bluuebunny/crossref_metadata_2025 huggingface dataset:
CHEK2 mutation in renal cell carcinoma (RCC): Single center experience.
Authors: Huszno Joanna , Mazur Magdalena , Nowara Elzbieta , Grzybowska Ewa
Published: March 2017

480

Background: Renal cell cancer (RCC) accounts for about 4% of all the adult malignancies. RCC occurs in both sporadic and heritable forms. Genetic mutations have been identified as the cause of inherited cancer risk in 1% to 2% of RCC cases overall. In some studies, variant I157T of CHEK2 gene were found to be associated with increased risk of clear cell renal cancer. The aim of this study was to evaluate the association between CHEK2 mutation and RCC in our centre. Methods: We reviewed the medical records of 43 clear cell renal cancer patients (pts) who were diagnosed and treated in COI in Gliwice. Mutation profile was assessed by RFLP-PCR technique. In Poland, there are three polymorphic variants of CHEK2 1100delC, IVS2+1G →A (premature protein truncation), and a common missense variant (I157T) (substitution of an isoleucine for a threonine). We evaluated the presence of CHEK2 mutation in clear cell carcinoma. Results: In our study CHEK2 mutation (variant I157T) was detected in 7% pts. The median age of pts was 57 years (range from 34 to 74). Most of the patients were women (87%). All CHEK2 mutation carriers were women and were >65 years old. Cancer in family history were reported in 80% pts. Most frequently were: breast cancer (33%), gynecological cancers (33%), gastrointestinal cancers (27%), and renal cell carcinoma (20%). There was also described lung cancer in family history (7%). The most frequent cancers in family history in CHEK2 mutation carriers were: breast cancer and gynecological cancers. 20% of pts had other cancers in their history (breast cancer, ovarian cancer, and contralateral renal cell carcinoma). Contralateral renal cell carcinoma was reported in CHEK2 mutation carrier. All pts had nephrectomy due to RCC and all had clear cell renal cancer in histopathologic examination. All CHEK2 mutation carriers had higher grade (grade 3) and capsular invasion. 5% of CHEK2 mutation carriers had TP53 (c.[215G>C])polymorphism. Conclusions: Variant I157T of CHEK2 gene were found to be associated with increased risk of cancer in family history (breast cancer, gynecological cancer), and renal cancer of contralateral kidney. Factors associated with CHEK2 mutation carriers were higher histologic grade (G3) and elderly age.
ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.
Authors: Bassanelli Maria , Felici Alessandra , Milella Michele , Giannarelli Diana , Giacinti Silvana , Gentile Giovanna , Carlini Paolo , Cognetti Francesco , Roberto Michela , Poti Giulia , Macrini Serena , Aschelter Anna Maria , Simmaco Maurizio , Marchetti Paolo
Published: March 2017

485

Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.
Determinants of treatment in patients with stage IV renal cell carcinoma.
Authors: Hollenbeak Christopher S. , Schaefer Eric W. , Doan Justin , Raman Jay D.
Published: March 2017

486

Background: Although there have been significant advances in the detection and treatment of renal cell carcinoma (RCC), many elderly patients—particularly those with stage IV disease—likely receive no treatment. The purpose of this research was to study treatment patterns for elderly patients with stage IV RCC and determine patient and disease characteristics associated with receiving no treatment. Methods: Data from the Surveillance Epidemiology and End Results (SEER) and Medicare linked data set were analyzed. We identified 949 stage IV RCC patients over age 65 years diagnosed between 2007 and 2011. Surgery was identified using Medicare Part A and B claims, and use of systemic therapy was identified from Part D claims in addition to Part A and B claims. Treatment approach, including no treatment, was modeled using multinomial logistic regression controlling for several patient and disease characteristics, allowing us to identify significant risk factors for no treatment. We also performed landmark analyses at 3 and 6 months to account for early death as a potential cause for no treatment. Results: Of the 949 patients with stage IV RCC, 26.2% received surgery and 34.1% received systemic therapy within 6 months of diagnosis. Of 324 patients who received systemic therapy, most received sunitinib (57.1%), temsirolimus (21.3%), or sorafenib (12.3%). Over half of patients (51.2%) had no evidence of receiving surgery or systemic therapy. Of the 618 patients who survived at least 3 months, 38.3% received no treatment within 3 months, and among the 447 patients who survived at least 6 months, 26.6% received no treatment within 6 months. Older patients and those with a higher Charlson Comorbidity Index had lower odds of being treated with surgery, systemic therapy, or both; married patients had higher odds of being treated. These results were largely sustained in 3- and 6-month landmark analyses. Conclusions: Many elderly patients with stage IV RCC did not receive surgery or systemic therapy despite surviving at least 6 months from diagnosis. Several factors appear to be associated with this phenomenon. Further investigation should determine reasons why physicians and/or patients are reluctant to use systemic therapy in patients.
BAP1 tumor predisposition syndrome: Preliminary data from a laboratory-based multigene panel testing cohort.
Authors: Horton Carrie , LaDuca Holly , Reineke Patrick
Published: March 2017

