bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing a CTC-based clinical trial assay for selecting AR-V7+ patients for enrollment in a pivotal phase 3 study (ARMOR3-SV).
Authors: Dransfield Daniel T. , Ball Glyn
Published: February 2017

348

Background: ARMOR3-SV is a randomized phase 3, multi-center study comparing galeterone to enzalutamide in men with metastatic (M1) castrate resistant prostate cancer (CRPC) expressing androgen receptor splice variant-7 mRNA (AR-V7) who have not yet received chemotherapy, or other second generation androgen signaling inhibitors. AR-V7 is a truncated, constitutively active splice variant of the androgen receptor (AR) that lacks the ligand binding domain (LBD) and has been implicated in prostate cancer progression. Recently, the presence of AR-V7 in circulating tumor cells (CTCs) has been associated with a lack of responsiveness to both abiraterone and enzalutamide, whereas galeterone, a selective small molecule that potently degrades the androgen receptor, has demonstrated activity in preclinical model systems expressing AR-V7 and clinically in patients with C-terminal loss, of which AR-V7 is the most common form. Methods: Utilizing the lab test developed at JHU as a model system, we sought to develop a clinical trial assay utilizing immunomagnetic bead isolation of CTCs followed by mRNA isolation and cDNA generation. We then developed a duplexed PCR assay using Taqman chemistry to detect the full-length AR (AR-FL) and AR-V7. Negative patient samples were used to establish the limit of blank and assay cut-off and synthetic oligonucleotides to establish the limit of detection. Results: The AR-FL and AR-V7 assay shows linear response to template dilution to the assay cut-off Ct. Blood spiked with LNCaP and LNCaP95 cells were used to demonstrate assay suitability and sensitivity. We have successfully detected AR-FL and AR-V7 in select CRPC patient samples. We have also demonstrated assay reproducibility and have shown that the assay remains consistent in the presence of select interfering substances. Conclusions: For the ARMOR3-SV trial, this clinical trial assay is being utilized globally at central laboratories to screen patient blood samples for AR-V7 expression in evaluable CTCs as the first criterion for inclusion in this study. Clinical trial information: NCT02438007.
Biopsychosocial distress screening using the National Comprehensive Cancer Network (NCCN) distress thermometer (DT) and patient reported outcome measurement information system (PROMIS) in an academic genitourinary (GU) medical oncology practice.
Authors: Guancial Elizabeth A. , DaSilva Christopher , Baran Andrea , Sabatka Sandra , Baumhauer Judith , Duberstein Paul
Published: February 2017

350

Background: The NCCN defines “distress” as a “multifactorial…emotional experience…that may interfere with the ability to cope effectively with cancer, its physical symptoms and its treatment.” NCCN DT scores ≥ 4 on a scale of 1-10 are associated with increased biopsychosocial distress among oncology patients. We piloted the use of an electronic tool for distress screening in an academic GU medical oncology practice to determine feasibility and impact on workflow. Methods: At each clinic visit, patients completed a modified NCCN DT with distress score only and pain interference, depression, and anxiety PROMIS domains on an iPad before meeting the clinician. Results were immediately available in the electronic medical record. Results: Between July 1, and August 31, 2015, 108 assessments were completed by 73 patients; 12% were new patients and 88% were follow-ups. Patients ranged from 30 to 93 years of age. Mean DT score was 3.67 [standard deviation (SD) 2.79]. DT scores of ≥ 4 were reported in 41% of assessments. Mean distress scores based on cancer stage were: stages 1-3, 4.04 (SD 2.96; N = 23); and stage 4, 3.56 (SD 2.75; N = 85). Mean distress scores based on cancer diagnosis were: prostate, 3.20 (SD 2.38; N = 46); urothelial, 3.97 (SD 3.35; N = 33); kidney, 3.92 (SD 2.55; N = 24); and testicular, 4.80 (SD 3.42; N = 5). Mean T scores for each of the PROMIS domains were: pain interference, 54.16 (SD 10.28; N = 103); depression, 49.54 (SD 8.95; N = 101), and anxiety, 50.79 (SD 9.37; N = 101). Median time to assessment completion was 3.77 minutes (mean 6.15 minutes). Mean times by age groups were: 50-59, 7.65 minutes (N = 21); 60-69, 5.57 (N = 48); 70-79, 11.61 (N = 16); and ≥ 80, 10.21 (N = 12). Conclusions: Electronic biopsychosocial distress screening at each clinic visit is feasible and has minimal impact on workflow. Pain interference but neither anxiety nor depression scores were increased in this population. Future research is needed on the influence of cancer stage and type on distress and on the associations between NCCN DT and PROMIS scores.
Effect of asymptomatic recurrence detection after nephroureterectomy on prognosis in patients with upper urinary tract urothelial carcinoma.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

