bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying predictive biomarkers for metastatic progression in stage I and II clear cell renal cell carcinoma.
Authors: Murphy Neal J , Shih Andrew , Kozel Zachary , Shah Paras , Yaskiv Oksana , Khalili Houman , Liew Anthony , Kavoussi Louis R , Hall Simon , Vira Manish Arvind , Lee Annette , Zhu Xinhua
Published: March 2019

631

Background: For most clear cell renal cell carcinoma (ccRCC) patients with early stage disease, surgical resection offers definitive cure. However, for the small percentage of tumors that metastasize, analyzing gene expression profiles from the primary site at the time of nephrectomy can serve as a model to understand the molecular aberrations behind a metastatic phenotype. Differences in gene expression profiles between patients with Stage I and II ccRCC who experience metastasis versus patients who maintain cure after surgery may help elucidate significant molecular targets and stratify patients at higher risk for metastasis. Methods: Nineteen Stage I and twenty Stage II ccRCC tumors preserved in FFPE blocks after nephrectomy were included in this study. Patients were matched for age, gender, tumor size and grade. In both stages, approximately half the patients that experienced metastasis within 5 years of surgery were part of the experimental group, whereas the control group had > 5 years of follow-up without evidence of disease. Extracted RNA for Stage I patients was sequenced using Illumina TruSeq RNA Access Library. Gene counts were assessed by ht-seq counts and differential expression using DESeq2. Significant genes found were validated in the Stage II group using RT-qPCR. Results: In the Stage I experimental group, statistically significant upregulation of several genes associated with unfavorable prognosis in RCC were found: COL1A1, NUMBL, and STEAP3. Random forest classification accurately separated Stage I control versus experimental patients based on expression of COL1A1. Affected genes were consistent with molecular changes seen in TCGA analysis. In the Stage II group, a double-blinded analysis correctly identified the clinical outcome for the majority of the patients using qPCR expression of COL1A1, NUMBL, and STEAP3. Conclusions: Differences in gene expression profiles harbored in the primary site of early stage ccRCC may be employed to predict patients at high risk for developing metastasis. Validating these findings in a larger study carries the potential to better understand mechanisms of metastasis and identify an at risk cohort of patients with early stage disease.
Molecular stratification of high-grade unclassified renal cell carcinoma to improve prognostication and management strategy.
Authors: Chen Yingbei , Di Natale Renzo G , Jayakumaran Gowtham , Ghanaat Mazyar , Marcon Julian , Brannon A. Rose , Al-Ahmadie Hikmat , Fine Samson , Gopalan Anuradha , Sirintrapun Sahussapont Joseph , Tickoo Satish , Arcila Maria E. , Motzer Robert J. , Hakimi A. Ari , Reuter Victor E.
Published: March 2019

640

Background: Unclassified renal cell carcinoma (uRCC) constitutes a large portion of aggressive non-clear cell RCC with limited response to standard therapy. Clinicopathologic parameters or biomarkers to stratify this heterogeneous group of tumors are currently lacking. In a recently reported analysis of 62 high-grade primary uRCC [“discovery cohort (DC)”], we identified distinct molecular subsets. We aimed to validate this molecular schema in an independent clinical cohort and further delineate the clinicopathologic and molecular features that may refine prognostication and management. Methods: All cases was reviewed by experienced GU pathologists based on the current WHO criteria. Primary (n = 54) or metastatic (n = 21) tumor samples from 75 uRCC patients [“validation cohort (VC)”] were analyzed by a CLIA-approved targeted NGS platform for somatic alterations. 37 had germline testing results available. We performed integrative analysis of both VC and DC. Results: Somatic mutations found in VC were NF2 (24%), SETD2 (13%), SMARCB1 (9%), TP53 (9%), TSC1 (9%), FH (8%), TSC2 (5%), MTOR (5%), EP300 (5%), BAP1 (5%), PBRM1 (5%) and PIK3CA (5%), highly consistent with findings in DC. Germline alterations [ FH (11), SDHB (4), and SMARCB1 (1)] were detected in previously unsuspected patients. Integrative analysis supported the presence of NF2-loss (NF2), hyperactive mTOR-driven (MTOR), FH/SDH-deficient (FH/SDH), and chromatin/DNA damage response (Chrom/DDR) molecular subsets. Univariate analysis of combined DC and VC (n = 137, median f/u 26 mos, death 74%) showed a significantly higher risk associated with NF2 subset than the MTOR group (Table). Clonality analysis confirmed NF2 inactivating mutation as a main driver in the NF2 subset. Rare cases with alterations indicating sensitivity or resistance to immunotherapy were also identified. Conclusions: Molecular features of high-grade uRCC improve risk stratification and provide rationale for distinct management strategies. [Table: see text]
Influence of access on survival of renal cancer in a Brazilian center.
Authors: Leite Luciana de Moura , Dettino Aldo A. , Rinck José Augusto , Zequi Stenio Cassio , Loose Simone , Formiga Maria Nirvana Cruz
Published: March 2019