490

Background: Germline mutations in BAP1 have recently been shown to cause a tumor predisposition syndrome characterized by renal cell carcinoma (RCC), uveal melanoma, cutaneous melanoma, and mesothelioma. However, mutations have thus far been identified in highly enriched cohorts and the tumor spectrum among individuals with a broader phenotype undergoing multi-gene panel testing (MGPT) has not been described. Other genes associated with familial RCC have been established, such as FLCN (Birt-Hogg Dube syndrome) and VHL (von Hippel Lindau), but the proportion of BAP1 mutations in individuals with RCC is not yet known. Here we aim to describe the clinical features of individuals with BAP1 mutations identified from a clinical laboratory cohort, and to estimate the frequency of BAP1 mutations in individuals with kidney cancer. Methods: Since May 2015, a total of 6956 tests have been ordered that include BAP1 at our diagnostic laboratory. Retrospective data review yielded molecular and clinical details for individuals with identified mutations. Results: Thirteen individuals with BAP1 mutations have been identified. Cancer diagnoses in probands and family members consist of breast cancer (reported in 69.2% of kindreds), RCC (61.5%), melanoma (61.5%), mesothelioma (46.2%), lung cancer (46.2%), non-melanoma skin cancer (30.8%), and cholangiocarcinoma (15.4%). Among probands with kidney cancer undergoing MGPT (n = 1012), there is no difference in mutation rate of BAP1 compared to VHL (n = 3; OR 2.01 p = 0.51) or FLCN (n = 10; OR 0.598 p = 0.45). Conclusions: Cancer histories in our laboratory-selected cohort of BAP1 mutation carriers are consistent with those reported in the clinical literature, lending credence to the notion that BAP1 tumor predisposition syndrome is highly penetrant and consists of a constellation of several core cancers. The observation of breast, lung, non-melanoma skin cancer, and cholangiocarcinoma has also been reported in the literature and warrants further study. Our results suggest that BAP1 mutations are found at a similar frequency as other well-known kidney cancer genes, supporting its position as an important differential when considering genetic testing for RCC.
Impact of rural/urban residence on relative survival (RS) in patients with kidney cancer: An analysis of 14576 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Hackl Monika , Rauchenwald Michael
Published: March 2017

491

Background: Access to medical diagnostics and treatment might be limited for patients living in rural areas compared to urban residents. To evaluate the potential impact of urban/rural residence, we analyzed trends in RS for patients diagnosed with kidney cancer between 1998 and 2009 in Austria. Methods: All patients with kidney cancer aged ≥18 years, diagnosed from 1998-2009 were derived from the ANCR (n=14,576). Patients were categorized into two groups: rural (n=7,537) and urban (n=7,039) based on a complex algorithm considering infrastructure, commuter interrelations, accessibility of centers, and tourism at the time of diagnosis. Relative survival was calculated based on complete follow-up until December 31st, 2014. Poisson regression modeling was used to evaluate survival differences between the two groups and to calculate the relative excess risk of dying (RER). Analyses were performed for the total patient population and primary metastatic patients (M+). Results: Distribution of sex, age, stage of disease, year of diagnosis, and surgical treatment did not differ between rural and urban patients. Five-year RS was 74% for rural compared to 73% for urban patients (RER for rural: 0.88, 95% CI 0.81-0.95). In M+ patients, 5-year RS was 14% for both residence groups. On multivariate analysis, residence remained as an independent predictor for survival in the overall kidney cancer population (RER of rural patients 0.87, 95% CI 0.81-0.94). For M+ patients the RER was 0.90 ( 95% CI 0.81-1.00). For patients without surgery, rural patients were even stronger benefited in their survival than urban patients (overall population: RER 0.81, 95% CI 0.74-0.89; M+ patients: RER 0.84, 95% CI 0.73-0.97) wherereas in surgical patients RS did not differ between rural and urban patients. Conclusions: An advantage in RS was observed for kidney cancer patients living in rural areas. This advantage was evident in metastatic and non-metastatic patients, especially in patients who did not undergo surgery for (metastatic) kidney cancer. These results suggest that access to medical health care for kidney cancer patients in Austria is not limited by rural residence.
Management of renal masses in an octogenarian cohort: Is there a right approach?
Authors: Nawlo Jude , Tang Dominic H. , Chipollini Juan , Gilbert Scott Michael , Poch Michael Adam , Sexton Wade Jeffers , Pow-Sang Julio , Spiess Philippe E.
Published: March 2017