364

Background: It is unknown whether routine follow up with body computed tomography (CT) to detect asymptomatic visceral recurrence after nephroureterectomy improves patient survival. We accessed the impact of follow up with body CT on patient survival after nephroureterectomy. Methods: A total 212 nephroureterectomy for upper urinary tract urothelial carcinoma were performed at our hospital between Feb 1995 and Oct 2015. All patients had regular follow up with chest x-ray, urine cytology and cystoscopy every 3 to 6 months, blood biochemical test, and CT of the chest and abdomen every 6 to 12 months. Additional examinations were required for symptomatic recurrence. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of diagnosis (asymptomatic vs. symptomatic) was estimated using the Kaplan-Meier methods and compared with the log rank test. Cox proportional hazard regression models were used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: A total 43 patients (20%) experienced recurrence after surgery, of whom 31 (72%) were asymptomatic and 12 (28%) were symptomatic. The most common symptoms at recurrence were pain in 7, hematuria in 2 , appetite loss in 1 , edema in 1 , palpable mass in 1, general malaise in 1 patients. Overall survival was not significantly different between in patients with asymptomatic vs. symptomatic recurrence; however, survival after tumor recurrence were better in patients with asymptomatic recurrence (P = 0.033). Moreover, multivariate analysis showed symptomatic recurrence was selected as a risk factor for overall survival after recurrence. Conclusions: Routine oncological follow up after nephroureterectomy for early detection of asymptomatic visceral recurrence was associated with patient survival. Further study is necessary to establish the optimal follow up regimen balancing the benefit of asymptomatic detection with the increased cost of routine surveillance.
Comprehensive genomic profiling of urothelial carcinoma of the kidney and ureter: Comparison with urothelial carcinoma of the bladder and impact on potential for targeted therapy selection.
Authors: Pal Sumanta K. , Elvin Julia Andrea , Ali Siraj Mahamed , Hoffman-Censits Jean H. , Vergilio Jo-Anne , Suh James , Mian Badar , Fisher Hugh A.G. , Nazeer Tipu , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S.
Published: February 2017

371

Background: Urothelial carcinoma of the upper tract (UTUC) has distinct clinical and pathologic features from UC of the bladder (UCB). We compared the comprehensive genomic profile (CGP) of UTUC with UCB. Methods: DNA was extracted from 40 microns of FFPE sections from 195 consecutive cases of relapsed/metastatic UTUC and 295 cases of UCB. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 627X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), insertions/deletions (INDELs), copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the UTUC patients was 65.7 years (range, 35-86); 74 (38%) were female and 121 (62%) were male. There were 174 (89%) kidney and 21 (11%) ureteral UTUCs assessed. In total, 51 (26%) and 138 (71%) were stage III and IV, respectively, at the time of CGP. Samples for sequencing were obtained from primary tumor in 157 (81%) cases and from metastatic sites in 38 (19%) cases. There were 1,243 total GA (6.4 GA/sample) involving 203 individual genes and 384 CRGA (1.97 CRGA/sample) involving 51 genes. The most frequent GA were non-CRGA mutations in TP53 (46%), CDKN2A (43%) and CDKN2B (36%). The most frequent CRGA were in FGFR3 (28%), PIK3CA (15%) and CCND1 (12%). In comparison with UCB, statistically equivalent CRGA in FGFR3 (28% vs 21%), PIK3CA (15% vs 20%) and total ERBB2 (11% vs 16%) were identified. Of the 14 UTUC with ERBB2 non-amplification alterations, 6 (43%) featured a micropapillary growth pattern virtually identical to the frequency in UCB (40%). Conclusions: CGP of UTUC uncovers a wide variety of CRGA that can respond to targeted therapy including frequent CRGA in FGFR3, PIK3CA and ERBB2. CRGA in UTUC are generally similar to those found in UCB. Further study of targeted therapy for genomically characterized cases in a clinical trial setting for UTUC appears warranted.
Comprehensive characterization of 412 muscle invasive urothelial carcinomas: Final analysis of The Cancer Genome Atlas (TCGA) project.
Authors: Lerner Seth P. , Kim Jaegil , Kwiatkowski David J. , Getz Gad , Weinstein John N. , Cherniack Andrew , Guo Guangwu , Akbani Rehan , Hoadley Katherine A. , Kim William Y. , Robertson Gordon , Mungall Andrew J. , Hinoue Toshinori , Laird Peter W. , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Bellmunt Joaquim , Bajorin Dean F. , Hansel Donna E. , Creighton Chad J. ,   TCGA Bladder Cancer Working Group
Published: February 2017

