bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world clinical outcomes of pazopanib immediately following immunotherapy discontinuation for the treatment of advanced renal cell carcinoma.
Authors: Cao Xiting , Tang Derek , Ratto Barbara Elizabeth , Poole Austin , Ravichandran Shoba , Jin Lixian , Gao Wei , Swallow Elyse , Vogelzang Nicholas J.
Published: March 2019

573

Background: In the first-line setting (1L), pazopanib (PAZ) is recommended by NCCN for treatment of advanced renal cell carcinoma (aRCC). In 2018, immuno-oncology (IO) therapy became commonly used 1L treatment option for aRCC. This study reports real-world clinical outcomes of PAZ following IO therapy among aRCC patients (pts) in an evolving treatment landscape. Methods: This retrospective chart review study used medical record data collected by medical oncologists. Included pts were those ≥ 18 at initiation of IO therapy who initiated 2L+ PAZ for clear cell aRCC before November 2017, and had complete medical records from the diagnosis of aRCC to discontinuation of PAZ, death, or the chart extraction date (May 2018), whichever occurred first. Primary outcome was PAZ duration of therapy (DOT). Secondary outcomes were progression-free survival (PFS) and overall survival (OS) since PAZ initiation, reasons for PAZ discontinuation, and adverse events (AEs). Time-to-event outcomes were analyzed by Kaplan-Meier method. Results: 258 eligible pts initiated the IO therapies before PAZ as follows: nivolumab (NIVO) (68%), NIVO+ipilimumab (IPI) (14%), pembrolizumab (12%), and IPI (3%). Ninety-seven (38%), 56 (22%), and 92 (36%) pts were grouped as favorable, intermediate, or poor risk by Heng criteria, respectively. Overall, the median PAZ DOT was 13.4 months (Ms) (95% confidence interval [CI] 10.1-16.0). When stratified by lines of therapy, pts who received PAZ as 2L (n=182) or 3L+ (n=76) had DOT of 13.4 Ms (95% CI 11.1-NR) and 9.6 Ms (95% CI 6.2-NR), respectively. The PFS and OS outcomes are shown in the Table. One hundred-nine (42%) pts reported an AE. The most frequently (>10%) reported AEs were fatigue (29%), diarrhea (14%), decreased appetite (14%), and hypertension (13%). Conclusions: In this real-world study, 2+L PAZ following prior IO therapy was well-tolerated, effective, and non-cross-resistant with IO therapy for aRCC pts. [Table: see text]
First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Preliminary results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Dudani Shaan , Graham Jeffrey , Wells Connor , Pal Sumanta K. , Dizman Nazli , Donskov Frede , Bjarnason Georg A. , Hansen Aaron Richard , Iafolla Marco Adelmo James , Vaishampayan Ulka N. , Porta Camillo , Beuselinck Benoit , Yan Flora , Wood Lori , Liow Elizabeth Chien Hern , Kollmannsberger Christian K. , Yuasa Takeshi , Zhang Chiyuan A , Choueiri Toni K. , Heng Daniel Yick Chin
Published: March 2019

584

Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L PD(L)1-VEGF (PV) inhibitor combinations. The efficacy of these two strategies has not been compared. Methods: Using the IMDC dataset, patients (pts) treated with any 1L PV combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 164 pts received 1L IO combination therapy: 104 treated with PV combinations and 60 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups (Table). When comparing PV combinations vs ipi-nivo, 1L response rates (RR) were 30% vs 39% (p = 0.29), time to treatment failure (TTF) was 13.2 (95% CI 8.3-16.1) vs 8.5 months (95% CI 5.7-14.0, p = 0.31), and median overall survival (OS) was not reached (NR) (95% CI 19.7-NR) vs NR (95% CI 27.6-NR, p = 0.39). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.77 (95% CI 0.44-1.35, p = 0.36) and the HR for death was 0.94 (95% CI 0.33-2.71, p = 0.91). Similar results were seen when restricting the cohort to IMDC intermediate/poor risk pts only. In pts receiving subsequent VEGF TKI monotherapy, second-line (2L) RR (13% vs 45%, p = 0.07) and TTF (5.5 vs 5.4 months, p = 0.80) for PV combinations (n = 15) vs ipi-nivo (n = 20) were not significantly different. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as PV combinations and ipi-nivo have comparable RR, TTF and OS. Although there is a trend towards differences in RR, there does not appear to be a significant difference in TTF for patients receiving 2L VEGF TKI therapy. [Table: see text]
Angiogenic factor and cytokine analysis among patients with renal cell carcinoma treated with adjuvant VEGFR TKIs.
Authors: Xu Wenxin , Puligandla Maneka , Haas Naomi B. , Flaherty Keith , Uzzo Robert , Dutcher Janice P. , DiPaola Robert S. , Bhatt Rupal Satish
Published: March 2019