497

Background: Although several guidelines outline management options for patients with renal masses, few studies describe treatment strategies and outcomes in octogenarians. We sought to review outcomes in this population managed with active surveillance (AS), partial nephrectomy (PN), or radical nephrectomy (RN). Methods: Data were collected on 113 octogenarian patients referred for management of renal masses at Moffitt Cancer Center between 2000 and 2013. Patients were treated with AS, PN, or RN. Univariate and multivariable Cox regression models measured association of management modality and survival. Kaplan-Meier survival analysis was used for overall survival and log-rank tests were used to compare survival curves. Covariates include age, Eastern Cooperative Oncology Group (ECOG) score, clinical and pathologic stage, tumor size, creatinine, creatinine clearance, and overall survival. Results: Out of 113 patients, 27 (22%) underwent AS, 33 (26.8%) underwent PN, and 53 (43%) underwent RN. The mean age was 83 years (range, 80-92). AS patients had a higher mean age (84 years) than PN patients (81.9 years), but not with RN patients (83 years) (p=0.008). At a median follow-up of 30.6 months (IQR 9.9-56), 13 (48%), 10 (30.3%), and 29 (54.7%) patients died from any cause in AS, PN, and RN patients respectively. PN patients tended to have a longer median overall survival at 81 months versus 55.8 and 57 months for AS and RN respectively, but this did not reach statistical significance on univariate (p=0.588) or multivariate analysis (p=0.29). On subgroup analysis of cT1a patients, there was also no difference in overall survival among treatment arms on univariate (p=0.654) and multivariate analysis (p=0.47). At 1 year follow-up, there was no difference in creatinine levels between treatment arms (p=0.331). However, mean creatinine clearance was lower in RN patients (35.8 ml/min) compared to AS (50.7 ml/min) and PN (48.1 ml/min) (p=0.024). Conclusions: Active treatment with PN and RN may not provide a survival advantage among octogenarians. Renal function was inferior in RN patients but comparable between AS and PN patients at 1 year follow-up.
Whole blood mRNA expression for prognosis of metastatic clear cell renal carcinoma (mCCRCC).
Authors: Giridhar Karthik , Hillman David W. , Sosa Carlos , Dalpiaz Candace Lee , Costello Brian Addis , Quevedo Fernando , Pitot Henry C. , Dronca Roxana Stefania , Ertz Donna , Cheville John C. , Donkena Krishna , Kohli Manish
Published: March 2017

500

Background: The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters and has several limitations. We analyzed whole blood mRNA expression in mCCRCC patients (pts) and compared it to MSKCC for predicting overall survival (OS). Methods: A prospective collection of whole blood in PAXgene RNA tubes from mCCRCC pts was performed between 2011 and 2015 with uniform processing. A discovery set (DS) of 19 randomly selected pt samples was used to generate whole transcriptome RNA sequencing and signatures describing differential gene expression patterns associated with OS. We calculated the fragment per kilobase of transcript per million (FPKM) of each transcript and gene to identify correlations between the differentially expressed genes and MSKCC score. Candidate genes were selected based on statistical significance (p<0.05) and associations with OS. In an independent validation set (VS) of 47 pts with mCCRCC, we used the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA) to quantify gene transcript expression selected from the DS. Cox regression and Kaplan-Meier analysis were used for association of candidate mRNAs in the VS with OS (time of metastatic recurrence to death or last follow-up). We compared our gene signature to the MSKCC prognostic score for poor versus good survival. Results: In the DS, at a median follow-up of 4.13 years (yrs) (range: 1.3-4.5), 11 patients had died. We identified eighteen genes in the DS with statistically significant differential gene expression patterns and ability to discriminate patient OS. In the VS at a median follow-up of 4.9 yrs (range: 0.1-11.3), twenty-five patients had died. We confirmed two of the eighteen selected genes that had strong prognostic significance: BAG1 [hazard ratio (HR) 0.31, p=0.007] and NOP56 [HR 0.28, p=0.004]. Comparing OS between good and poor outcome groups for these 2 scores, our two-gene panel had higher prognostic ability (HR 20.07, p <0.0001) than the MSKCC prognostic score (HR 3.19, p 0.04). Conclusions: Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.
Impact of cytoreductive nephretomy on timing of systemic therapy in metastatic kidney cancer.
Authors: Macleod Liam Connor , Dash Atreya , Schade George , Harper Jonathan D. , Lin Daniel W. , Tykodi Scott S. , Gore John L.
Published: March 2017

503

Background: High rates of disease control with systemic therapy (ST) in the post-cytokine era for metastatic renal cell carcinoma (mRCC) cause apprehension that cytoreductive nephrectomy (CN) may delay effective therapy. We therefore evaluated factors associated with early mortality and time to ST after CN. We hypothesized markers of poor performance status and morbid CN would be associated with postoperative mortality and therapeutic delays. Methods: The National Cancer Database was screened for adult mRCC cases having CN followed by ST, years 2006-2013. We classified a delay in systemic therapy as interval > 45 days (median time to ST in the cohort). Multivariable logistic regression was performed, identifying factors associated with perioperative mortality and delays to initiation of ST. Results: Of 10,913 patients with initial CN (45% of mRCC), 30- and 90-day mortality were 3% and 11%, respectively. 6,362 later received ST (87% targeted therapy, 13% immunotherapy), median start was 45 days post-operatively (IQR 9-72), with 73% receiving ST within 30 days of CN. Multivariable factors associated with 30-day mortality included, older age, (OR 2.3, 95% CI 1.5-3.5 for those >75 [referent < 55 years]), Charlson index >0 (OR 1.3, 95% CI 1.0-1.6), lack of insurance (OR 1.9, 95% CI 1.2-2.8 [referent private payer]), node-positive disease (OR 1.4 95% CI 1.1-1.7), length of stay > 90th percentile (> 10 days, OR 3.2, 95% CI 2.0-5.3), larger tumor size (T4 lesion OR 1.7, 95% CI 1.2-2.5 [referent T1]). Delayed ST was associated with travel burden > 50 miles (OR 1.2, 95% CI 1.0-1.4), concurrent metastasectomy (OR 1.3, 95% CI 1.2-1.5), and length of stay > 90th percentile (OR 1.5, 95% CI 1.1-2.3). Conclusions: These data suggest that markers of frailty, more progressive disease, and surgical morbidity may contribute to surgical-related deaths or hinder patients receiving potentially disease-controlling therapy when treated with initial CN in mRCC. Going forward, existing surgical prognostic models could incorporate risks of surgical-related mortality and delay to ST when considering CN.
Pattern of glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) expression in peripheral blood as a marker for myeloid-derived suppressor cells (MDSCs) in metastatic renal cell cancer (mRCC) patients.
Authors: Kato Tomoyuki , Takeda Yuji , Kurota Yuta , Ito Hiromi , Araki Akemi , Nara Hidetoshi , Asao Hironobu , Tsuchiya Norihiko
Published: March 2017