405

Background: We reported the integrated molecular analysis of 131 tumors in 2014 (Nature 507:315, 2014) and now report on the entire cohort of 412 tumors from the TCGA project in chemotherapy-naïve muscle invasive urothelial bladder cancer. Methods: Following strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations (WES), DNA methylation, mRNA, microRNA and (phospho-) protein expression, transcript splicing, gene fusions, viral integration, pathway perturbation, clinical correlates, and histopathology Results: There was a high overall somatic mutation rate (8.0/Mb), as previously reported, with a median of 245 and mean of 348 coding region mutations per sample. There were 54 significantly mutated genes (SMGs) (MutSig_2CV), increased from 32 in the original report. TP53 remained the most commonly mutated gene, and chromatin-modifying genes (MLL2, ARID1A, KDM6A) were also frequently mutated. KRAS, ERBB2, RB1, and ELF3 showed significant increased frequencies of mutation. High mutation burden was associated with improved outcome (p = 0.0004). APOBEC mutagenesis explained 70% of the mutation burden and also was associated with survival. 167 genes were silenced by promoter DNA hypermethylation in at least 5% of tumors. Several SMGs were also epigenetically silenced at various frequencies (ZNF773, CDKN2A, FAT1, CASP8). The previously identified four mRNA subtypes were predicted on the larger set identifying a similar proportion of samples in each subtype. We identified 5 expression subtypes based on reverse-phase protein arrays(344 tumors). Five miR expression subtypes were strongly associated with 4 mRNA-based subtypes (P = 3.8E-37) and associated with overall survival (P = 0.05). Conclusions: This integrated analysis of 412 TCGA patient samples validates and extends observations from the first 131 patients and significantly increases our power to detect additional low-frequency aberrations. The results provide a robust basis for functional studies to further our understanding of the biology of bladder cancer, and aid in the development of more precisely targeted therapies.
Impact of relapse site on oncological outcomes after radical nephroureterectomy for upper urinary tract urothelial carcinoma.
Authors: Yamashita Shinichi , Ito Akihiro , Mitsuzuka Koji , Kawasaki Yoshihide , Shintaku Ichiro , Tochigi Tatsuo , Soma Fumihiko , Namima Takashige , Katoh Shinnosuke , Ota Shozo , Kyan Atsushi , Orikasa Kazuhiko , Takeda Atsushi , Numahata Kenji , Aizawa Masataka , Ioritani Naomasa , Adachi Hisanobu , Kawamorita Naoki , Kaiho Yasuhiro , Arai Yoichi ,   Tohoku Urological Evidence-Based Medicine Study Group
Published: February 2017

426

Background: Most upper urinary tract urothelial carcinomas (UTUC) are invasive and advanced with a poor prognosis. Patients often relapse after treatment with radical nephroureterectomy (RNU). However, little is known about an association between sites of recurrence after RNU and oncological outcomes. The present study retrospectively evaluated the impact of a first recurrence site on survival. Methods: A total of 650 patients with UTUC treated by RNU at 12 institutions that participated in the Tohoku Urological Evidence-Based Medicine Study Group between 2000 and 2011 were initially enrolled. Patients who experienced relapse other than intravesical recurrence after RNU were included in this study. Those who had metastasis at the time of UTUC diagnosis or missing data regarding the time and location of relapse were excluded. Finally, 173 patients were eligible to participate in this study. Survival rates were analyzed using Kaplan-Meier curves and the log-rank test, and factors predicting survival were assessed using multivariate analyses. Results: The median follow-up after relapse was nine months. The cancer-specific survival rates at one and two years after relapse were 49% and 22%, respectively. Cancer in 59 (34%), 32 (18%), 23 (13%), and 94 (53%) patients recurred in the lung, liver, bone and lymph nodes, and 23 (13%) had local recurrence. The one-year cancer-specific survival rates were 44%, 27%, 22% and 52% among patients with metastasis of the lungs, liver, bone and lymph nodes respectively, and 41% among those with local recurrence. The survival rate was worse among 48 patients with metastasis at multiple sites, than in those with metastasis at a single site. Fourteen (8%) patients with a single lymph, lung or local recurrence survived for over three years after a first relapse. Multivariate analyses selected the liver, bone and local recurrence as critical factors for cancer-specific survival. Conclusions: Liver or bone metastasis was a negative prognostic factor for UTUC with relapse after RNU. Information about recurrence sites might be helpful for patient counseling.
The impact of androgen deprivation and pelvic radiation on the development of bladder cancer.
Authors: Hafez Navid , Wang Rong , Hurwitz Michael E. , Ma Xiaomei , Petrylak Daniel Peter
Published: February 2017

439

Background: The male predilection of urothelial bladder cancer (UBC) as well as the expression of the androgen receptor in bladder tissue point to the role for androgens in UBC tumorigenesis. Animal studies demonstrate a potential role for androgen deprivation in diminishing UBC. More recently, two separate groups demonstrated decreased rates of both primary and recurrent UBC in prostate cancer patients previously receiving androgen deprivation therapy (ADT). Given the common use of radiation therapy (RT) in the treatment of localized prostate cancer, and previous data supporting the increased frequency of UBC in prostate cancer patients treated with RT, the interaction between ADT and RT in UBC remains an important consideration. Methods: Using the linked SEER-Medicare database, we investigated the interactions among ADT, RT and UBC by performing a retrospective cohort study of elderly (age 66-99) prostate cancer patients diagnosed between 1999-2011. Kaplan-Meier analysis and Cox proportional modeling were used to determine the risk of developing secondary bladder cancer after prostate cancer treatment (based on exposure to ADT, RT, both, or neither). All analyses were two-sided. Results: Of 121,927 patients with primary prostate cancer, 1,466 (1.20%) developed subsequent UBC with a median follow up of 5.08 years (range 0.003-12.00). Compared with patients never receiving ADT or RT (n = 43,809), the hazard ratios for the development of secondary bladder cancer in patients ever receiving ADT but no RT (n = 14,009), RT but no ADT (n = 16,672), or both ADT and RT (n = 17,465) were 0.76 (95% confidence interval [CI]: 0.63-0.91 ), 0.73 (95% CI: 0.64-0.83), and 0.69 (95% CI: 0.61-0.79), respectively. Conclusions: Both ADT and RT are independently associated with a reduced risk of secondary bladder cancers in prostate cancer patients. The finding of decreased UBC incidence in patients receiving RT was surprising, and in direct contradiction to previous studies of similar patient populations. Possible explanations include differences in cohort selection, changes in RT delivery, and differences in control groups.
Phase I trial of ALT-801, a first-in-class T-cell receptor (TCR)-interleukin (IL)-2 fusion molecule, plus gemcitabine (G) for Bacillus Calmette Guerin (BCG)-resistant non-muscle-invasive bladder cancer (NMIBC).
Authors: Sonpavde Guru , Rosser Charles Joel , Pan Chong-xian , Parikh Rahul Atul , Nix Jeffrey , Gingrich Jeffrey R. , Hernandez Liza , Huang Bee-Yau , Wong Hing C.
Published: February 2017