644

Background: The introduction of tyrosine kinase inhibitors (TKI) and recently immunotherapy has brought major survival benefits for metastatic renal cancer (mRCC) patients (pts). In Brazil, there is no approved 2nd line treatment for mRCC in the Public Health System (PHS). Our center is unique, because it provides care for both PHS and Private System (PrS) population, enabling us to make the comparison of overall survival (OS) of these pts. Methods: We retrospectively reviewed medical records of all mRCC pts treated with 1st line TKI at our service from 2007 to 2018. Categorial variables were compared by Fisher’s exact test and continuous by Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: 171 pts were eligible, 37 (21.6%) PHS and 134 (78.4%) PrS pts. Between the two groups, there was no differences in age, gender, number and sites of metastasis (mets). PHS pts had worst ECOG (≥2, in 35.1 vs 13.5%, p .007), a trend towards more poor IMDC risk (IMDC favorable 16.2 vs 26.6%, intermediate 51.4 vs 57%, poor 32.4 vs 16.4%, p.09), had less nephrectomies (73 vs 92.5%, p.008) and more non clear cell histology (32.4 vs 12.7%, p.01). Median lines of therapy were 1 for PHS vs 2 for PrS pts (p.03). Sunitinib was the 1st line agent for 91.9 vs 67.2%, and pazopanib 8.1 vs 29.9%, of the PHS and PrS pts, respectively. Median time from diagnosis of mets to treatment start was 2.29 vs 1.79 m (p.59). Median OS was 16.5 vs 26.5 m (p.0002) and progression free survival, 8.4 vs 11 m (p.01), for the PHS vs PrS. On multivariate analysis, after adjusting for factors that were present before the beginning of treatment and were statistically significant for OS in the univariate model, PHS pts still had higher risk of death (HR 1.85, IC 95 1.2-2.9, p.01), probably due to having received fewer lines of therapy (≥2 lines of therapy vs 1, HR 0.51, IC95 0.4-0.7, p .001). Conclusions: Brazilian PHS pts had significant worse OS compared to PrS pts, in part due to less access to drugs. Access to cancer drugs is a challenge worldwide, and in Brazil effort has to be done to change this reality.
Prognostic and predictive role of comprehensive geriatric assessment (CGA) in elderly patients with metastatic renal cell cancer (RCC) treated with sunitinib (SUN) or pazopanib (PAZ): A single center experience.
Authors: Pierantoni Francesco , Basso Umberto , Maruzzo Marco , Brunello Antonella , Anile Giuseppe , Lettiero Annunziata , Tierno Giuseppina , Lamberti Evelina , Zagonel Vittorina
Published: March 2019

647

Background: Few data are available concerning the prognostic and predictive role of CGA in elderly pts ≥70 years with metastatic RCC treated with either Sun or Paz. Materials and Methods: We retrospectively reviewed the charts of all elderly pts with advanced RCC treated at our Institute with either Sun or Paz, with at least 6 months follow-up after starting treatment. Every pt received at baseline a CGA and was classified as fit, vulnerable or frail according to Balducci’s Criteria. Results: We identified 73 pts who started therapy from January 2006 to March 2018, median age 76 years (range 70-89), 63% males; 42.5% fit and 57.5% unfit pts (38.3% vulnerable, 19.2% frail). Sun to Paz ratio was 40 to 33 pts with a median duration of treatment of 10.8 months; incidence of G1/2 toxicities was 85% vs 93.9% (p = 0.28), G3/4 was 37.5% vs 30.3% (p = 0.63), dose reduction was necessary in 77.5% vs 78.8% of pts (p = 0.9), respectively. Median PFS and OS with Sun or Paz were 13.6 vs 9.4 months (p = 0.152) and 27 vs 22.3 months (p = 0.641), respectively. CGA fit category predicted longer PFS (p = 0.039) and OS (p = 0.001) in the whole cohort. We found no significant differences between fit and unfit pts according to incidence of G1/2 adverse events, incidence of dose reduction or necessity to early suspend treatment due to toxicity, while the incidence of G3/4 events was lower in the fit subgroup (p = 0.026). Out of 67 pts progressing after first line therapy, 27 (40.3%) received a second line consisting in Nivolumab (22.4%), Everolimus (13.4%) and Sorafenib (4.5%), while 40 (59.7%) received only palliative treatments. CGA fit category significantly correlated with a higher chance of receiving a second line treatment (p = 0.004). Conclusions: In our retrospective single-center experience, CGA has a strong prognostic value in terms of OS and has the ability to discriminate pts at higher risk of experiencing G3/4 toxicities with Sun or Paz, with shorter PFS and lower chance of receiving a second line treatment. There were no striking differences in terms of toxicity rates between Sun or Paz, although different in type and possibly biased by patient selection.
Treatment disparities among patients in the National Cancer Database (NCDB) with clinical TIa and TIb renal masses.
Authors: Sterling Joshua , Rivera-Nunez Zorimar , Farber Nicholas , Modi Parth K. , Radadia Kushan Dilip , Kim Sinae , Sharad Goyal , Rahul Parikh , Weiss Robert E. , Kim Isaac , Elsamra Sammy , Jang Thomas , Singer Eric
Published: March 2019