586

Background: VEGFR TKIs are important therapeutic agents in RCC, but their adjuvant use remains limited. Investigating the effects of these medications on circulating angiogenic factors and cytokines in the adjuvant setting can elucidate whether changes in cytokine levels result from drug-host or drug-tumor interactions, and may reveal biomarkers to guide patient selection for adjuvant treatment. Methods: In the ECOG-ACRIN 2805 (ASSURE) trial, patients with resected RCC were randomized to sunitinib, sorafenib, or placebo. Plasma was collected at start of treatment and 4 or 6 weeks after treatment initiation. All paired samples available by July 2010 were analyzed, corresponding to 413 patients. We analyzed VEGF, PlGF, sFlt1, KDR/sVEGFR-2, Ang2, bFGF, HGF, IFNg, IL8, CXCL9, CXCL10, and CXCL11. Mixed effects models were used to test for changes from baseline. Cox models were used to assess associations between disease-free survival (DFS) and angiogenic factor and cytokine levels. Results: VEGF and PlGF increased after 4 weeks on either treatment (p < 0.0001 for both), and at 6 weeks VEGF and PIGF levels returned to baseline for patients on sunitinib (corresponding to the 2 week break in the sunitinib schedule) but not sorafenib. Levels of sFLT-1 decreased after 4 weeks on suntinib and after 6 weeks on sorafenib (p < 0.0001). sVEGFR2 decreased after both 4 and 6 weeks of treatment on both sunitinib and sorafenib (p < 0.0001). Patients on placebo had no significant changes in circulating angiogenic factor or cytokine levels. CXCL-10 levels increased after 4 weeks on both sunitinib and sorafenib but not on placebo, and remained elevated at 6 weeks on sunitinib. Higher baseline CXCL-10 was associated with worse DFS (HR 1.41 per log increase in CXCL-10, Holm adjusted p-value 0.003, 95% CI 1.18-1.70). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG PS. Conclusions: Among patients treated with VEGFR TKIs in the adjuvant setting for RCC, drug-host interactions mediate changes in cytokines and angiogenic factors. Elevated CXCL-10 prior to treatment was associated with higher recurrence risk. Studies to understand the functional consequences of these changes are underway.
Eficacy and safety of first-line TKI in elderly with metastatic renal cancer.
Authors: Leite Luciana de Moura , Rinck Jose A. , Dettino Aldo A. , Zequi Stenio Cassio , Da Costa Alexandre Andre B. A. , Garcia Daniel , Formiga Maria Nirvana
Published: March 2019