451

Background: Novel agents are necessary to treat BCG-resistant NMIBC to avoid radical cystectomy (RC). This phase I clinical trial evaluated the safety and activity of ALT-801, a recombinant humanized TCR-IL-2 fusion protein in BCG-resistant NMIBC. Methods: This is a Phase I trial using the 3+3 design to evaluate intravenous (IV) ALT-801 plus IV G 1000 mg/m2 in BCG-resistant high-risk NMIBC patients (pts) defined as high grade Ta, T1 or carcinoma in situ, size > 4 cm or multi-focal tumors. BCG-intolerant pts, those who refused or were unfit to undergo RC were also eligible. Initially, patients received ALT-801 monotherapy; an amendment added G. Pts received induction of 2 cycles, with a 13-day rest between cycles. Each cycle consisted of 4 doses of ALT-801 on Day 3, Day 5, Day 8, and Day 15 and 2 doses of G, one each on Day 1 and Day 8. Pts who have a biopsy-proven complete response (CR) after induction received one maintenance cycle and underwent response assessment. The initial dose of ALT-801 was 0.08 mg/kg with 2 step-down doses allowed if dose limiting toxicities (DLTs)- 0.06 mg/kg and 0.04 mg/kg. Results: 2 pts in cohort one received ALT-801 alone at 0.08 mg/kg per dose, a 3rd pt received G and ALT-801 at 0.08 mg/kg per dose. Grade ≥ 3 hepatotoxicity in the 3rd patient led to a step-down to 0.06 mg/kg dose. One pt in the 0.06 mg/kg dose experienced a DLT (Grade ≥ 3 hepatotoxicity) and the cohort was expanded to 6 pts with no further DLTs. Other attributed adverse events were: anorexia, pruritus, rash, edema, fatigue, chills. For the 0.06 mg/kg ALT-801 + G regimen, 6 pts received up to 2 cycles of induction and 4 pts received the maintenance cycle. All pts have completed therapy without further DLTs. CR was observed in 3 pts, which was durable in 2 pts lasting ≥ 18 months. Preliminarily immune studies have shown transient IFN-γ and IL-6 but not TNF-α and IL-10 induction after ALT-801 dosing. Conclusions: ALT-801 plus gemcitabine was feasible in BCG-resistant NMIBC and demonstrated immune responses and potential durable clinical activity. Further evaluation in expansion cohorts in a phase Ib/II trial is planned. Clinical trial information: NCT01625260.
Whole-exome sequencing (WES) of penile squamous cell carcinoma (PSCC) to identify multiple recurrent mutations.
Authors: Naik Gurudatta , Chen Dongquan , Crowley Michael , Crossman David , Sexton Katherine C. , Grizzle William E. , Mehta Amitkumar N. , Sonpavde Guru
Published: February 2017

484

Background: Molecular alterations and drivers of PSCC, an orphan malignancy, remain unclear. The Cancer Genome Atlas is not studying PSCC and the Catalogue of Somatic Mutations in Cancer has performed targeted analyses only. We report WES of PSCC tumors from a group of patients (pts). Methods: Freshfrozen macrodissected PSCC tumor tissue and adjacent normal tissue samples were procured from the Cooperative Human Tissue Network. DNA was isolated from tissue sections by phenol chloroform extraction. Exome capture was performed with the Agilent SureSelect clinical research exome kit and whole exome-seq was done on the Illumina HiSeq2500 with paired end 100bp chemistry. Raw sequence data in Fastq format were aligned to human reference genome and quantified, and compared by using a local instance of Galaxy (galaxy.uabgrid.uab.edu). These data were analyzed for mutations (SNPs) analysis, by Partek Genomic Suite/Flow(PGS, Partek, St. Louis, MO) for variance calling against human reference genome (hg19) as referenced to dbSNP; and copy number variants (cnv) by FishingCNV tool together with picard tools/samtools/GATK). We focused on missense mutations and amplifications among ≥ 2 tumor samples but not in normal samples as they may cause upregulation of gene/protein function, which may be therapeutically actionable. Results: PSCC tumors were available from 11 patients and adjacent normal tissue from 3 patients. The 10 most common genes with > 4 missense mutations among ≥ 2 tumor samples overall were the following in decreasing order of frequency: MUC4, HLA-DPA1, MUC16, XIRP2, SSPO, TTN, FCGBP, PABPC3, ALPK2 and MKI67. The top upstream transcriptional regulators were PIH1D3, PRDM5, PTK2, Coup-Tf and NBEAL2. When examining candidate actionable genes, recurrent missense alterations were seen in PIK3C2A and PIK3C2G. Additional analysis will study alterations in functional domains and cnv. Conclusions: WES identified a relatively high mutation burden in PSCC withrecurrent missense mutations in multiple genes, notably including the PI3K gene among potentially actionable genes. Validation of these findings and further study of downstream effects is required.
The impact of chemotherapy on cognition: A longitudinal study in testicular cancer.
Authors: Toner Guy C. , Whitford Hayley S. , Kalinowski Pawel , Grimison Peter S. , Stockler Martin R. , Martin Andrew James , Davis Ian D. , Olver Ian N. ,   ANZUP Cancer Trials Group
Published: February 2017

