TT and outcomes of this unique population. Methods: We collected data on consecutive patients with metastatic RCC who had disease recurrence >10 years after nephrectomy. Outcomes were tabulated using basic statistical techniques; adverse events were graded using CTCAE v4.0 and treatment response graded using RECIST 1.1. Results: Among 720 RCC patients treated with nephrectomy, we identified 8 who developed recurrent metastatic disease after a >10 year disease free interval (median: 16.7 years; range: 11.7-29.0). All patients presented with clear cell histology; 88% favorable IMDC and MSKCC risk subgroups. All patients presented with multiple metastases, with the most common sites being lung and bone, while unusual sites such as soft tissue, pancreas and adrenal were also detected. Median time on first-line TT was 20.1 months; 4, 3 and 1 patient received pazopanib (best response: PR), sunitinib (best response: SD) and cytokine (best response: PD) as first-line therapy, respectively. The median number of sequential TT received was 2 (range: 1-4). Four patients died, median OS was 46.6 months (range: 9.8-129), 3 year OS rate was 63%. Common adverse events to TT were fatigue (88%), anorexia (38%) and diarrhea (50%), 94% grade 1/2. Conclusions: Patients are at life-long risk of recurrence after resection of localized RCC as it is possible for metastases to present >10 years after resection. Patients in our study had relatively large metastatic burden and a wide distribution of metastatic sites, insights that may be useful clinically during surveillance. Our cohort demonstrated favorable prognostic features and outcomes when compared to historical controls.
Do pathological parameters of primary tumor correlate with overall survival (OS) of metastatic clear-cell renal cell carcinoma (ccRCC)?
Authors: Basso Umberto , Maruzzo Marco , Fraccon Anna Paola , Sava Teodoro , Massari Francesco , Sacco Cosimo , Valcamonico Francesca , Maines Francesca , Lo Re Giovanni , Donati Donatella , Baier Susanne , Durante Emilia , Soraru' Mariella , Nicodemo Maurizio , Bearz Alessandra , Sartori Donata , Fiduccia Pasquale , Zustovich Fable , Pasini Felice , Zagonel Vittorina
Published: February 2017

549

Background: T and N stage, Fuhrman grade, necrosis and sarcomatoid features in the primary tumor are key prognostic factors for relapse of ccRCC, but they are not part of Heng's algorithm applied to predict OS in the metastatic setting, which instead is based on 6 clinical/laboratory items. Methods: Retrospective analysis on correlation between pathological parameters and OS (from start of first-line targeted therapy) and Heng's prognostic factors in a multicenter cohort of pts with advanced ccRCC, all of whom had undergone surgery on the kidney. Results: From 2006 to 2012, data of 903 eligible metastatic pts were collected from 33 Italian Oncology Institutions, median age 66 years, 72.6% males, 36.4 metastatic at diagnosis. After a median observation of 42 mo, 70,5% of pts died, estimated OS is 28.5 mo. Heng good prognosis pts were 14.45%, intermediate 69.1% and poor 16.45%. Univariate analysis showed that all pathological parameters significantly correlated with OS: T stage 3-4 vs 1-2 (HR 1.3), N1 vs N0 (1.3), Fuhrman grade 3-4 vs 1-2 (1.7) presence of necrosis (1.5) and sarcomatoid features (1,6). All pathological parameters had a strong correlation with a time to metastases < 1 year, while only weak correlations were found with the other clinical prognostic items of Heng's model. At multivariate analysis only N stage showed an independent impact on OS (table). Conclusions: T3-4 stage, N1, Fuhrman grade 3-4, presence of necrosis and sarcomatoid features negatively affect OS of metastatic ccRCC, but clinical items of Heng's model confirm to have a more robust prognostic significance at multivariate analysis. [Table: see text]
Sunitinib scheduling in metastatic renal cell cancer: A single-center experience.
Authors: Picardo Sarah Louise , Collins Dearbhaile , Al Khamis Amnah , Mallett Victoria Teresa , Keegan Niamh M. , Ismail Irnani , Hennessy Bryan , Breathnach Oscar S. , Grogan William , Morris Patrick G.
Published: February 2017