588

Background: Data on 1st line treatment with tyrosine kinase inhibitors (TKI) in elderly patients(pts) with metastatic renal cell carcinoma (mRCC) is controversial, and there is rationale for inferior outcomes due to multiple comorbidities and polypharmacy. We aimed to compare the efficacy and safety between the elderly (E) and non-elderly (NE) in 1st line therapy, and to explore factors influencing survival and toxicity. Methods: We retrospectively reviewed all medical records of mRCC pts treated with 1st line TKI at our institution (2007 – 2018). Categorial variables were compared by Fisher’s exact test and continuous, Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: From 171 eligible pts, 64 (37.4%) had ≥ 65years old, with median age of 70.5 for E and 56 for NE. In both groups most were male, had clear cell histology, good/intermediate IMDC risk, prior nephrectomy and > 1 metastatic (mets) site. Sites of mets were evenly distributed. E pts had more diabetes (35.9 vs16.8%, p.009) , hypertension (67.2 vs 46.7%, p.01), cardiovascular disease (15.6 vs 6.5%, p.06), moderate/severe renal dysfunction (62.5 vs 28.8%, p < 0001), high Charlson Comorbidities Index (CCI≥3, 48.4% vs 20.8%, p < .0001), polypharmacy (34.4 vs15.9%, p.008), worst ECOG (≥2, 28.2 vs 12.3%, p.01), and a trend to worst nutrition (weight loss 35.9 vs 22.5%, p.07). Sunitinib was used for 60.9 vs 79.4%, Pazopanib 35.9 vs 18.7%, Sorafenib 3.1 vs 1.9%, comparing E and NE pts. Median overall survival (OS) and progression free survival (PFS) was 23.7 vs 25.6m (p.8) and 9.3 vs 10.9m (p.7), respectively. After adjusting for prognostic factors, age continues not to influence OS (HR 1.17, IC95 0.77-1.78, p.45). Grade (G) 3/4 toxicity was seen in 59.4 vs 53.3%, dose reduction in 54.7 vs 53.3% and suspension due to toxicity 25 vs 13.3% for E and NE, respectively. In the E, none of the comorbidities, CCI or polypharmacy impaired OS or toxicity, but pts using sunitinibe had greater G3/4 toxicity than with pazopanib (71.8 vs 39.1%, p.02). Conclusions: Elderly had similar outcomes to NE pts, despite greater comorbidities and polypharmacy, hence efficacious therapies shouldn’t avoided. Pazopanib seems to be safer in this subgroup.
Expectations of cure among patients with advanced genitourinary cancer treated with immunotherapy.
Authors: Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Philip Errol James , Hsu Joann , Dizman Nazli , Vaishampayan Ulka N. , Dorff Tanya B. , Pal Sumanta K.
Published: March 2019

591

Background: Over the past 15 years, considerable progress has been made in systemic therapy options for genitourinary (GU) cancers. In diseases such as metastatic renal cell carcinoma (RCC) and urothelial cancer (UC), immunotherapeutic strategies such as programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition have elicited durable responses, albeit in a minority of patients. We examined expectations for clinical outcome with immunotherapy among patients with advanced GU cancers. Methods: A survey study was conducted in patients with advanced GU cancers initiating PD-1/PD-L1 inhibitors from October 2017 to September 2018. Patients were screened prior to initiation of immunotherapy for their expectation of cure (divided into 4 quartiles), symptoms of anxiety and depression (PROMIS-A and PROMIS-D), and quality of life (QOL; FACT-G). For purposes of the survey, cure was equated to a durable complete response. Differences in frequency of anxiety, depression and QOL were compared amongst subsets of patients divided by expectation of cure. Results: Among 60 patients, median age was 67, 72% were male and 81% were married. Types of cancer included RCC (69%), UC (19%) and prostate cancer (12%). The majority were in the 1st or 2nd line of therapy (40% and 31%, respectively). Despite extensive counseling from GU medical oncologists, 23% of patients thought that cure was “very likely”, defined as in the range of 76-100%. Approximately 70% of patients estimated cure in the range of 0-25%, in line with clinical counseling. These patients had higher rates of anxiety (P = 0.01), depression (P = 0.002) and poorer QOL (P = 0.003) compared to patients who felt cure was very likely. Conclusions: A considerable proportion of patients with advanced GU malignancies harbor unrealistic expectations around the potential benefit of immunotherapy. Although a first instinct may be to remedy these expectations, it is important to bear in mind that these patients had better emotional well-being and QOL. We will validate these findings and assess these parameters longitudinally in an upcoming SWOG trial for patients with mRCC receiving upfront immunotherapy.
The significance of insulin receptor expression to predict the resistance to VEGFR-TKIs and induce PD-L1 expression in advanced clear cell renal cell carcinoma.
Authors: Takahashi Masayuki , Daizumoto Kei , Fukawa Tomoya , Fukuhara Yayoi , Ozaki Keisuke , Tsuda Megumi , Kusuhara Yoshito , Mori Hidehisa , Yamamoto Yasuyo , Yamaguchi Kunihisa , Fukumori Tomoharu , Kanayama Hiroomi
Published: March 2019