504

Background: Metastatic renal cell cancer (mRCC) patients are afflicted with the immunosuppressed condition, and myeloid-derived suppressor cells (MDSCs) are considered to be associated with this condition. MDSCs are difficult to detect in peripheral blood as their cell structures are not uniform, resembling both neutrophils and monocytes. GPI-80 is known as a regulator of Mac-1 (CD11b/CD18) and closely related with neutrophilic maturation. In this study, we investigated whether the pattern of GPI-80 expression could serve as a useful marker for the detection of MDSCs in peripheral blood among mRCC patients. Methods: This study was approved by the Ethics Committee of Yamagata University’s Faculty of Medicine. Peripheral blood samples, collected from 12 mRCC patients before treatment and 12 healthy volunteers, were stained with several differentiation markers such as CD11b, CD16, CD15, CD33, and GPI-80. The samples were examined using flow cytometry to detect unusual differentiation of myeloid cells. To investigate the immunosuppressive function of GPI-80 positive cells, reactive oxygen species (ROS) was measured, and T cell proliferation assay was performed. Results: The coefficient of variation (CV) of GPI-80 was significantly augmented in the CD16hi neutrophil cell population (p = 0.0001). The mean fluorescence intensity (MFI) of GPI-80 was significantly increased in the CD33hi monocyte cell population (p = 0.0074) in the peripheral blood cells of mRCC patients. Furthermore, the GPI-80 CV in the CD16hi population was inversely correlated with the proliferative ability of T cells (p = 0.0214), and the GPI-80 MFI of the CD33hi population was correlated with ROS production (p = 0.0497). Conclusions: These results showed that the pattern of GPI-80 expression in peripheral blood cells is a simple and useful marker for unusual differentiation, which is linked to MDSC functions among mRCC patients. Further studies are, however, required to identify the role of GPI-80 as a prognostic or predictive marker in such patients.
Ablative therapy to induce local and systemic immune changes in patients with metastatic renal cell carcinoma.
Authors: Campbell Matthew T. , Matin Surena F. , Slack Rebecca , Sun Jing Jing , Ng Tang Derek , Chen Hong , Blando Jorge M , Zhang Li , Rao Priya , Sharma Padmanee
Published: March 2017

505

Background: Ablative therapy including cryoablation or radiofrequency ablation is a therapeutic option for small renal cell carcinomas (RCC) and provides effective palliation for symptomatic metastatic lesions, with reports of associated abscopal phenomenon in small numbers of patients. Pre-clinical animal modeling has suggested potential synergy with the use of ablative therapy and immune checkpoint blockade with ipilimumab. Methods: We performed retrospective analysis of 17 patients who underwent an ablative procedure followed later by nephrectomy. These samples were analyzed by IHC and gene expression studies. We also prospectively evaluated pre and post treatment blood samples from a different cohort of 13 patients. These samples were evaluated for immune cell subsets and cytokine profiles. Results: IHC studies revealed an increased frequency of PD-1 + immune cells in post-ablative tumor samples as compared to control samples. Gene expression studies also revealed higher expression of immune gene signatures as compared to control samples. Blood samples detected changes in regulatory T cell subsets and interleukin-6 cytokine levels in the short term, which normalized by 1 month post-ablation, suggested an active downregulation of the initial immune response. Based on these data, we initiated a clinical pilot study to treat patients with anti-CTLA-4 (tremelimumab) with or without cryoablation in patients with metastatic RCC. The primary endpoint of the trial will be safety. Secondary endpoints include objective response rate, progression free survival, and immune monitoring. A total of 30 patients, 15 in each arm, will be accrued. Initial data from the clinical trial will be presented. Conclusions: Ablative therapy causes immune changes that can be detected both at the tissue and systemic level. We hope to capitalize on these changes by combining immune checkpoint blockade and ablation in an ongoing prospective clinical trial.
Impact of pharmacokinetics (PK) of sunitinib (SU) and its metabolite SU12662 on clinical outcome and toxicity in metastatic renal cell cancer (mRCC) patients.
Authors: Martin Nicolas , Borchiellini Delphine , Viotti Julien , Chamorey Emmanuel , Milano Gerard A. , Ferrero Jean-Marc
Published: March 2017