487

Background: Neuropsychological assessments suggest chemotherapy may lead to cognitive impairment but causal links remain unclear. Prospective longitudinal studies are needed to address methodological limitations, with different chemotherapy regimens, appropriate controls and adjusting confounders. Methods: This 16 centre, prospective observational study accrued 145 patients with testicular cancer treated with surgery, or surgery + chemotherapy, as determined by disease staging. Cognition was assessed by CogHealth, a 10-minute online playing-card format tool designed to overcome language limitations, assessment burden, and practice/ceiling effects. Quality of life, fatigue, anxiety, depression and self-perceived cognitive function were also assessed. Comparisons were made between baseline (≤6 months from orchidectomy/pre-chemotherapy) and follow-Up (12-18 months), for 3 groups with sufficient data; cisplatin-based chemotherapy (BEP/EP, n=41), carboplatin (n=20), and controls (n=41). Results: With age as a covariate, linear mixed models were used to compare the 3 groups over time. There were no significant differences between groups over time for cognitive tasks assessing psychomotor function, complex decision making, visual learning, working memory, and visual attention; self-perceived cognitive function matched actual performance. At baseline, for fatigue (p = 0.008), BEP/EP scored significantly worse than carboplatin (d = -0.75) and control groups (d = -0.80). For anxiety (p = 0.005), BEP/EP scored worse than controls (d = -0.91). For all groups anxiety (p = 0.03), emotional (p = 0.001) and functional wellbeing (p = 0.002), improved over time. BEP/EP with poorest scores at baseline, improved the most by follow-up (d = 0.63, -1.24, -1.17, respectively). Only physical wellbeing showed significant effects (p ≤ 0.03) for group, time, and a differing pattern of change across groups; the BEP/EP group scoring worse at baseline compared to carboplatin (d = -0.94) and control groups (d = -1.16), improving by follow-Up (d = -1.21). Conclusions: For patients with testicular cancer there were no statistically significant differences between groups for cognition scores or self-reported cognitive function. Clinical trial information: 12609000545268.
Association of a combined panel of tumor infiltrating lymphocytes, plasma cells, and macrophages with recurrence of localized clear cell (cc) renal cell carcinoma (RCC) undergoing surgery.
Authors: Ghatalia Pooja , Gordetsky Jennifer , Bae Sejong , Watkins Stacey M , Sudarshan Sunil , Naik Gurudatta , Sonpavde Guru
Published: February 2017

502

Background: Tumor infiltrating Programmed-Death (PD)-1 and FoxP3-expressing lymphocytes and macrophages appear to be associated with higher risk of recurrence in patients (pts) with ccRCC undergoing surgery for localized disease. We aimed to combine the presence of morphologically identified lymphocytes, plasma cells and macrophages into a readily available composite immune cell panel and to evaluate its association with tumor recurrence. Methods: We identified pts with ccRCC who underwent nephrectomy at UAB for whom we had annotation for objective tumor recurrence and a minimum follow-up of 2 years. Central pathology review was conducted by a single urologic oncology certified pathologist to capture pathologic variables (stage, grade, necrosis, histologic components, cystic changes) and immune cell (lymphocyte/plasma cell/macrophage) infiltration. Logistic regression (univariate and multivariate) analyses were conducted to evaluate the association of these variables with tumor recurrence. Results: Of the 159 identified and evaluable pts, 33 (20.7%) recurred and 126 did not. On univariate analyses, sarcomatoid/rhabdoid histologic components, lymphocyte/plasma cell infiltration, necrosis, pathological T stage and histologic grade were all statistically significantly associated with a risk of recurrence (p < 0.05). On multivariate analysis, in addition to pathologic stage (p = 0.0018), only the combination of higher lymphocyte/plasma cell and macrophage infiltration (p = 0.0347) was independently associated with recurrence; patients were 8.7 times more likely to recur (95% CI: 1.66, 45.28). Conclusions: A readily available and widely applicable composite panel of morphologically identified lymphocytes, plasma cells and macrophages infiltrating the tumor predicts recurrence of pts with localized ccRCC undergoing surgery, after controlling for clinical and pathologic prognostic factors. Our hypothesis-generating data require validation and further interrogation of specific markers expressed on immune cells may refine an immune panel that confers prognostic impact.
Everolimus and sunitinib as first- and second-line treatments of patients with metastatic papillary renal cell carcinoma (pRCC): A retrospective study of the GETUG (Groupe Français d’Etude des Tumeurs Uro-Génitales).
Authors: Linassier Claude , Albiges Laurence , Chevreau Christine , Laguerre Brigitte , Oudard Stephane , Gross-Goupil Marine , Gravis Gwenaelle , Goldwasser Francois , Rolland Frederic , Delva Remy , Moise Laura , Tourani Jean-Marc , Vassal Cecile , Zanetta Sylvie , Penel Nicolas , Flechon Aude , Theodore Christine , Barthelemy Philippe , Saldana Carolina , Escudier Bernard
Published: February 2017