648

Background: AUA guidelines on the management of renal cell carcinoma (RCC) recommend prioritizing partial nephrectomy (PN) for the treatment of clinical T1a (cT1a) tumors, using PN for clinical T1b (cT1b) tumors when feasible, and performing minimally invasive surgery (MIS) when possible. Since cT1 RCC is a heterogeneous disease, we evaluated patterns of care in this population to examine factors associated with receipt of PN and MIS. Methods: We queried the NCDB from 2010-2014 to identify patients treated surgically for cT1N0M0 RCC. Patient socio-demographics, clinical characteristics, and treatment parameters were compared between cT1a and cT1b patients. Logistic regression models examined factors associated with receiving MIS. Results: Our population included 69,694 patients (44,043 cT1a and 25,651 cT1b). For cT1a tumors, 70% of patients received PN, while 30% received RN; 35% of patients underwent an open procedure and 65% underwent MIS. For cT1b tumors, 32% of patients received PN and 68% received RN; 38% of patients underwent an open operation and 62% underwent MIS. In both cohorts, African Americans and those earning <$62,000 were less likely to have MIS. Distance to treatment was not significant in cT1b patients, but cT1a patients who traveled >31 miles were more likely to undergo MIS. Patients treated at a community hospital were less likely to receive MIS compared to those treated at academic centers (cT1a OR: 0.48, 95% CI: 0.44-0.53 and cT1b OR: 0.63, 95% CI: 0.56-0.7). cT1a patients without private insurance were less likely to receive MIS (OR range: 0.58-0.93). However, only uninsured cT1b patients were less likely to undergo MIS (OR: 0.74, 95% CI: 0.64-0.86). Conclusions: PN occurred more frequently for cT1a (70%) vs. cT1b (32%) tumors. Most cT1 tumors received MIS; 35% of cT1a patients and 38% of cT1b patients underwent an open procedure, presenting an opportunity for improvement. cT1a and cT1b patients with lower household income, without private insurance, and those treated outside academic centers were less likely to receive MIS. Based on these findings additional research on the impact of regionalization of RCC surgery on utilization of PN vs. RN, receipt of MIS, and outcomes is warranted.
Patient perspectives on cytoreductive nephrectomy after CARMENA.
Authors: Battle Dena , George Daniel J. , Bex Axel , Staehler Michael D.
Published: March 2019

658

Background: Conducted over eight years, enrolling 450 patients at multiple centers in Europe, the CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiongeniques) trial demonstrated that systemic therapy using sunitinib alone is not worse than cytoreductive nephrectomy (CN) plus sunitinib in metastatic RCC in an intention to treat analysis (hazard ratio HR): 0.89, 95% confidence interval (CI), 0.71-1.10) (Mejean, NEJM, 2018). We wanted to assess patient views related to CN following the publication of these results. Methods: The Kidney Cancer Research Alliance (KCCure) conducted a survey among kidney cancer patients. The short survey was created via SurveyMonkey and was disseminated in various patient communities using social media and was posted to the KCCure website in June 2018 after the presentation of the CARMENA trial. Patients were asked “The CARMENA trial presented recently at ASCO found that for kidney cancer patients diagnosed with metastatic disease, there is no overall survival benefit of having a nephrectomy prior to starting systemic therapy. Knowing that information, would you still want to have a nephrectomy at diagnosis if you were metastatic?” Patients were also asked whether they had already had a nephrectomy and their stage at diagnosis, whether they were on systemic therapy, gender and age. Results: 186 patients responded with 60.5% being female. Median age 56.5 years (range 26-84). On the question of whether they would want CN. 75.2% of the patients indicated they would still prefer nephrectomy. Of the patients with primary metastatic disease and the tumor in place treated with systemic therapy, 20.1% wanted their kidney tumor to be removed. There was no statistically significant difference between patients who had experience with systemic therapy and those who hadn’t, answers were also consistent regardless of gender and age. Conclusions: Overall survival should not be overestimated as the most important aim in an end-stage patient population. Patients might think differently about benefits, risks and value of surgical procedures then physicians.
Associations of rurality and disease outcomes in urologic malignancies.
Authors: Abello Alejandro , Casilla-Lennon Marianne , Kenney Patrick Aloysius , Leapman Michael
Published: March 2019

661

Background: Patients residing in rural regions have comparatively worse outcomes for many cancers. However there is less known about treatment and outcome for patients with urologic cancers. The objective of this study is to evaluate differences in treatments and outcomes among patients with urologic malignancies when coming from rural compared to metropolitan communities using national, population-level data. Methods: We queried the Surveillance, Epidemiology and End-Results database to identify patients with urological cancers from 1973 to 2015. We compiled patient clinical, demographic, and outcome data, including rurality at the county level. Rural counties is defined as those with > 50% population living in rural areas. We evaluated the association of rurality with treatment received and cancer-specific death using Cox proportional hazard models. Results: We identified 989,239 patients including those with Kidney (112,477) Bladder (208,230), Prostate (637,005), and Testis cancer (28,527). Among all, 898,050 (90.4%) were male and 64,992 (6.55%) lived in rural counties. Overall, rural patients were older at cancer diagnosis (mean 70 ± 12.1 vs 67.41 ± 12.7) and more frequently of white race (97.1% vs 82.46%) vs urban counterpart. Patients residing in rural counties were less likely to undergo definitive treatment with surgery for stage 1 or stage 2 disease P < 0.001). In multivariable regression, rural status was associated with greater risk of cancer-specific death in kidney cancer (HR: 1.1, 95% CI: 1.02-1.24; P: 0.03) but was not seen in other cancers. Based on % of rurality, adjusted kidney cancer-specific death increased among most rural populations: 15% rurality or more (HR: 1.16, 95% CI: 1.05-1.27; P: 0.03), 40% rurality or more (HR: 1.31, 95% CI: 1.15-1.49; P < 0.001) and 70% or more (HR: 1.32, 95% CI: 1.05-1.67; P: 0.01). Conclusions: There are notable differences in cancer incidence, treatment and outcome for patients residing in rural areas. Rural status was associated with poorer cancer-specific survival for kidney cancer but was not seen in other genitourinary malignancies, independent of stage at diagnosis and treatment received. Further research is warranted to understand the factors underlying these differences in outcome.
Tobacco as a possible prognostic factor in advanced renal cell carcinoma.
Authors: Solis-Hernandez Maria Pilar , Iglesias Clara , Revuelta Alfonso , Gonzalez Mendez Carmen , Juan Rodriguez Lucia , Quiñones Roces Teresa , Gonzalez Lolo Sara , del Río Fernández Jorge , Gómez David , Valcárcel González Sena , Fernandez Arrojo Sara , Alvarez-Fernandez Carlos , Villanueva Noemí , Faez Laura , Uriol Esther , Esteban Emilio
Published: March 2019