592

Background: Previously we have identified the prognostic gene set of ccRCC patients, where insulin receptor (INSR) expression was decreased in the patients with poor outcome (Proc Natl Acad Sci U S A., 2001). We examined the clinical significance of decreased INSR expression and sought to elucidate the underlying mechanisms. Methods: The INSR expression was immunohistochemically examined in the nephrectomy specimens of RCC patients (n = 33) who then received axitinib. We established patient derived Xenograft model (PDX) of ccRCC and examined the INSR expression in the axitinib resistant PDX tumors by Western blotting. As the INSR is expressed in the vascular endothelial cells, we co-cultured the RCC cell lines with the human renal glomerular endothelial cells (HGEC) treated with si-RNA of INSR (si-INSR) and the microarray experiment was conducted. Results: In RCC patients with axitinib, those with low INSR expression had poor outcome (median PFS 19.5 vs 2.3 months, p < 0.001; median OS 34.2 vs 5.6 months, p = 0.001). The INSR expression was the significantly independent predictor of PFS (p = 0.006). In the axitinib-resistant PDX tumors, the expression of INSR was decreased. In the co-culture experiments, the microarray experiments revealed that the decreased INSR expression in the HGECs may be involved with the important signaling pathway including interferon response in Caki-1 cells. Interferon- β was highly expressed in HGECs with si-INSR. The decreased INSR expression and the increased interferon-β expression in HGEC were confirmed when axitinib was administered. The Caki-1 cells that was co-cultured with HGECs treated with si-INSR demonstrated high expression of PD-L1. The PD-L1 expression was increased in a concentration-dependent manner of recombinant interferon-β and increased phosphorylation of STAT1 and STAT3 were observed. Conclusions: In conclusion, the decreased INSR expression could be a biomarker to predict the resistance to VEGFR-TKIs. The decreased INSR expression was correlated with the increased interferon-β expression in HGECs, which leads to the induction of PD-L1 through increased phosphorylation of STAT1 and STAT3.
Disparities in survival outcomes in African Americans in renal cell carcinoma: Impact of oncological versus nononcological factors.
Authors: Meagher Margaret Frances , Bradshaw Aaron , Anyakora David , Patil Dattatraya H , Saito Kazutaka , Cotta Brittney , Yasuda Yosuke , Eldefrawy Ahmed , Ryan Stephen , Nasseri Ryan , Alksne Juliana , Wan Fang , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar
Published: March 2019