506

Background: Pharmacological activity of SU is usually attributed to SU and its active metabolite SU12662, known to exhibit similar potency in inhibiting tyrosine kinase activity and cellular proliferation in vitro. However, equivalence is not clearly demonstrated towards clinical endpoints. The objective of this phase 2 study was to determine the impact of SU and SU12662 on clinical outcomes and toxicity in mRCC patients (NCT00943839). Methods: Patients with mRCC, eligible for SU in the first line setting, were prospectively included. SU was given orally at 50 mg qd for 4 weeks on/2 weeks off until progression or unacceptable toxicity. Minimal concentration at steady-state (CSSmin) was evaluated by high-performance liquid chromatography at day 28 of each cycle for both SU and SU12662. Data for tumor response, survival, and toxicity were recorded. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between PK parameters and survival. Chi2 tests and student t-tests were used to identify relationships with toxicity. Results: 41 patients in 7 French centers were included between 2009 and 2012. 16 patients had favourable prognosis, 13 intermediate prognosis, and 1 poor prognosis according to IMDC risk groups (Heng, J Clin Oncol 2009). Median follow-up was 30.6 months. Median progression-free survival (PFS) was 20.2 months and median overall survival (OS) was 39.5 months. Mean CSSmin for SU and SU12662 were 57.2 and 29.8 ng/ml, respectively. CSSmin of SU12662 was independently correlated to poor PFS and OS (p = 0.01 and 0.003 respectively). Patients with a mean CSSmin of SU12662 higher than 42.5 ng/ml had a worse PFS and OS compared to patients with lower concentrations: 5.7 months and 5.7 months versus 20.6 months and 39.5 months (p = 0.01 and 0.002 respectively). High CSSmin of both SU and SU12662 were associated with increased incidence of asthenia (p<0.001). Conclusions: High exposure to SU12662 was associated with poor outcomes and increased asthenia for patients with mRCC treated with SU in the first line setting. It may be related to a higher metabolism and unequal activity between SU and SU12662 in vivo. Clinical trial information: NCT00943839.
Correlation between inflammatory markers in blood and expression of costimulatory molecules on tumor-infiltrating CD8+ lymphocytes in renal cell carcinoma.
Authors: Kissick Haydn T. , Kim Kyu Seo , Chang Yun Min , Master Viraj A.
Published: March 2017

508

Background: Loss of co-stimulatory molecules by CD8 T-cells is associated with reduced proliferative and cytotoxic function in chronic viral infections, aging, and cancer. Several lines of evidence suggest that a more functional immune system is associated with better patient outcomes, and improved response to immunotherapy in a range of different cancers. For this reason, understanding the features of a patient that predict the loss of T-cell function is important. In this study we characterized how co-stimulatory molecules are expressed by T-cells in the tumors of RCC patients. Additionally, we characterized how distant sites of metastasis differ from the primary tumor, and finally, we evaluated levels of blood inflammatory markers (BIMs) to predict how co-stimulatory on CD8+ TILs change. Methods: Patients that underwent resection of primary and/or metastatic RCC at Emory University Hospital were prospectively enrolled in the study. Levels of pre-op BIMs were retrieved from medical records. A portion of resected tumor tissue was analyzed by flow cytometry to measure percentage of CD8+ cells expression of the co-stimulatory molecules, ICOS, CD27, CD40L, CD226, CD28, and CD2. A composite co-stimulatory score (co-stim score) was calculated by taking a weighted average of the number of co-stimulatory receptors expressed per cell. BIMs were correlated with CD28 expression and co-stim score. Expression of co-stimulatory receptors was compared between patient-matched primary tumor and metastatic tumor pairs. Results: We found that by CD8 T-cells in tumors often lost co-stimulatory molecules. Furthermore, albumin and Hgb both had a strong positive correlation with CD28 expression and overall co-stim score, while WBC, Plt, neutrophil-lymphocyte ratio (NLR), ESR, and CRP was negatively correlated. Expression of co-stimulatory receptors did not differ significantly between primary tumor and metastatic tumor pairs suggesting that a systemic effect controlled TIL phenotype rather than site specific factors. Conclusions: Our data show that BIMs have the potential to predict the immunologic phenotypes of cytotoxic TILs in RCC noninvasively.
Predicting disease progression in men with localized high risk prostate cancer undergoing radical prostatectomy.
Authors: Nyame Yaw A. , Tosoian Jeffrey J. , Alam Ridwan , Wilkins Lamont , Yousefi Kasra , Chappidi Meera , Reddy Chandana A. , Humphreys Elizabeth B. , Sundi Debasish , Chapin Brian F. , Stephenson Andrew J. , Klein Eric A. , Ross Ashley
Published: March 2017

51

Background: Currently utilized pre-treatment nomograms for prostate cancer were developed and validated using populations primarily composed of men with low and intermediate risk disease. This study aims to construct a nomogram that predicts for biochemical recurrence (BCR) and metastasis (mets) from a contemporary cohort of men with with NCCN high (HR) and very high risk (VHR) prostate cancer. Methods: From 2005 to 2015, 1,241 men with NCCN HR or VHR prostate cancer were identified from two large academic medical centers. The cohort was divided into training (n = 620) and validation (n = 621) cohorts. Primary endpoints were BCR and mets. Cox multivariable regression was performed to model characteristics and outcomes in the training cohort. Model accuracy was assessed using the time-dependent area under the receiver operator characteristic curve (AUC) in the validation cohort. Results: 494 men (245 training and 249 validation) developed BCR, and 123 men (64 training and 59 validation) developed mets, with BCR-free and mets-free probability of 49.0% and 86.5% at 5- years, respectively. Predictive nomograms including age, ethnicity, PSA, Gleason grade, clinical stage, and the number of cores with Gleason 8-10 disease were developed. Models for BCR and mets had AUCs of 0.72 and 0.75. By comparison, the MSKCC preoperative nomogram and CAPRA nomogram provided AUCs of 0.69 and 0.68 for predicting BCR and 0.66 and 0.67 for mets. Conclusions: Individualized risk assessment is imperative for optimal decision making and to design and power clinical trials. The nomograms described here, created from a population exclusively comprised of HR/VHR men, have better discrimination than those previously established on cohorts of primarily low and intermediate risk men, and may represent an ideal way by which oncologic outcomes can be predicted in men with HR or VHR disease.
Genomic profiling of nephrectomy and metastatic sites in patients with advanced clear cell renal cell carcinoma (RCC).
Authors: de Velasco Guillermo , Madison Russell , Ali Siraj Mahamed , Signoretti Sabina , Mullane Stephanie Anne , Ross Jeffrey S. , Miller Vincent A. , Stephens Philip J. , Schrock Alexa Betzig , Young Lauren , Pal Sumanta K. , Choueiri Toni K.
Published: March 2017