665

Background: It is widely known the causal relationship establised between tobacco use and the development of renal cancer is widely known. Nevertheless, the impact of smoking on the efficacy and safety of anti-angiogenic drugs is unclear. Sunitinib is a tyrosine kinase inhibitor with proven efficacy metastatic renal cell carcinoma (mRCC). Methods: A retrospective analysis was carried out including 194 mRCC patients (pts) who received Sunitinib in a single Institution (Hospital Universitario Central de Asturias) with a high incidence of this disease. The aim of this study is to explore the impact of the smoking habit on treatment response in terms of progression‐free survival (PFS) and overall survival (OS). Results: Most patients presented clear cell histology (92%). Smoking status: 42% (n=82) never‐smoker, and 39% (n=76) former‐smoker and 19% (n=36) current‐smoker. Male predominance 78% (n=145). Median age was 65 (range: 40‐84). Survival analysis favors patients with a history of tobacco use. There was no significant difference in PFS between never‐smoker vs ever-smoker groups: median PFS 8.13 months (95% IC: 4.75‐11.52), vs 12 months (95% IC: 9.97‐14.03) was found respectively (p=0,086). Fewer than 10% developed grade 3 toxicity. A significative improvement in OS in patients ever-smokers: median OS 16.23 months (95% IC: 12.22‐20.25) vs 26.46 months (95% IC: 16.21‐36.73) (p=0.044). The advantage observed in patients with any smoking history became more evident for poor prognosis cases. A median OS 5.03 months (95% IC: 0.84‐9.23) vs 14.03 months (95% IC: 7.81‐20.26). A median PFS 6.4 months (95% IC: 2.53‐10.27) vs 13.33 months (95% IC: 1.14‐26.19) p > 0.05. Conclusions: In this series, tobacco seems to play a role on the efficacy and safety of anti‐angiogenic agents in mRCC. However, additional prospective studies in well‐balanced populations are required to confirm this data.
Effects of sunitinib and pazopanib on patients physical, social, and emotional function: Result of a prospective patients reported outcome tool.
Authors: Das Prantik , Ali Akram , Simmonds Karen , Mckenna Lesley
Published: March 2019

667

Background: Sunitinib and pazopanib are are effective treatment options for metastatic Renal cell carcinoma (mRCC) and both may impair patient’s quality of life (QOL). There has been no direct comparison between these agents and their effect on these domains. Methods: A prospective study of mRCC patients who had received Sunitinib or Pazopanib as a first line treatment was conducted. A set of questionnaires has been developed in-house, influenced by existing recognised tools, such as EORTC-C 30 and PHQ-9, and is tailored to focus on relevant QoL issues patients face. This questionnaire named as Patient reported outcome tool. They primarily relate to physical, emotional and social functioning in the quality of life of patients. Each category has 4 questions. The questions are quite generic and allow patients to apply them to what’s important in their lives. Answers are on a scale of 0-10. The purpose of the questionnaire is to assess a balance of physical, cognitive and independence related aspects of their life over the course of their treatment. All patients are asked to complete the baseline questionnaire and then in every clinical visit. Results: Data were collected prospectively of metastatic RCC patients who had received Sunitinib or Pazopanib from May 2017 to Aug 2018. Total 45 patients were included, 23 received Pazopanib and 22 were on Sunitinib. There was a higher rate of significant worsening for the physical well-being subscale for Sunitinib versus Pazopanib. Patients on Sunitinib reported worsening tiredness, skin problems and sleep disturbance. Socially, patients on Sunitinib reported more closer to family, better interaction with friends and more motivated to go out. Problem with feeling sad, fear of death and anxiousness were more pronounced on Pazopanib arm. Conclusions: Our study suggested that there are marked differences between Sunitinib vs Pazopanib and their effects on patients physical, emotional and social wellbeing. Physical function was more influenced by sunitnib while pazopanib has more effect emotional wellbeing. Further studies are warranted to confirm these findings.
Sarcopenia is independently associated with decreased overall survival after surgery for inferior vena cava tumor thrombus patients.
Authors: Williams Milton , Nabavizadeh Reza , Khan Amir Ishaq , Patil Dattatraya H , Psutka Sarah P. , Sekhar Aarti , Ogan Kenneth , Bilen Mehmet Asim , Master Viraj A.
Published: March 2019