595

Background: African-Americans have increased incidences of renal cortical tumor subtypes of lower oncological potential in the setting of lower risk disease when compared to other ethno-racial groups. However, survival outcomes are similar. We investigated the impact of African-American race on overall survival, oncological outcomes, functional outcomes, and non-cancer mortality. Methods: Multi-institutional retrospective analysis of patients who underwent partial or radical nephrectomy between 1998-2018. Primary outcome was overall survival (OS). Secondary outcomes included non-cancer mortality (NCM), recurrence free survival (RFS), and estimated glomerular filtration rate (eGFR) decline. Multivariable logistic regression (MVA) were used to elucidate predictive factors for OS, NCM, and RFS, and eGFR <45 and <30 ml/min/1.73m2. Results: 3,088 patients were divided into African American (AA, n=353) and Non-African American (NAA, n=2735) sub-groups. No difference was noted between groups with respect to mean tumor size (p=0.211) or metastases presence (p=0.846). African-American race was an independent risk factor for functional decline to eGFR<45 (OR 4.43, p<0.001) and eGFR<30 (OR 5.15, p<0.001). MVA for worsened NCM demonstrated African-American race (OR=1.72, p=0.042), increasing age (OR=1.03, p=0.001), radical nephrectomy (OR=2.98, p<0.001), and increasing tumor size (OR=1.26, p<0.001) to be independent risk factors. MVA for worsened OS included increasing age (OR=1.04, p<0.001), tumor size (OR=1.182, p<0.001), clear cell histology (OR=1.62, p<0.001), high tumor grade (OR=2.12, p<0.001), and post-operative eGFR <45 (OR=2.12, p<0.001). MVA for worsening RFS demonstrated high tumor grade (OR=2.38, p<0.001) and increasing clinical tumor size (OR=1.152, p<0.001) to be independent factors. Conclusions: African Americans undergoing renal surgery for RCC appear to have similar OS and RFS, but poorer NCM than non-African American patients. The cause of these disparities is multi-faceted and likely associated with functional decline. Nephron-sparing management should be considered in African-Americans presenting with renal cortical tumors.
Development and validation of a novel scoring index (C-reactive protein, age, race, and tumor size) to predict renal functional decline post partial nephrectomy.
Authors: Meagher Margaret Frances , Patil Dattatraya H , Saito Kazutaka , Cotta Brittney , Yasuda Yosuke , Bradshaw Aaron , Eldefrawy Ahmed , Ryan Stephen , Nasseri Ryan , Anyakora David , Alksne Juliana , Wan Fang , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar
Published: March 2019

597

Background: Functional decline is a sequelae of extirpative renal surgery with potential for significant morbidity. We utilized pre-operative patient demographics, C-reactive protein, and tumor size to design and validate a novel scoring index to predict functional decline post partial nephrectomy. Methods: A multi-institutional dataset was utilized for analysis of patients with pre-operative estimated glomerular filtration rate (eGFR) > 60mL/min/1.73m2 by CKD-EPI equation. Multivariable analysis (MVA) was carried out for potential variables associated with development of post-operative chronic kidney disease (CKD) stage IIIB at last follow-up (eGFR < 45 mL/min/1.73m2). Significant variables were included in the predictive model and assigned an index score based on odds ratio. Receiver-operating-characteristic (ROC) analysis was employed to evaluate predictive validity, and bootstrapping technique was utilized to validate the model. Results: 924 patients were analyzed. 826 patients had post-operative eGFR > 45, while 111 patients had eGFR. Factors on MVA independently associated with increased risk of development of eGFR < 45 included age 65+ (OR = 2.6, p < 0.001), African-American race (OR = 2.3, p = 0.006), C-reactive protein level > 0.5mg/dL (OR = 5.3, p < 0.001), and tumor size > 4 cm (OR = 1.458, p = 0.189). For CART (C-reactive protein, Age, Race, Tumor size) score, the following values were assigned: age ( < 65 = 1, age > 65 = 3), race (non-African-American = 1, African-American = 2), tumor size ( < 4 = 1, > 4cm = 2), and CRP ( < 0.5mg/dL = 1, > 0.5mg/dL = 4). Analysis demonstrated 2.6% (12/469) of patients with a low (4-6) score had de novo eGFR < 45 postoperatively, while 35% (41/117) of patients with a high (10-11) score had de novo eGFR < 45. ROC analysis revealed AUC of 0.778, and ROC bootstrapping validation of 95 randomly selected patients revealed an AUC of 0.808. Conclusions: CART score represents a novel composite score that significantly predicts development of eGFR < 45 after surgery. This scoring system may assist in patient counseling and clinical decision making, as well as an impetus to improve outcomes in at-risk patient subgroups.
A phase I pilot study of preoperative radiotherapy for prostate cancer: Long-term toxicity and oncologic outcomes.
Authors: Sanmamed Noelia , Glicksman Rachel , Thoms John , Zlotta Alexandre , Finelli Antonio , Van Der Kwast Theodorus , Sweet Joan , Jewett Michael , Klotz Laurence , Rosewall Tara , Fleshner Neil Eric , Bristow Robert G. , Warde Padraig , Berlin Alejandro
Published: March 2019