513

Background: Novel biomarkers are required to accurately assess response in renal cancer. Genomic alterations (GAs) in samples from primary (nephrectomy) (N) as compared distant metastases (M) in clear cell RCC (ccRCC) may have clinical implications as well as mutations in circulating tumour DNA (ctDNA). Methods: 237 primary ccRCC nephrectomy specimens and 156 samples from distant metastases were assayed by hybrid capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify GAs suggesting benefit from targeted therapy. Tumor mutation burden (TMB) was assessed as the number of somatic coding point mutations per megabase of targeted territory. Aditionally, 17 patient-specific assays were developed to quantify ctDNA allele fraction (AF) in plasma of mRCC patients. Results: 1263 GAs and 34 clinically relevant GA (CRGAs) were identified. Most common GA identified were VHL (74%/72%), PBRM1 (40%/51%), SETD2 (28%/26%) in N and m respectively (Table). Additionally, most common CRGA identified were TP53 (8%/15%), PTEN (10%/10%), TSC1 (6%/6%), and TERT(5%/9%) in N and m respectively. No difference in TMB was seen between primary and metastatic samples. By site of metastases, soft tissue, and adrenal gland had the highest TMB and lymph node the lowest. In the 17 patients with available ctDNA, 15/17 (88.2%) have a maximum somatic AF < 1% (median 0.33% [0% - 22%]) suggesting generally low tumor content. Interestingly, ctDNA in 3 patients were successfully sequenced including a patient with an EML4-ALKfusion treated with alectinib. Conclusions: This data supports that both primary and metastatic RCC share the majority of common GA. Quantitation of ctDNA is a promising biomarker for response. [Table: see text]
DNA methylation signature for the assessment of metastatic risk in primary renal cell cancer.
Authors: Peters Inga , Reese Christel , Dubrowinskaja Natalia , Antonopoulos Wiebke Inga , Krause Martin , Dang Tu Nghi , Grote Alexander , Becker Albert , Hennenlotter Jörg , Stenzl Arnulf , Tezval Hossein , Kuczyk Markus A , Serth Juergen
Published: March 2017

516

Background: Transition from localized renal cell cancer (RCC) to metastatic disease is associated with an immense mortality. Beside clinicopathological risk estimation, a molecular prediction of metastatic risk from primary cancers with a sufficient diagnostic accuracy is not available. We biometrically identified a candidate metastasis associated methylation signature (MAMS) in a genome-wide in silico DNA methylation analysis of TCGA data and carried out a double evaluation study using tissues from localized RCC, primary metastatic RCC, and distant metastases. Methods: Candidate MAMS was identified by genome-wide random forest analyses of TCGA methylation level 3 data aiming for classification of 230 primary RCC without distant metastases and 52 metastasized tumors. Forty-nine pyrosequencing and/or quantitative methylation specific PCR analyses were established for a total of 20 candidate methylated loci. For evaluation of MAMS, DNA was isolated and bisulfite converted from the primary RCC tissue cohort (n=187) as well as 99 distant metastases. Localized RCCs consisted of 92 pT1a/b tumors (clear cell, 73; papillary, 16; chromophobe, 2; not classified, 1) without lymph node or distant metastases. RCC samples of primary metastatic disease were obtained from 31 patients. Results: Single candidate loci showed specific hypermethylation when metastatic tissues were compared to primary RCC samples. Random forest analysis showed that MAMS including nine methylation loci achieved a sensitivity of 93% and a specificity of 89% (AUC 0.95) for differentiation of localized RCC and metastases (chi square, p = 3.4*10-29). Positive, negative likelihood, and diagnostic odds ratios were 8.6, 0.08, and 108. Using this random forest model for prediction of primary RCCs associated with distant or lymph node metastases revealed a sensitivity of 58% and specificity of 94% (AUC 0.84, p = 1.0*10-9). Positive, negative likelihood, and diagnostic odds ratios were 9.2, 0.45, and 20.5. Conclusions: A negative MAMS test result retrospectively reduced the probability of metastasis 15-fold in the localized disease cohort, suggesting a prospective evaluation for a possible clinical translation of MAMS in handling RCC patients.
An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.
Authors: Lin Jianqing , Hoffman-Censits Jean H. , Kelly William Kevin , Tuluc Madalina , Shaw Colette , Louie Jennifer , Harshyne Larry , Kean Rhonda , Bar-Ad Voichita , Den Robert B. , Hurwitz Mark , Johnson Jennifer Maria , Hubert Christine , Philipose Sherin , Leiby Benjamin E. , Deshmukh Sandeep P. , Dicker Adam , Hooper D. Craig , Lu Bo
Published: March 2017