674

Background: The presence of sarcopenia, a lean muscle mass deficiency is independently associated with inferior survival following the surgical treatment of localized renal cell carcinoma (RCC). This association has not yet been studied in more advanced disease such as patients with RCC and concomitant IVC thrombus tumors. In this study we retrospectively examined the association between preoperative sarcopenia and overall survival following definitive surgery for IVC tumor thrombus patients. Methods: Baseline lumbar skeletal muscle index (SMI) for patients who underwent surgical treatment for known IVC thrombus tumors between 2006 and 2018 by a single surgeon were quantified at the 3rd lumbar vertebra from preoperative computerized tomography (CT) or magnetic resonance imaging (MRI). The SMI thresholds used to define sarcopenia were developed using ROC analysis of our data and had the most significant relation to overall survival. Overall survival was compared between patients with and without sarcopenia using the Kaplan-Meier method as well as univariate and multivariate cox proportional hazards regression models. Results: The cohort consisted of 194 patients of whom 128 (65%) were male and 146 (75%) were non-Hispanic white. There were 143 (74%) clear cell renal cell carcinoma cases. 110 patients (57%) were sarcopenic. Patients with sarcopenia had significantly decreased overall survival, log-rank p=0.009 (Figure). The presence of sarcopenia was also associated with decreased overall survival in univariate analysis, (hazard ratio (HR)=1.80, 95% CI 1.15-2.83; p=0.010). In multivariable analysis controlled for age, number of comorbidities, and AJCC Stage, sarcopenia maintained significance as a predictor of decreased overall survival (HR= 1.66, 95% CI 1.05-2.61; p=0.030). Conclusions: Preoperative sarcopenia is independently associated with mortality in patients with IVC thrombus tumors.
The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) after treatment with systemic therapy.
Authors: Van Der Mijn Johannes , Eng Kenneth , Fernandez Evan , Oromendia Clara , Zhang Tuo , Bareja Rohan , Ramazanoglu Sinan , Vosoughi Aram , Gudas. Lorraine J. , Elemento Olivier , Tagawa Scott T. , Faltas Bishoy Morris , Nanus David M. , Beltran Himisha , Mosquera Juan Miguel , Sboner Andrea , Molina Ana M.
Published: March 2019

675

Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.
Correlation between PSA kinetics and detection rate of PSMA-PET in the setting of biochemical recurrent prostate cancer: A systematic review and meta-analysis.
Authors: Pereira Mestre Ricardo , Treglia Giorgio , Ferrari Matteo , Pascale Mariarosa , Mazzara Calogero , Azinwi Ngwa C , Llado Anna , Stathis Anastasios , Giovanella Luca , Roggero Enrico
Published: March 2019

71

Background: Serum prostate-specific antigen (PSA) may predict the risk of positive positron emission tomography/computed tomography with radiolabeled prostate-specific membrane antigen (PSMA-PET/CT) in patients with biochemical recurrent prostate cancer (BRPCa). However, to date, there are no clear data regarding the correlation between PSA kinetics and PSMA-PET findings. We performed a systematic review and meta-analysis to provide evidence-based data in this setting. Methods: A comprehensive literature search of studies published through October 2018 in PubMed/MEDLINE, EMBASE and Cochrane library databases was performed. A meta-analysis to establish the detection rate (DR) of PSMA-PET using different cut-off values of PSA doubling time (PSAdt) and a pooled analysis to establish whether shorter PSAdt may predict positive PSMA-PET results was performed in patients with BRPCa. Results: Twelve articles were included in the systematic review and eight articles (including 1398 patients) were selected for the meta-analysis. The pooled DR including 95% confidence intervals (95% CI) of PSMA-PET in restaging prostate cancer (PCa) patients was 72% (95% CI: 60-82%), increasing to 83% (95% CI: 75-90%) when PSAdt was ≤ 6 months and decreasing to 60% (95% CI: 37-80%) when PSAdt was > 6 months. PSAdt ≤ 6 months may predict the positive result of PSMA-PET (pooled odds ratio: 3.22; 95% CI: 1.17-8.88). Statistical heterogeneity among the included studies was found. Conclusions: PSA kinetics, and in particular shorter PSAdt, may be predictor of PSMA-PET positivity in patients with BRPCa. Further larger studies in this setting are warranted.
Cascade testing of men with prostate cancer in families with a spectrum of inherited cancers: Importance of attention to race.
Authors: Giri Veda N. , Chandrasekar Thenappan , Hegarty Sarah , Gross Laura , Leong Joon Yau , Gomella Leonard G.
Published: March 2019