60

Background: Pre-operative radiotherapy (PreORT) improves local control in various cancer types, and has become an established oncologic treatment strategy. During 2001-2004, we conducted a phase I pilot study assessing the role of short-course PreORT for men with unfavourable intermediate- and high-risk localized prostate cancer (PCa). We present long-term follow-up toxicity and oncologic outcomes. Methods: Eligible patients had histologically proven PCa, cT1-T2N0M0, PSA > 15-35 ng/ml with any Gleason score, or PSA 10-15 ng/ml with Gleason score ≥7. Patients received 25 Gy in five consecutive daily fractions to the prostate, followed by radical prostatectomy (RadP) within 14 days after RT completion. Primary outcomes were intra-operative morbidity, and late genitourinary (GU) and gastrointestinal (GI) toxicities. Acute toxicity was assessed during radiotherapy treatment on daily basis using RTOG grade scoring scale. Patients were assessed post-RadP clinically and with PSA at 1 and 6 months, and every 6 months. Intra- and Post-RadP toxicity was documented prospectively and scored as per Common Terminology Criteria for Adverse Events v4.0. Biochemical failure (BF) was determined based on two consecutive post-RadP PSA > 0.2 ng/ml. Results: Fifteen patients were enrolled; 14 patients completed PreORT followed by RadP, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2 years (range 6.7-16.3 years). Late GU toxicity was common, with 2 patients (14.3%) experiencing G2 toxicity, and 6 patients (42.8%) G3 toxicity. There were no G4-5 late GU toxicity. Late GI toxicity was infrequent, with only 1 patient (7.1%) experiencing transient G2 proctitis. At last follow-up, 8 (57.1%) and 6 (42.8%) patients experienced BF and metastatic disease recurrence, respectively. Conclusions: The use of PreORT in men with high-risk PCa is associated with unexpected high-rates of late GU toxicity. Future studies examining the role of RT pre-RadP must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data is essential to fully determine the therapeutic index of PreORT in the management of localized PCa. Clinical trial information: NCT00252447.
The prognostic value of glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) positive myeloid derived suppressor cells (MDSCs) in peripheral blood of metastatic renal cell carcinoma (mRCC) patients.
Authors: Kato Tomoyuki , Takeda Yuji , Kurota Yuta , Naito Sei , Ito Hiromi , Araki Akemi , Asao Hironobu , Tsuchiya Norihiko
Published: March 2019

601

Background: Myeloid derived suppressor cells (MDSCs) are found to play essential roles in various tumors and to associate with the prognosis of patients. However, the prognostic values of MDSCs in metastatic renal cell cancer (mRCC) are still undefined. Glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) is known as a regulator of Mac-1 (CD11b/CD18) and closely related with differentiation of myeloid cells. The object of our study was to interrogate the association of MDSCs in peripheral blood with clinical outcomes of mRCC patients by using GPI-80. Methods: Peripheral blood samples, collected from 23 mRCC patients before treatment and 16 healthy volunteers, were stained with several myeloid cell antigens such as CD16, CD15, CD33, and GPI-80 to mark neutrophils and monocytes. We measured the expression levels (mean of florescence intensity, MFI) and deviation (coefficient variation, CV) of myeloid antigens by flow cytometry. To investigate the immunosuppressive function of GPI-80 positive cells, reactive oxygen species (ROS) and LAP-1 (precursor of TGF-β1) were measured. The impact of the cell surface antigens on overall survival (OS) was evaluated using the univariate and multivariate Cox regression analysis. Results: The MFI or CV of GPI-80 on neutrophilic or monocytic cells were significantly difference in between patients and healthy volunteers. LAP-1 expression and ROS production in monocytic cells were increased in patients than in healthy volunteers, and correlated with expression of GPI-80 MFI (p = 0.0107 and p = 0.0381, respectively). Regarding the prognostic values, both GPI-80 CV of neutrophilic cells and GPI-80 MFI of monocytic cells were associated with poor OS of mRCC patients (p < 0.01). Multivariate analysis showed that GPI-80 MFI of monocytic cells were independent unfavorable prognosis marker (HR 2.427, p = 0.044). Conclusions: These results showed that change of GPI-80 expression on myeloid cells in peripheral blood representing appearance of MDSCs was likely to be negative predictors in patients with mRCC.
PAzopanib as first line in MEtastatic RCC patients: A “real-world” ITalian experience (PAMERIT study)—Preliminary results.
Authors: Mosca Alessandra , De Giorgi Ugo , Procopio Giuseppe , Basso Umberto , Carteni Giacomo , Buti Sebastiano , Naglieri Emanuele , Galli Luca , Caffo Orazio , Fornarini Giuseppe , Boccardo Francesco , Facchini Gaetano , Morelli Franco , Zucali Paolo Andrea , Caserta Claudia , Di Lucca Giuseppe , Sirotova Zuzana , Gennari Alessandra , Bruzzi Paolo , Porta Camillo
Published: March 2019