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Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b) pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: 12 RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of September 30, 2016, 5 pts were still on study with 3 pts having partial response (27.2%, responders) and were on study for at least 9.8 months. 2 responders were treated with 8 Gy f/b pembro while 1 was treated with pembro f/b RT f/b pembro. Six pts (54.5%, non-responders) had PFS between 2 – 4 m and were off study. For adverse events, 1 pt developed grade 4 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include fatigue, nausea, hyperglycemia, lymphopenia, thrombocytopenia, and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders compared with responders. CD4+, CD8+, and NK cells and other markers are under-analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T, and NK cell kinetics are being examined. Clinical trial information: NCT02318771.
The necessity of dynamic contrast enhanced imaging for prostate MRI: A study of pathologic outcomes on prostate biopsy.
Authors: Druskin Sasha C. , Tosoian Jeffrey J. , Young Allen , Ghabili Kamyar , Andreas Darian , Macura Katarzyna , Ross Ashley
Published: March 2017

52

Background: PIRADS version 2 guidelines for the interpretation of multi-parametric prostate MRI (mpMRI) stipulates that dynamic contrast-enhanced (DCE) imaging be used to classify diffusion weighted imaging (DWI) score 3 peripheral zone lesions into PIRADS-3 (DCE-) or PIRADS-4 (DCE+) lesions. Despite this, it is unknown if DCE based classification separates lesions into clinically meaningful pathologic groups. Because use of contrast adds time, risk (though modest), and cost to mpMRI, we sought to examine whether use of DCE indeed improves detection of clinically-significant cancer. Methods: Using the Johns Hopkins MRI-ultrasound fusion prostate biopsy database and including only patients without a prior diagnosis of prostate cancer (n = 232), we identified patients with peripheral zone DWI-3 or DWI-4 lesions who underwent targeted biopsy of those lesions. Each lesion meeting the MRI criteria was considered separately, and grouped into one of three lesion MRI classifications – DWI-3/DCE-/PIRADS-3, DWI-3/DCE+/PIRADS-4, or DWI-4/PIRADS-4. The rates of benign, grade group (GG) 1, and GG ≥ 2 pathology were compared between the MRI classification groups. Results: One hundred forty-eight peripheral zone DWI-3 or DWI-4 lesions from a total of 106 patients were identified. The rate of benign(%)/GG1(%)/GG ≥ 2(%) biopsy pathology in the groups DWI-3/DCE-/PIRADS-3 (61 lesions), DWI-3/DCE+/PIRADS-4 (37 lesion), and DWI-4/PIRADS-4 (47 lesions) was 68.9/18.0/8.2, 59.5/13.5/18.9, and 44.7/23.4/27.7, respectively (P > 0.05 for the difference in rates of GG ≥ 2 pathology between the two PIRADS-4 groups and the two DWI-3 groups). Conclusions: Given the cost and morbidity of using intravenous contrast agents in prostate MRI, their clinical utility must be determined. In this study, DWI-3 peripheral zone lesions with DCE positivity appear to have a higher rate of clinically-significant (GG ≥ 2) cancer on biopsy. This study supports the use of DCE to better classify DWI-3 peripheral zone lesions however further study with expanded cohorts is indicated.
Analysis of overall survival (OS) based on tumor target lesion change in the phase 3 METEOR trial of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC).
Authors: Pal Sumanta K. , Motzer Robert J. , Fishman Mayer N. , McDermott Raymond S. , Passos-Coelho Jose , Kopyltsov Evgeniy , Garcia del Muro Xavier , Donas Jesus Garcia , Yildiz Ramazan , Wood Lori , Zalewski Pawel , Costello Brian Addis , Stadler Walter Michael , Kuzel Timothy M , Williamson Stephen K. , Kondo Takeyoshi Alfonso , Markby David W , Escudier Bernard , Powles Thomas , Choueiri Toni K.
Published: March 2017

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Background: In the METEOR study (NCT01865747), cabo demonstrated improved progression-free survival (median 7.4 vs. 3.8 mo; HR 0.58, 95% CI 0.45–0.74; p<0.0001), OS (median 21.4 vs. 16.5 mo; HR 0.66, 95% CI 0.53-0.83, p=0.0003), and objective response rate (17% vs. 3%; p<0.0001) compared with eve in patients (pts) with advanced RCC who had received prior VEGFR TKI therapy (Choueiri NEJM 2015, Lancet Oncol 2016). Here we evaluate the impact of changes in target lesion size from baseline on OS. Methods: 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed per independent radiology review by CT/MRI scans at baseline, every 8 weeks for the first 12 months, and every 12 weeks thereafter. Three subgroups were defined by best change in target lesion size from baseline: decrease ≥30%, decrease <30%, and any increase. Results: The rate of target lesion regression was higher in the cabo arm (75%) compared with the eve arm (48%). A higher fraction of pts had a decrease ≥30% in target lesion size in the cabo arm, while a higher fraction of pts had an increase in target lesion size in the eve arm (Table). Medians for OS with cabo were not estimable (NE) (95% CI, NE‒NE), 20.8 mo (95% CI, 18.1‒NE), and 11.1 mo (95% CI, 7.6‒15.2) for the ≥30% decrease, <30% decrease, and any increase subgroups, respectively. Medians for OS with eve were NE (95% CI, 19.3‒NE), 18.0 mo (95% CI, 15.9‒20.4), and 14.0 mo (95% CI, 10.5‒16.3) for the ≥30% decrease, <30% decrease, and any increase subgroups, respectively. Median duration of follow-up for OS was 18.7 mo (IQR 16.1–21.1) for cabo and 18.8 mo (16.0–21.2) for eve. A higher proportion of pts received subsequent anticancer therapy in the any increase subgroup compared with the other subgroups. Conclusions: Cabo demonstrated a higher rate of tumor target lesion regression than eve, and greater target lesion regression was associated with improved OS in pts with advanced RCC. Clinical trial information: NCT01865747. [Table: see text]
Retrospective review of cytotoxic chemotherapy and anti-angiogenic combinations in renal cell carcinoma: A single institution experience.
Authors: Carthon Bradley Curtis , Tabba Manal , Ellis Carla , Harris Wayne , Bilen Mehmet Asim , Canter Daniel , Master Viraj A. , Kucuk Omer
Published: March 2017