75

Background: Prostate cancer (PCa) is increasingly recognized as a part of hereditary cancer syndromes (HCS) with implications for cascade genetic testing (CGT) of men with PCa in these families. However, race-specific rates of HCS in probands presenting for inherited cancer assessment who report a family history (FHx) of PCa is not known has implications for CGT of men with PCa. Methods: A prospectively maintained genetic testing database at a tertiary care cancer genetics program was queried for all probands reporting a PCa FHx. Pedigrees were analyzed for three HCS linked with PCa: hereditary breast and ovarian syndrome (HBOC), classic Hereditary PCa (HPC), and Lynch syndrome (LS). Associations between HCS and race were evaluated using Fisher’s exact test. Each HCS was evaluated for potential genetic link to the male relative with PCa and associations with race were tested using Fisher’s exact test. Results: 345 probands met inclusion criteria: 53 African-American (AA), 292 Caucasian (Wh), 74.5% female. Proband cancer diagnoses included breast (43.2%), prostate (12.8%), pancreatic (3.8%), ovarian (3.2%), and colorectal (2.9%). Overall, 63.8% of probands met criteria for ≥ 1 HCS based on personal and FHx. Male relatives with PCa in these families with potential genetic link to HCS were found in 75.5% AA families and 61.6% Wh families. HBOC was identified in a higher percentage of AA families with a potentially-linked male relative with PCa compared to Wh families (69.8% vs. 52.4%, respectively; p=0.051). Among probands with HCS potentially linked to PCa (n = 169), 19.5% were found to carry a genetic mutation in a cancer risk gene (17.9% AA and 19.9% Wh). BRCA1/2 mutations accounted for all mutations identified in AA probands and 66.7% of Wh probands. Conclusions: A significant percentage of patients who present for inherited cancer assessment report a FHx of PCa potentially linked with a HCS. Importantly, AA probands with a PCa FHx have comparable rates of HCS as Wh probands, with potentially higher rates of HBOC in AA families accounted for by BRCA mutations. Cascade testing of men with PCa in families with HCS is crucial with a need to address any race-specific barriers.
A genomic classifier shows improved prediction of oncologic outcomes in African-American men treated with radical prostatectomy.
Authors: Freedland Stephen J. , Du Plessis Marguerite , Zhang Jingbin , Howard Lauren , de Hoedt Amanda , Davicioni Elai
Published: March 2019

8

Background: Accurate risk stratification after radical prostatectomy (RP) is important to help select men at risk of recurrence who will benefit most from postoperative radiation or multi-modal therapy. Increasingly genomic testing is being used in the clinic for this purpose. However, little is known about how these tests predict outcomes in African-American men (AAM), an underserved at risk population. Here we evaluate Decipher within a large Veteran Affairs cohort and compare its performance to the CAPRA-S clinical model for predicting outcomes in patients. Methods: Decipher genomic classifier (GC) scores were generated for 557 patients, who underwent RP at the VA Medical Center Durham between 1989 and 2016. This was a clinically high-risk cohort which all underwent RP. Cox UVA and MVA proportional hazards models and survival c-index were used to compare the performance of Decipher and CAPRA-S for predicting risk of metastasis and PCa specific mortality (PCSM). Results: Overall, 55% (n = 306) of patients in the cohort were AAM. CAPRA-S classified 10.4% as low risk for recurrence while for GC it was 50.4%. With a median follow-up of 9 years, only 40 patients developed metastases and 18 patients died of PCa. In multivariable analyses, both GC (p = 0.044 HR:1.30 95% CI:1.01-1.69) and CAPRA-S (p = 0.037 HR:1.27 95% CI:1.01-1.58) were significant predictors for metastasis within non-AAM; however, only GC (p < 0.001 HR:1.70 95% CI:1.31-2.20), was significant within AAM. GC but not CAPRA-S was a significant predictor of PCSM for both EAM (p = 0.044 HR:1.54 95% CI:1.01-2.53) and AAM (p = 0.002 HR:1.65 95% CI:1.19-2.42). The survival c-index of GC for predicting metastasis 8 years post RP was 0.84 (95% CI: 0.76-0.90) in AAM and 0.70 (95% CI:0.63-0.80) in non-AAM. For PCSM endpoint, it was 0.82 (0.61-0.93) in AAM and 0.73 (95% CI:0.63-0.84) in non-AAM. Conclusions: Our results among non-AAM confirm many prior studies showing that GC is a powerful predictor of metastasis and PCSM. Among AAM, not only was GC a very strong predictor of poor outcome, there was actually a suggestion that GC may perform better among AAM than EAM, though this requires further validation.
Machine learning approaches to improve prostate cancer outcome.
Authors: Rodrigues Pereira Ronnie , Miller Crispin , Baena Esther , Bristow Robert G.
Published: March 2019

82

Background: High-risk Prostate Cancer (PCa) occurs in as much as 37% of PCa cases in England and Wales. This proportion is much higher than in other developed countries. Furthermore, there is an imprecision in the primary treatment of these patients. More specifically, in the administration of systemic therapy. Currently, surgeons prescribe radical prostatectomy and radiation, while radiation oncologists often combine radiation with androgen deprivation therapy (ADT). However, ADT has significant side effects and not all patients develop Biochemical Recurrence/Metastasis. Furthermore, clinical factors have limited ability to identify these patients. Consequently, we turn to biomarker discovery for more accurate disease management. Methods: We applied a machine learning strategy to identify discriminatory DNA Methylation patterns between patients with biochemical recurrence from those with stable disease in high-risk PCa (D’Amico Classification, T-stage ≤ 3a). Training and feature selection occurred in cross-validation (4 Folds, 10 reps) on 102 patients from the TCGA-PRAD dataset (26 BCR). Gene co-expression networks were derived from mRNA expression (|Pearson correlation| > 0.70). Network clustering maximised global modularity (Louvain algorithm) and unsupervised clustering evaluated complete linkage. Functional enrichment employed MiSigDB Hallmarks and g:ProfileR. Results: A linear support vector machine outperformed Naïve Bayes, Random Forest and Artificial Neural Networks with an AUC = 0.91 ± 0.14 (95% CI). This epigenomic test preferentially sub-stratifies high-risk patients, as it shows no improvement over the “No Information Rate” of intermediate- and low-risk patients (p-value > 0.05, t-test). We identified functional clusters from a co-expression network superimposed with the genes most correlated to the epigenomic test. The most enriched cluster reveals disturbances in MYC targets, cell cycle and RNA splicing. Conclusions: Preliminary results indicate that an epigenomic test identifies a sub-group of patients which could benefit from ADT at the stage of primary treatment, however it requires further validation.
Changing physician PSA screening behavior in men 70 years of age and older by use of the electronic medical record.
Authors: Presti Joseph , Alexeeff Stacey , Horton Brandon , Prausnitz Stephanie , Avins Andrew
Published: March 2019