611

Background: Pazopanib (Pazo) became a standard of care in metastatic renal cell cancer (mRCC) patients (pts) based on 2 prospective trials, but “real life” data are slight. Methods: We retrospectively analyzed clinical outcomes in a large series of mRCC pts routinely treated with 1st line Pazo, among 39 Italian Centers. Descriptive statistics has been performed using Chi-Square and Pearson rank correlation test. Progression-free survival (PFS), overall survival (OS) and safety data are still under investigation. Results: 474 mRCC pts have been collected and divided in 4 age categories: 1) ≤50 yrs old (9.4%); 2) 51-64 yrs old (32.6%); 3) 65-74 yrs old (33.0%); 4) ≥75 yrs old (25.0%). According to Heng score, 25.6%, 48.4% and 10.4% pts had good, intermediate and poor prognosis, respectively, without correlations with age (p = 0.128). Clear cell was the most represented histology (87.3%), independently from age (p = 0.556). 84.6% pts underwent nephrectomy, mainly younger pts (p = 0.000). Pazo initial daily dose was 800 mg in 76.5% pts, 600 mg in 10.8% pts and 400 mg in 12.7% pts, with a significant dose reduction in elderly pts: Pazo 800 was administered in 86.7% of ≤50 yrs old pts and in 54.2% of ≥75 yrs old pts (p = 0.000). Complete (CR)/partial response (PR), stable and progressive disease have been recorded in 37%, 39.5% and 23.5% pts, respectively. Radiological response directly correlated either with age (CR/PR in 55.6% of ≤50 yrs old pts vs 28.8% of ≥75 yrs old pts; p = 0.009) and with Heng score (CR/PR in 47.1% of good prognosis pts vs 24.5% of poor prognosis pts; p = 0.002). Conclusions: “Real world” data showed that younger (≤50 yrs old) mRCC pts more frequently underwent nephrectomy, received Pazo 800 mg daily and obtained CR/PR, with respect to elderly pts (≥75 yrs old). CR/PR to Pazo is associated with good prognosis. PFS and OS will be provided.
Association of inflammation and clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: March 2019