505

Background: pRCC accounts for 15% of all renal cancers. Two French prospective phase II trials demonstrated efficacy of both Sun and Eve in first-line treatment of metastatic disease (RAPTOR (NCT00688753) and SUPAP (NCT00541008)). Most patients (pts) usually receive the alternate drug at progression. We report the first series of drug sequencing in pRCCs. Methods: We updated clinical data of metastatic pts with pathologically documented pRCC, who were treated in firs line or more with Sun or Eve, from 2/06 to 6/15, in 24 GETUG centers. Results: 196 pts (166 men, 30 women), median aged of 61 years, with histological subtypes (HST) I (28 pts), II (122 pts) or unclassified (46 pts), were treated for metastatic pRCC in 1st-line: group 1 Su 50 mg daily 4/6 weeks (n=158 pts) ; group 2 Eve 10 mg daily (n=38 pts). 76 pts were included in the RAPTOR or SUPAP studies. The median follow-up was 59.5 months. We found no difference between the 2 groups in terms of patients’ characteristics, clinical benefit in first-line (CR+PR+SD) (71% vs 72%; p=0.95) or progression-free survival (PFS) (PFS-1: 5.7 vs 4.6 months; p=0.152). Reasons for treatment discontinuation were tumor progression (74% vs 70%) or toxicity (26 vs 30%) (p=0.58). 134 pts received the alternative drug in second-line (group 1: Eve; group 2: Sun) with similar clinical benefit (64% vs 58%; p=0.69) and median PFS (PFS-2: 3.5 vs 3.0 months p=0.98). Overall survival (OS) did not differ between the two groups (16.4 vs 17.6 months; p=0.58). Age, Karnofsky performance status < 80 (KPS-80), HST, platelet (Plts) and absolute neutrophil counts (ANC), hemoglobin and calcium levels, time from diagnosis to metastases (TTM) were studied as prognostic variables. In multivariable analysis, only Plts and KPS-80 had prognostic impact on EFS-1, whereas ANC, KPS-80 and TTM were prognostic for OS. We found a trend in favor of HST I vs non I, with no statistical difference in terms of PFS or OS. Conclusions: In this large retrospective series of metastatic pRCC pts, Sun and Eve had good compliance and similar efficacy in terms of first-, second-line PFS and overall survival.
Understanding the genomic underpinnings of metastatic chromophobe renal cell carcinoma.
Authors: Casuscelli Jozefina , Wang Patricia , Redzematovic Almedina , Lee William , Seshan Venkatraman E. , Shen Ronglai , Donin Nicholas , Chen Yingbei , Cheville John C. , Pantuck Allan J. , Thompson Robert Houston , Coleman Jonathan A. , Russo Paul , Reuter Victor E. , Tickoo Satish , Hakimi A. Ari , Hsieh James
Published: February 2017

513

Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.
Mutation burden and tumor neoantigens in RCC patients (pts) treated with nivolumab.
Authors: Voss Martin Henner , Hellmann Matthew David , Chen Yingbei , Gold Theresa Margaret , Lambert Courtney Rose , VanAllen Eliezer , Choueiri Toni K. , Snyder Charen Alexandra , Motzer Robert J.
Published: February 2017

514

Background: Durable benefit with CTLA4 or PD1 blockade associates with high somatic mutation burden in melanoma and lung cancer (Snyder, NEJM 2014; Rizvi, Science 2015). The same studies suggest that tumor neoantigens arising from somatic mutations may be mediating this association. For RCC, a disease with a comparatively low mutation burden but good response to PD1 directed therapy, such associations are unknown. To examine these concepts, we used whole exome (WES) and transcriptome (RNAseq) sequencing of RCC samples from pts treated with nivolumab (Nivo). Methods: WES and RNASeq were performed on frozen pre-treatment tumor/normal tissue for 7 pts treated with Nivo and 1 pt treated with ipilimumab/Nivo (Ipi/Nivo) x 4 followed by Nivo. Efficacy was assessed by RECIST. Neoantigen prediction and HLA typing were performed in silico using NetMHC3.2 and ATHLATES, respectively. Expression of predicted neoantigens and putative pathways of resistance/response were investigated using DESeq-normalized reads. Results: Two of 7 Nivo-monotherapy pts achieved durable clinical benefit (DCB, PR > 12 months); 1 pt had a non-durable PR (5 months). For 2 Nivo/DCB pts, the burden of non-synonymous somatic mutations was 113 and 224 compared to a median of 95 in those with no DCB (range 53-124). The ratio of predicted neoantigens/total mutations was higher for pts with DCB/Objective response (all ≥ 0.5) compared to those with progressive disease (all < 0.5). The Ipi/Nivo pt experienced > 95% tumor regression ongoing 2+ years, but harbored the lowest mutation count (29) and lowest neoantigen/mutation ratio ( < 0.2) in the cohort. Across all pts, 80% of predicted neoantigens were expressed. Further, RNASeq findings differed distinctly for DCB vs. non-DCB pts in various genes of interest, including mediators of antigen presentation to T-cells (HLA-A, -B, -C; B2M) and composition of other immune regulators (CSF1R, LGALS1), but not for PDL1. Conclusions: In RCC, somatic mutations, particularly those causing tumor neoantigens, and the counterbalance between molecular immune compartments may be determinants of treatment benefit from Nivo and warrant future study. Their impact might be distinctly different in pts treated with combination immunotherapy.
Risk of hyperglycemia attributable to everolimus in renal cell and non–renal cell carcinoma patients: A meta-analysis.
Authors: Xu Kevin Y , Shameem Raji , Wu Shenhong
Published: February 2017