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Background: Despite many therapeutic advances, Renal Cell Carcinoma (RCC) still is a leading cause of cancer morbidity and mortality. A recent phase 2 study has examined the combination of Sunitinib and Gemcitabine in a poor risk RCC trial population (Michaelson et al., Cancer 2015). There is limited data on such combinations in a non-clinical trial population. This retrospective study examines our institutional experience in treating predominantly high risk RCC patients with a combination of gemcitabine and an anti-angiogenic agent. Methods: IRB approval was obtained in order to review pathological and clinical data of RCC patients. A retrospective cohort was identified of RCC patients treated with Gemcitabine as well as an anti-angiogenic agent (Sunitinib or Pazopanib) between January 2011 and December 2015 at the Winship Cancer Institute at Emory University. Patient data was reviewed for clinical and pathological characteristics, treatments, prognostic factors, and tolerance. Kaplan Meier analysis was used to assess treatment associated time-to-disease progression (TTP) and overall survival (OS). Results: 12 patients received Gemcitabine and either Sunitinib (n=11) or Pazopanib (n=1). Clear cell (n=5) and non-clear cell varieties including papillary (n=5), chromophobe (n=1), and collecting duct (n=1) RCC were represented. The median line of therapy was 2 (range 0-5 prior therapies). 50% of patients were poor risk, 33% were intermediate risk, and 17% of patients had good risk disease by Heng Criteria. The overall median TTP was 2.9 months (range 0.82-16.5 months) and overall median OS was 8.3 months (range 2.3-16.5 months). This regimen was well tolerated with the most common adverse effects being fatigue in 50% (6/12) of patients, fever in 33% (4/12) of patients, and nausea in 33% (4/12) of patients. Conclusions: Our experience suggests that this combination is effective in advanced and heavily pretreated RCC patients, including poor risk RCC patients outside of a clinical trial format. Additional prospective data using similar combinations, may provide improved outcomes of RCC patients, especially with non-clear cell RCC patients.
Predictors of long-term responders in patients treated with pazopanib for advanced renal cell carcinoma (aRCC).
Authors: Park Jinhee , Jiao Xiaolong , Wilson Thomas , Ghate Sameer , Ahmad Qasim , Perez Jose Ricardo , Vogelzang Nicholas J.
Published: March 2017

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Background: The objective of this study was to characterize the long term responders to pazopanib (PAZ) treatment in aRCC patients treated in a real-world community oncology setting. Methods: This retrospective study used US Oncology’s (USON) iKnowMed electronic health record database (Nov 2009 – Oct 2014), supplemented with chart review. Eligible patients: Age ≥ 18 at first diagnosis of aRCC, treated with PAZ as first-line between 11/1/2009 – 8/31/2012, and had at least 2 office visits during the follow-up period. Patients were excluded if they were enrolled in a clinical trial and diagnosed or treated for other primary cancers during the study period. Long-term responders were defined as patients with progression free survival (PFS) ≥18 months. Predictors of long-term responders to PAZ were assessed using multivariate logistic regression analysis. Results: A total of 153 PAZ patients were included of which, 33 patients (22%) were identified as long-term responders. The median PFS in long-term responders and non-long-term responders was 27.2 months (95% CI: 23.0, 35.2) vs. 6.9 months (95% CI: 5.03-8.55), respectively. Long-term responders were more likely to have Eastern Cooperative Oncology Group (ECOG) score=0 at baseline (42.4% vs. 18.3%, p=0.004), and a history of nephrectomy (81.8% vs. 57.5%, p=0.010) than non-long-term responders. Other patient characteristics including age, gender, or comorbidities did not differ significantly between the two groups even though long-term responders tend to be slightly younger (mean 64.7 vs. 66.2), female (33% vs. 25%), and less likely to have a comorbid condition (36.4% vs. 51.7%) compared to non-long-term responders. In the multivariate analysis, the only predictors of long-term response were ECOG = 0 at baseline (vs. ECOG = 1 (OR: 0.38; 95% CI 0.16-0.89) and vs. ECOG≥2 (OR: 0.07, 95% CI: 0.01-0.54) and history of nephrectomy (OR: 3.33; 95% CI 1.28-8.65). Conclusions: A subset (22%) of PAZ patients had clinically relevant long term responses in a US community oncology setting. ECOG score of 0 and history of nephrectomy were predictors of long term response in PAZ.