85

Background: Since 2013, both the United States Preventive Services Task Force and the Kaiser Permanente National Prostate Cancer Guidelines have recommended against PSA-based screening for prostate cancer in men ≥70 years of age. Adherence to these guidelines has been variable. A “Best Practice Alert” (BPA) was activated in the electronic medical record (EMR) system in October 2015 at Kaiser Permanente Northern California (KPNC). This alerted physicians, in real time, if they attempted to order a PSA test in a man ≥70 years of age with no history of prostate cancer. No additional physician training or education was used. The objective of the present study was to determine the impact of this BPA on the frequency of inappropriate PSA testing. Methods: This was a retrospective study spanning the years 2013 to 2017, in men ≥70 years of age in KPNC with no prior history of prostate cancer. We compared the annual rates of PSA testing between the pre-BPA period, 2013 and 2014; and the post-BPA period , 2016 and 2017 (the post-BPA period began 3 months after the BPA was instituted). The primary outcome was the annual rate of PSA testing. The percent change between the two time periods, the rate ratio and 95% confidence interval (CI) were calculated. Results: The annual number of eligible men (men ≥70 years of age and no history of prostate cancer) and annual number of these men undergoing PSA testing are shown in the Table. Annual screening rates declined from 34.3% in the pre-BPA era to 13.5% in the post BPA era. The rate ratio was 0.394 (95% CI, 0.390-0.398). Conclusions: Following the activation of a simple and inexpensive BPA within the EMR, the rate of inappropriate PSA testing decreased 61% in men ≥70 years of age. This change was durable over the study period, demonstrating that well-conceived, straightforward interventions can have a marked effect on physician behavior. [Table: see text]
Immune infiltrate with CD8 low or PDL1 high associated with metastatic prostate cancer after radical prostatectomy (RP).
Authors: Vicier Cecile , Werner Lillian , Huang Ying , Hamid Anis , Evan Carolyn , Loda Massimo , Sweeney Christopher
Published: March 2019

86

Background: Given limited information about the prostate cancer (PC) immune infiltrate in men with localized disease, we profiled 6 markers and correlated them with risk of metastases after RP, using a single-institution cohort. Methods: Using a tissue microarray (TMA) with formalin-fixed, paraffin-embedded radical prostatectomy specimens, we performed a multiplex immunohistochemistry (IHC) analysis of immune checkpoint markers (PD1, PDL1), T-cell regulator / helper (FOXP3, CD4) and killer T cells (CD3, CD8). Quantitative multispectral imaging analysis was used to define the “density” of each marker: a ratio between number of positive cells divided by glandular and stromal area. Data collected included patient characteristics, time to biochemical relapse (BCR), time to metastasis (M1) and overall survival (OS). Results: TMA staining resulted data for at least one marker for 129 patients and all 6 markers for 109 patients. Median follow-up for this cohort was 14 years (0.25-27 years). As detailed in the table, either low CD8 or high PDL1 had a statistically significant association with biochemical and metastatic relapse and trend toward poorer OS on univariate analysis (UVA). A risk score of 0, 1 or 2 with CD8 low and PDL1 high each being one point revealed a strong association with higher score and incremental risk of BCR and metastasis. Conclusions: Multiplex IHC profiling of primary prostate cancer revealed high PDL1 and low CD8 density as poor prognostic markers alone and more impactful as part of a risk score for biochemical and metastatic relapse. [Table: see text]
Prospective evaluation of a new patient decision aid to enhance prostate cancer screening decision-making.
Authors: Brooks Michael Austin , Misra-Hebert Anita , Zajichek Alexander , Carlsson Sigrid V. , Hugosson Jonas , Kattan Michael W. , Stephenson Andrew J.
Published: March 2019