515

Background: Everolimus has been used widely in cancer patients and is associated with the development of hyperglycemia. Due to confounding factors, everolimus’ specific impact on hyperglycemia has not been well understood. We performed a meta-analysis to determine the risk of hyperglycemia attributable to everolimus in cancer patients of varying tumor types. Methods: PubMed and ASCO conference abstracts up to June 2015 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which everolimus was compared to placebo in cancer patients with or without additional cancer therapies. Heterogeneity tests were performed to examine between-study differences in hyperglycemia. The incidence and relative risk of all-grade and high-grade hyperglycemia attributable to everolimus were determined using random- or fixed-effects models. Results: A total of 7 phase III and 2 phase II RCTs with various tumors were included in our analysis. Everolimus significantly increased the risk of all-grade (RR = 2.60, 95% CI: 2.03-3.31, P < 0.001) and high-grade (RR = 3.00, 95% CI: 1.72-5.23; P < 0.001) hyperglycemia. The incidences of all-grade and high-grade hyperglycemia attributable to everolimus were 6.8% (95% CI: 3.4-13.2%) and 2.5% (95%: 1.2-4.9%) respectively. The everolimus-specific risk of all-grade hyperglycemia varied significantly with tumor types (P < 0.001), with the highest incidence seen in renal cell carcinoma (27.2%, 95% CI: 22.2-32.8%) and the lowest in breast cancer (3.3%, 95% CI: 1.3-8.2%). No significant variation was found between everolimus alone or everolimus in combination with other agents. Similar results were also found for the risk of high-grade hyperglycemia attributable to everolimus. Conclusions: The specific contribution of everolimus to both all-grade and high-grade hyperglycemia may be modified significantly by tumor types. Close monitoring should be given to patients with renal cell carcinoma.
Change in International mRCC Database Consortium (IMDC) prognostic category and implications for efficacy of second-line targeted therapy.
Authors: Davis Ian D. , Xie Wanling , Pezaro Carmel Jo , Donskov Frede , Wells Connor , Agarwal Neeraj , Srinivas Sandhya , Yuasa Takeshi , Beuselinck Benoit , Wood Lori , Ernst D. Scott , Kanesvaran Ravindran , Knox Jennifer J. , Pantuck Allan J. , Saleem Sadia , Alva Ajjai Shivaram , Rini Brian I. , Lee Jae-Lyun , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2017

534

Background: Currently no predictive markers exist for choosing second-line targeted therapy (2L) in metastatic renal cell carcinoma (mRCC). A change in IMDC prognostic group when calculated at first-line therapy (1L) and 2L and its association with 2L efficacy was examined. Methods: The IMDC database was interrogated for patients who received 1L VEGF inhibitors (VEGFi) and then 2L with VEGFi or an mTOR inhibitor (mTORi). IMDC prognostic categories (Favorable, F; Intermediate, I; Poor, P) were defined prior to each line of therapy. Overall survival (OS), time to treatment failure (TTF) and response to 1L or 2L were assessed in relation to change in IMDC prognostic risk category. Results: Data for 1516 patients were analyzed; 89% had clear cell histology. Prognostic risk categories at 1L were F: 21.7%; I: 59.5%; P: 18.8%. 60.3% of patients remained in the same risk category at start of 2L; 9.0% improved (3% I→F; 6% P→I); 30.7% deteriorated (14% F → I or P; 16% I → P). Improvement in prognostic risk category was associated with better response and longer duration of 1L. Patients who improved prognostic risk (I → F or P → I), or maintained I or F grouping, had longer TTF if they remained on VEGFi for 2L compared to those who switched to mTORi (p < 0.05). In contrast, patients whose risk category deteriorated (F → I or P) may be more likely to benefit from switching to mTORi. Conclusions: Changes in IMDC prognostic category may predict the subsequent clinical course of patients with aRCC and provide a rational basis for selection of subsequent therapy. [Table: see text]
DNA methylation signature to define cell ontogeny of renal cell carcinomas.
Authors: Malouf Gabriel G. , Su Xiaoping , Zhang Jianping , Ho Thai Huu , Lu Yue , Raynal Noel J-M , Karam Jose A , Tamboli Pheroze , Allanick Frederick , Mouawad Roger , Khayat David , Wood Christopher G. , Jelinek Jaroslav , Tannir Nizar M.
Published: February 2017