554

Background: Sunitinib is a receptor tyrosine kinase inhibitor that has proven activity as first line treatment for metastatic renal cell carcinoma (mRCC). The recommended dose is 50mg once daily in a 4 week on 2 week off schedule. However this regimen has a significant side effect profile and alternative schedules have been used to minimize dose reductions and maintain dose intensity. We sought to identify the incidence of dose modifications and assess toxicity in patients treated with two sunitinib schedules in a National Cancer Center. Methods: Patients with mRCC who had sunitinib as first line treatment were identified retrospectively and patient data reviewed. Two patient groups were identified: those who received sunitinib 50mg day 1-28 in 6 week cycles (cohort 1) and those who received sunitinib 50mg day 1-14 in 3 week cycles (cohort 2). Primary end point was incidence of dose modification. Secondary end points included incidence of common sunitinib-related side effects. Known prognostic variables, including prior nephrectomy, body mass index (BMI) and use of angiotensin system inhibitors (ASI) were correlated with time to disease progression (TTP). Results: Between 2009 and 2014, 28 patients were identified. Of those, 23 (83%) patients were treated in cohort 1, and 5 (17%) patients in cohort 2. Dose modifications were required in 13 (56.5%) patients in cohort 1, but only 2 (40%) patients in cohort 2. Common sunitinib-related side effects in cohort 1 included hypertension in 19 (79%), weight loss in 10 (41.6%), fatigue in 9 (37.5%) and nausea in 8 (33.3%) patients respectively. Overall, the use of ASIs correlated significantly with longer median TTP (10.5 months) compared to non-users (4 months) (p = 0.04). BMI ≥ 25 (TTP 9 vs. 3 months, p = 0.008) demonstrated a similar correlation. However, no difference in median TTP was noted between patients who had prior nephrectomy compared to those who had not (5 vs. 4 months) (p = 0.18). Conclusions: In this small retrospective study, standard sunitinib scheduling was associated with a high incidence of dose modifications and side-effects. Consistent with previous studies, we identified known prognostic variables. The use of sunitinib 50mg day 1-14 in 3 week cycles may be more tolerable for patients.
RECORD-4 phase 2 trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC): Final OS analysis.
Authors: Cosgriff Thomas , Yang Lin , Alyasova Anna , Ye Dingwei , Karpenko Andrey , Li Hanzhong , Alekseev Boris , Xie Li-ping , Kowalyszyn Ruben Dario , Karyakin Oleg , Neron Yeni Verónica , Collins LaTonya , Brechenmacher Thomas , Lin Chinjune , Morgan Liza , Motzer Robert J.
Published: February 2017

560

Background: The phase 2 RECORD-4 study assessed EVE in pts with mRCC who progressed after 1 prior anti-VEGF or cytokine (J Clin Oncol 2015;abstr 4518). At primary analysis, median progression-free survival (PFS, primary end point) in the overall population was 7.8 months (95% CI, 5.7-11.0). Here we present results of the final updated primary PFS and final overall survival (OS) analysis. Methods: RECORD-4 enrolled 134 pts with clear cell mRCC into 1 of 3 cohorts based on prior first-line therapy: sunitinib (cohort 1, n=58), other anti-VEGF (cohort 2, n=62: 23 sorafenib, 16 bevacizumab, 13 pazopanib, 10 other), or cytokines (cohort 3, n=14). Pts received EVE 10 mg/d until progression of disease (PD; RECIST, v1.0) or intolerance. Database lock for final analysis was June 26, 2015. Results: Demographics were balanced among cohorts; overall most pts were men (68%) and most had good/intermediate MSKCC prognosis (90%); median age was 59 yrs. Median duration of exposure was 5.8 mo. At the time of final analysis, study discontinuation was primarily due to disease progression (61%). In the overall population, median PFS (95% CI) was 7.4 (5.6-10.5) mo and median OS (95% CI) was 23.8 (17.0-not evaluable [NE]) mo (Table). Overall rate of grade 3 or 4 adverse events (AEs) was 56%. There were 13 on-treatment deaths; primary causes were disease progression, multi-organ failure, and respiratory failure (2.3% each). Conclusions: RECORD-4 final OS analysis supports EVE as a second-line option after sunitinib and other first-line therapies. EVE safety profile was consistent with previous experience. Clinical trial information: NCT01491672. [Table: see text]
Contemporary utilization of non-surgical management for stage I renal masses.
Authors: Ristau Benjamin T. , Handorf Elizabeth , Schaff Matthew , Kim Simon P. , Haseebuddin Mohammed , Waingankar Nikhil , Haifler Miki , Cahn David , Greenberg Richard Evan , Viterbo Rosalia , Chen David Y. T. , Kutikov Alexander , Uzzo Robert G. , Smaldone Marc C.
Published: February 2017