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Background: We previously developed screening nomograms to predict 15-year risk of all-cause mortality, prostate cancer diagnosis, and prostate cancer mortality, and incorporated them into a graphical patient decision aid (PtDA). Our objective was to prospectively recruit primary care patients interested in shared-decision making regarding prostate specific antigen (PSA) screening and assess the impact of individualized counseling using our new PtDA. Methods: 50 patients from one internal medicine practice were enrolled in a single-arm sequential trial design, with face-to-face clinician counseling and questionnaires. Eligibility criteria included men age 50-69 years old and life expectancy > 10 years. Patients were excluded for a personal history of prostate cancer or PSA screening within the prior year. Participants completed baseline questionnaires regarding prior PSA testing, demographic information, health literacy, and the Control Preferences Scale (CPS). They then received standardized counseling (based on large trial and epidemiologic data) regarding PSA screening, followed by individualized counseling using our new PtDA. Participants then made a screening decision, and completed a post decision questionnaire including a Decisional Conflict Scale. Results: The median age was 60 (IQR 54; 65). 41 (82%) had a prior PSA test, while 9 (18%) had not. 42 (84%) of participants received some education beyond high school, 41 (82%) demonstrated high health literacy, and 45 (90%) desired to have an active role in decision-making based on the CPS. After undergoing counseling, 34 (68%) participants chose to undergo initial or repeat PSA screening, 8 (16%) chose against future screening, and 8 (16%) remained uncertain. 45 (90%) participants found individualized counseling using the PtDA more useful than standardized counseling. Finally, patients reported reduced decisional conflict compared to historical controls (P < 0.001). Conclusions: Our process of standardized counseling followed by individualized counseling using our new PtDA was effective in reducing decisional conflict. The majority of participants found the PtDA more useful for decision making than standardized counseling. Clinical trial information: NCT03387527.
Outcomes of active surveillance for African-American men with prostate cancer: Results of a matched analysis.
Authors: Thomas Lewis , Nyame Yaw A. , El-Shafei Ahmed , Dai Charles , Ganesan Vishnuvardhan , Zampini Anna , Arora Hans , Crane Alice , Hettel Daniel , Fareed Khaled , Stein Robert , Gong Michael C. , Klein Eric A. , Stephenson Andrew J.
Published: March 2019

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Background: Prior work has questioned the safety of active surveillance (AS) for African-American (AA) men with prostate cancer. However, studies of AA men on AS are rare, and some show contradictory results as more AA men may undergo definitive therapy leaving a well-selected AS population. To overcome these limitations we performed a retrospective matched cohort study of AA men on AS. Methods: We queried our AS database (2000-2016) for all AA patients. AA men were matched to non-AA men using a 1:1 algorithm based on National Comprehensive Cancer Network (NCCN) risk, age at diagnosis, and year of diagnosis. Cohorts were compared on outcomes of NCCN risk reclassification, receipt of treatment, post-treatment recurrence, development of metastases, and prostate cancer specific mortality. Results: Fifty-nine AA patients were identified and matched, including 18 very low risk (31%), 24 low risk (41%), and 17 intermediate risk patients (29%). Groups were equally matched by NCCN risk and year of diagnosis, and had similar ages at diagnosis (65.6 years AA, 65.9 years non-AA, p=0.97). Initial PSA values were similar between groups (5.2 AA versus 5.1 non-AA, p=0.77). Rates of risk reclassification during AS were higher among AA patients (54% versus 39% p=0.09), though treatment (46% vs 44%) and post-treatment recurrence (11% vs 19%) rates were similar. While AA patients were more often reclassified, many were due to PSA rise (40% AA, 8% non-AA upgraded by PSA alone) rather than pathologic upgrading. AA patients had a longer time to reclassification and treatment than non-AA patients (2.9 and 2.8 years vs 0.9 and 1.0 years, p=0.14). Similar follow-up time was noted (AA 6.0 years versus non-AA 6.4 years, p=0.91). One patient in each group developed metastases. No cancer specific mortalities occurred. Conclusions: In a matched analysis of AA versus non-AA patients on AS, rates of risk reclassification were higher among AA patients, though receipt of treatment and treatment outcomes were similar between groups. Metastatic progression and prostate cancer mortality were rare in both groups. AS appears to be a reasonable option for AA patients with long treatment free periods and reasonable post-treatment outcomes.
Trends in complementary and alternative medicine use among newly diagnosed prostate cancer patients.
Authors: Zuniga Kyle Brian , Zhao Shoujun , Cedars Benjamin E , Cowan Janet E. , Kenfield Stacey , Van Blarigan Erin , Broering Jeanette M , Carroll Peter , Chan June M.
Published: March 2019

92

Background: Complementary and alternative medicine (CAM) use is common among prostate cancer (PCa) patients. The benefits and risks of the majority of CAM is inconclusive, and thus understanding trends in use is necessary to guide future research. We sought to investigate the prevalence of CAM use and trends in newly diagnosed PCa patients using the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). Methods: Between 1996-2017, 7,989 CaPSURE subjects completed questionnaires on use of over 50 CAM types. For prevalence, subjects were identified as users if they ever indicated CAM use. We then performed univariate analyses to examine associations between sociodemographic and clinical characteristics with CAM use using chi-squared tests. To observe trends in CAM use among newly diagnosed patients, we limited subject responses to questionnaires completed within 24 months of diagnosis (7,358 subjects). We then grouped subjects by diagnosis year and calculated percent change in use. Results: Overall, 56% of subjects reported any CAM use. Commonly used CAM were multivitamins (40% of participants) and essential fatty acids and omega-3 (24% of participants). Compared to non-CAM users, a greater proportion of CAM users were college-educated, had a higher household income, and lived in the West and Midwest regions of the U.S (all p < 0.01). In exploring trends, we found that overall CAM use increased by +203% (19% to 56%) between those diagnosed in 1996-1999 and 2010-2017. Between those diagnosed in 2005-2009 and 2010-2017, the largest changes in use were seen in acupuncture (+289%), Vitamin D (+204%), selenium (-59%), and vitamin E (-39%). Conclusions: PCa patients reported widespread CAM use in 1996-2017. Multivitamins were the most prevalent CAM, and use of acupuncture and Vitamin D increased dramatically. This information may help to prioritize research needs and reinforces the importance of discussing CAM use with patients, with referral to specialists (e.g., nutritionists) when indicated.