536

Background: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype-phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron. Methods: We performed deep profiling of DNA methylation in diverse histopathological RCC subtypes and validated DNA methylation and transcriptome signatures in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets. Results: Our data provide the first mapping of methylome epi-signature and indicates that RCC subtypes can be grouped into two major epi-clusters: C1 which encompasses clear cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2 which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed three fold more hypermethylation as compared to C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC. Conclusions: Taken together, our data defines the epi-clusters that can discriminate between distinct RCC subtypes and for the first time, to our knowledge, define the epigenetic basis for proximal versus distal tubule derived kidney tumors.
Integrated genomic correlates of response to PD-1 inhibitor nivolumab in metastatic renal cell carcinoma (mRCC).
Authors: de Velasco Guillermo , Miao Diana , Shukla Sachet , Voss Martin Henner , Wu Catherine , Murray Bradley , Meyerson Matthew , Signoretti Sabina , Motzer Robert J. , Van Allen Eliezer Mendel , Choueiri Toni K.
Published: February 2017

545

Background: Nivolumab (nivo) is a programmed death-1 (PD-1) inhibitor that has recently been shown to increase overall survival in patients with mRCC. The association between benefit from nivo with neoantigen load, mutation load and signatures of immune infiltration has yet to be explored in mRCC. Methods: Publicly available whole exomes (WES) and whole transcriptomes (RNA-seq) from over 300 clear-cell RCC patients in the Cancer Genome Atlas (TCGA) were analyzed for mutational load, neoantigen load and expression of immune-related genes. HLA types were inferred from WES with Polysolver and neoantigens were predicted from somatic nonsynonymous mutations with NetMHCpan3.2. The same analysis pipeline was applied to paired pre-treatment germline and metastatic tumor specimens from 9 patients who received nivo for mRCC: 3 responders (CR or PR by RECIST; R) and 6 non-responders (SD or PD by RECIST; NR), all with available pre-nivo fresh biopsies of metastatic lesions. Matched RNA-seq was available on a subset of these patient samples (3 R, 3 NR). Results: Across the TCGA and nivo-treated patients cohorts, RCC had relatively few nonsynonymous mutations and neoantigens. Among the nivo-treated patients, neoantigen load was significantly higher in NR compared to R (p = 0.048), but nonsynonymous mutation load was not. An exceptional R who experienced CR (PFS > 30 months) had outlying higher expression of selected immune-related genes compared to the 8 other patient samples (p < 0.05 for PD-L1, PD-L2; p < 0.01 for CTLA4, PD-1, PRF1; p < 0.001 for GZMA, BTLA, CD8A), and was in the top 1-5% of expression of these genes among all TCGA data. Bootstrapping analysis comparing mean expression in R vs NR compared to an empirical distribution of TCGA RNA-seq data showed significantly higher expression of PD-1, PD-L1, GZMA, LAG3, IDO1, ICOS, and BTLA in R vs. NR (p < 0.05). No genes were enriched for nonsynonymous mutations in R or NR. Conclusions: This analysis suggests that both DNA- and RNA-level data may be relevant for explaining clinical benefit from nivo in mRCC. In contrast with results from other tumor types, responders to nivo did not have more mutated tumors, though immune-related gene expression may be related to response.
Association between diabetes mellitus and the survival of sunitinib-treated patients with metastatic renal cell carcinoma.
Authors: Suyama Takahito , Fujimoto Ayumi , Kanesaka Manato , Hou Kyokushin , Araki Kazuhiro , Masuda Hiroshi , Kojima Satoko , Sazuka Tomokazu , Nakamura Kazuyoshi , Nihei Naoki , Ichikawa Tomohiko , Naya Yukio
Published: February 2017

546

Background: Diabetes mellitus is one of the major risk factor for renal cell carcinoma (RCC) development. Although, in various cancers, the relationship between diabetes mellitus and worse prognosis is pointed out, the association between RCC prognosis and diabetes mellitus is under discussion. We sought to determine the association between diabetes mellitus with outcome of sunitinib treatment in metastatic RCC (mRCC) patients. Methods: A retrospective study of sunitinib-treated mRCC patients was performed. 69 patients who had been treated with sunitinib in Japanese two institutions (Teikyo University Chiba Medical Center and Chiba University) were entered. Kaplan-Meier and the log-rank test were performed to investigate the association between the pretreatment status of diabetes mellitus and the outcome of the patients who received the treatment with sunitinib. Results: Between 2008 and 2015, 69 mRCC patients were treated with sunitinib. 53 (76.8%) patients received sunitinib treatment as the first line molecular target drug. 15 (21.7%) patients were diagnosed as diabetes mellitus at the time of sunitinib treatment. Median time to treatment failure (TTF) was 7.1 months, cancer specific survival (CSS) was 33.9 months for all patients. With regard to TTF, there was no difference between diabetic and non-diabetic patients, 9 months for diabetic patients and 7.1 months for non-diabetic patients respectively (P = 0.3271). CCS was significantly shorter for diabetic patients, 11 months for diabetic patients and 39.4 months for non-diabetic patients respectively (P = 0.0469). When focusing on HbA1c, CSS was significant longer for the patients with HbA1c under 6.5% than the patients with HbA1c was 6.5 or more, median CSS was 44.5 months and 11.3 months, respectively (P = 0.0055). Conclusions: Diabetes mellitus did not influence the TTF of sunitinib treatment for mRCC patients. Diabetes mellitus may negatively affect the CSS of sunitinib-treated mRCC. Clinicians should consider controlling patient’s HbA1c status at the initiation of sunitinib treatment for mRCC.