564

Background: While active surveillance has gained traction as a primary treatment strategy for small renal masses in patients with significant competing risks, population level trends of non-surgical management (NSM) remain poorly characterized. Using a large national cancer registry, our objective was to assess temporal trends in utilization of NSM for stage I renal cell carcinoma (RCC). Methods: The National Cancer Database (NCDB) was queried for all patients with stage I RCC from 2003-2012. Patients were categorized as surgical intervention (partial [PN] or radical nephrectomy [RN]) or NSM, and patients undergoing ablative techniques were excluded from analyses. Temporal trends were assessed using Cochran-Armitage tests. Adjusting for patient, clinical, and tumor characteristics, multivariable logistic models were used to examine the association between clinicopathologic characteristics and receipt of NSM. Results: Of 176,975 patients identified, 89% underwent surgical intervention (PN 35.5%, RN 53.5%) and 11% underwent NSM respectively (Stage Ia: 13.1%, Stage Ib: 6.3%). From 2003-2012, utilization of NSM (6.1 vs. 13.1, p < 0.001) and PN (24.4 vs. 47.3%, p < 0.001) significantly increased, while performance of RN significantly declined (69.5 vs. 39.6, p < 0.001). Following adjustment, increased age (51-60 years: OR 1.70 [CI 1.6-1.8]; 61-70 years: OR 2.61 [CI 2.4-2.8]; 71+ years: OR 6.37 [CI 5.7-7.1]), African American race (OR 1.11 [CI 1.03-1.2]), Charlson score 2+ (OR 1.34 [CI 1.2-1.4]), and insurance status (uninsured: OR 1.71 [CI 1.5-2.0]; Medicaid: OR 1.92 [CI 1.7-2.1]; Medicare: OR 1.39 [CI 1.3-1.5]) were associated with receipt of NSM, while patients with tumors > 4cm (OR 0.42 [CI 0.40-0.45]) were less likely to undergo NSM. Conclusions: In hospitals reporting to the NCDB, utilization of NSM as a primary treatment strategy for stage I RCC has doubled from 2003-2012, most notably for tumors ≤ 4cm (Stage Ia). In absence of validated algorithms differentiating between active surveillance, watchful waiting, and those who lost access to care, racial and insurance disparities should be interpreted cautiously.
Expression of PD-1 and PD-L1 in patients with renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).
Authors: Kawakami Fumi , Sircar Kanishka , Rodriguez-Canales Jaime , Tamboli Pheroze , Tannir Nizar M. , Jonasch Eric , Wistuba Ignacio Ivan , Wood Christopher G. , Karam Jose A.
Published: February 2017

582

Background: sRCC is a very aggressive malignancy, with limited treatment options. Given the recent surge in novel immunotherapeutic agents targeting PD-1 and PD-L1, we decided to investigate the expression of these markers in patients with sRCC. Methods: PD-1 and PD-L1 immunohistochemistry was performed on whole sections from nephrectomy specimens in 118 patients with sRCC and 92 patients with clear cell RCC without sarcomatoid dedifferentiation(ccRCC). PD-1 staining was manually evaluated. PD-1 cell numbers ≥ 1/HPF was defined as positive. PD-L1 staining was evaluated with semiquantitative method (H-score = 0-300) with digital analysis. Results: Of the 118 patients with sRCC, 94 had clear cell epithelioid component and 24 had non-clear cell epithelioid component. In the cohort with ccRCC, 20 were grade 4, 58 were grade 3, and 14 were grade 2. 21 cases of sRCC that received neoadjuvant therapy and 2 sRCC and 1 ccRCC where digitally calculated H-score was at variance with manual evaluation were eliminated from the study. 98.6% (73/74) of clear cell sRCC were positive for PD-1. Similarly, 100% (20/20) of the non-clear cell sRCC, 95% (19/20) of the grade 4, and 55/58 (94.8%) of grade 3 ccRCC were positive for PD-1, whereas 9/14 (64.3%) of the grade 2 ccRCC expressed PD-1 (P= 0.0002). 43.2% (32/74) of clear cell sRCC and 55.0% (11/20) of the non-clear cell sRCC were positive for PD-L1, whereas only 10% of the grade 4 non-sarcomatoid ccRCC were positive for PD-L1 (P= 0.0047). None of the grade 2 and 3 ccRCC expressed PD-L1. All the PD-L1 positive cases except 1 clear cell sRCC case were also PD-1 positive. We found a threshold H-score ≥ 25 in sRCC to stratify patient groups with worse prognosis (P= 0.0435) with 29.3% of the cases showing H-score ≥ 25. High PD-L1 H-score was significantly associated with presence of metastatic disease (P= 0.0284). Conclusions: sRCC (both clear and non-clear cell) showed higher frequency and stronger expression of PD-L1 and higher PD-1 positive cell density compared to ccRCC without sarcomatoid component. High expression of PD-L1 is at significant risk of cancer related mortality for sRCC patients. These findings form a rationale to study PD-1 and PD-L1 targeting agents in patients with sRCC.
Role of non-neoplastic renal parenchyma abnormalities in the population with preoperative CKD.
Authors: Mir Maria Carmen , Pavan Nicola , Soodana-Prakash Nachiketh , Balise Raymond R , Venkatramani Vivek , Shabtaie Sam , Channagiri Varun , Fornoni Alessia , Thomas David B , Parekh Dipen
Published: February 2017

586

Background: Renal cancer is associated with chronic kidney disease. Several studies have shown a 20% rate of preoperative CKD in the population undergoing partial nephrectomy. The non-neoplastic abnormalities (NNA) surrounding a tumor have been suggested as surrogates for long term renal failure. We have endeavored to describe the most relevant features within the above mentioned kidney area in patients with and without preoperative CKD. Methods: We retrospectively reviewed 201 patients who underwent nephrectomy between 2012 and 2014 with available histological assessment of NNA. Additional factors were included in the analysis such as demographic characteristics (age, sex, BMI) and comorbidities (hypertension, diabetes, Charlson comorbidity index). Pathological features were grouped as follows: glomerular (GA), interstitial (IA) or vascular abnormalities (VA). Univariate and multivariate logistic regression analyses were used to determine the associations between NNA and the presence of preoperative CKD stage III. Results: CKD stage III patients were older (68 vs. 56 years, P < .004) and presented a higher rate of DM with end-organ damage (n = 10, 13% vs N = 2 2%). Otherwise, people with and without CKD showed similar demographics. Overall, 56% of patients showed GA, 86% showed IA and 98% of patients presented with VA. In the multivariate analysis adjusted for comorbidities, the most relevant GAs were diabetic glomerulosclerosis (OR 7.32; p = 0.01), segmental sclerosis (OR 4.54; p = 0.0006) and glomerular adhesion (OR 2.80; p = 0.04). In the IA group, interstitial fibrosis (OR 7.36; p < 0.001), tubular atrophy (OR 2.75; p = 0.02) and acute interstitial inflammation (OR 12.47; p = 0.02) were significantly associated with decreased eGFR. Hyperplastic arteriolosclerosis (OR 2.30; p = 0.025) was an independent predictor of baseline eGFR < 60. Conclusions: NNA assessment from surgical specimen is feasible. Patients with baseline CKD present with several abnormalities related to inflammation and healing within the three nephron areas. The further investigation of these abnormalities might have a role in the evaluation of ultimate renal deterioration.
Analgesic use and risk of renal cell cancer: Results from two prospective cohort studies.
Authors: Preston Mark A , Zhang Xuehong , Graff Rebecca E , Sanchez Alejandro , Chang Steven L , Stampfer Meir J. , Choueiri Toni K. , Wilson Kathryn M , Cho Eunyoung
Published: February 2017

588

Background: The relationship between the widely used analgesics (i.e., aspirin, other nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen) and risk of total and lethal renal cell cancer remains unclear. Methods: We examined the associations between analgesic use and risk of renal cell cancer overall and by subtypes, in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We collected information on aspirin, other non-aspirin NSAIDs, and acetaminophen in 1990 in the NHS and in 1986 in the HPFS, and every 2 years thereafter. We used Cox proportional hazards models, controlling for other known and suspected risk factors, to examine the associations between baseline and duration of use of each analgesic and risk of total renal cell cancer, lethal renal cell cancer (resulted in death due to disease), as well as clear cell renal cell cancer. We pooled results using a random-effects model. Results: During follow-up of 22 years among 77,527 women and 26 years among 45,913 men, we documented 438 cases of renal cell cancer (230 in women and 208 in men), of which 106 were fatal (56 in women and 40 in men) and 300 were clear cell (165 in women and 135 in men). The pooled multivariable relative risks (RRs) for total renal cell cancer were 1.13 (95% CI: 0.91-1.39) for aspirin use, 1.34 (95% CI: 1.03-1.75) for non-aspirin NSAID use, and 1.07 (95% CI: 0.80-1.44) for acetaminophen use. Similar results were observed for lethal renal cell cancer and clear cell renal cell cancer. Importantly, longer duration of non-aspirin NSAID use was associated with an increased risk of renal cell cancer. The pooled (all p-heterogeneity > 0.05) multivariable RRs for total renal cell cancer were 1.23 (95% CI: 0.94-1.62) for non-aspirin NSAID users of 4-10 years and 1.81 (95% CI: 1.21-2.72) for over 10 years. The corresponding RRs were 1.91 (95% CI: 1.04-3.49) and 3.97 (95% CI: 1.46-10.83) for lethal renal cell cancer, and 1.36 (95% CI: 0.99-1.88) and 1.58 (95% CI: 0.94-2.63) for clear cell renal cell cancer. Conclusions: Our findings support a significant positive association between non-aspirin NSAID use and risk of developing renal cell cancer, especially the lethal form.
Pattern of recurrence after partial and total nephrectomy in non-metastatic renal cell carcinoma (RCC) of low, intermediate and high risk: Implications for follow-up.
Authors: Bex Axel , Kuijpers Yvette , Noe Allard , Bosch Ruud , Horenblas Simon , Meijer Richard
Published: February 2017

601

Background: Guidelines recommend risk-adapted follow-up (FUP) after (partial) nephrectomy in non-metastatic RCC. VEGF-targeted therapy does not cure multiple metastatic RCC. FUP should therefore focus on local recurrences or single-/-oligometastases that may potentially be cured by local therapy. The rate of potentially curable recurrences per risk group is unknown and their pattern and management were analyzed in this study. Methods: From an IRB approved database non-metastatic RCC patients who underwent (partial) nephrectomy from 2004 to 2011 with a minimum FUP of ≥4 years and regular cross-sectional imaging were identified. Risk stratification was assigned to Leibovich- (clear-cell ) or UICC-stage- (non-clear cell) risk groups . Local recurrence, solitary and oligometastases defined as < 3 lesions at a single site were considered potentially curable by local therapy modalities. Recurrences were recorded as was the time to detection of recurrence (TDR) and their management. Results: From 230 patients identified, 191 (clear-cell) and 39 (non-clear cell) were assigned to the Leibovich- or UICC-risk groups respectively. Together, 69 developed recurrences (30 %), of whom 29 (42 %) were potentially curable. Of low-risk patients (32.6 %), only 9 (12 %) had recurrences of which 5 (55.6 %) were potentially curable. In high-risk (19.1 %), of 26 (59.1%) recurrences, the majority were multiple and rapid at a median TDR of 8.4 months (IQR 13.7) with only 6 (23.1 %) potentially curable at a median TDR of 17.6 (IQR 53.8) months. Of 24 recurrences (33.8 %) in intermediate risk, 12 (50 %) potentially curable lesions were detected after a median TDR of 26 (IQR 36.2) months. Together, of 29 potentially curable lesions 15 (51.7 %) were not treated because of comorbidity, poor performance or prognosis and irresectability. Conclusions: High-risk patients predominantly develop multiple metastases early during FUP. A benefit of FUP might derive from identifying potentially curable lesions which develop with latency especially in intermediate and high risk. With only 48 % of potentially curable lesions treated locally the impact of FUP on OS remains controversial.