612

Background: Ratios of neutrophils, monocytes, and platelets to lymphocytes (NLR, MLR, and PLR) are associated with poor CO in cancer pts. We investigated the association of NLR, MLR, and PLR and CO in mRCC pts treated with cabo. Methods: We performed a retrospective study of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016-2018. Overall survival (OS) and progression free survival (PFS) were calculated from first dose to date of death and radiographic or clinical progression, respectively. NLR, MLR, and PLR were obtained at baseline (BL) and 6 (±2) weeks (6W) after cabo initiation. Optimal cut (OC) was determined searching all cuts and testing them by bias adjusted log rank test to associate with PFS. Multivariate analysis (MVA) was performed using Cox proportional hazard model. Results: The medians were: 2.8 (NLR), 0.4 (MLR), and 176.7 (PLR). Increased NLR, MLR, and PLR were significantly associated with worse CO (Table). Conclusions: High NLR, MLR, and PLR may be poor prognostic factors in mRCC pts treated with cabo. Larger studies are needed to validate the results of this study. [Table: see text]
Activity of NEO2734, a novel dual inhibitor of both BET and CBP-P300, in SPOP-mutated prostate cancer.
Authors: Yan Yuqian , Wang Dejie , Ma Jian , Pang Xiaodong , Lin Dong , Giles Francis , Wang Yuzhuo , Huang Haojie
Published: March 2019

62

Background: We have previously reported that mutations in SPOP promote bromodomain and extra-terminal motif (BET) protein upregulation and BET inhibitor resistance in prostate cancer (Zhang et al., Nature Medicine 23(9):1055-1062, 2017). Other studies indicate that histone acetyltransferases (HATs) such as P300 are also upregulated in SPOP-mutated prostate cancer (Blattner et al., Cancer Cell 31: 436-451, 2017). Methods: We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. Results: We demonstrated that while prostate cancer cell lines expressing F133V, the most frequent SPOP mutant, are very resistant to both BET inhibitor JQ1 and CBP/P300 inhibitor CPI-637, they are very sensitive to simultaneous cotreatment with JQ1 and CPI-637. Similarly, we demonstrated that F133V mutant cells are also very sensitive to NEO2734. We established PDX and organoid models from a patient with prostate cancer expressing a novel SPOP mutation Q165P. Computer simulation analysis reveals that the Q165P mutation causes larger conformational fluctuation, indicating that the structure of Q165P is less stable than that of wild type SPOP. Accordingly, co-immunoprecipitation assay showed that Q165P mutation impaired the dimerization ability of SPOP. We further showed that the Q165P mutant organoid was very sensitive to NEO2734 in vitro and the Q165P mutant PDX was very sensitive to NEO2734 in mice. Conclusions: These PDX-based pre-clinical studies indicate that the inhibition of both BET and CBP-P300, either by co-administration of two agents, or by treatment with the dual inhibitor, NEO2734, is effective in SPOP-mutated prostate cancer. These data provide a strong rationale for the inclusion of patients with SPOP-mutated prostate cancer in clinical studies of NEO2734.
Fumarate hydratase expression in localized, radically-resected clear cell renal cell carcinoma and its association with clinical outcomes.
Authors: FucÃ Giovanni , Vernieri Claudio , Massa Simona , Bertolotti Alessia , Garzone Giovanna , Hosseini Amir , Verzoni Elena , Ratta Raffaele , Pruneri Giancarlo , Minucci Saverio , De Braud Filippo G. , Colecchia Maurizio , Procopio Giuseppe
Published: March 2019

620

Background: Prognostic stratification of localized clear cell renal cell carcinoma (lccRCC) mainly relies on clinical characteristics and TNM staging system, while biological biomarkers are currently lacking. We previously showed that reduced expression of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) was associated with better clinical outcomes in patients (pts) with metastatic ccRCC. In the present study we aimed at assessing the association between intratumor FH expression and clinical outcomes in pts with radically-resected lccRCC. Methods: Pts with radically-resected lccRCC and available formalin-fixed, paraffin-embedded (FFPE) primary (renal) tumor tissue were included. FH protein expression was assessed by means of immunohistochemistry (IHC) and defined as normal (comparably to non-neoplastic tubular cells) or low (lower than in non-neoplastic tubular cells). Results: Out of 50 pts included, we found a normal FH expression in 20 cases (40%) and a low FH expression in 30 cases (60%). Median age was 57 years (interquartile range 49-68) and 48 pts (96%) had pN0 disease, while 2 pts (4%) had pN1 disease. Low FH expression was associated with pT ( P= .003) but not with sex, age, Fuhrman grade or pN. After a median follow-up of 76.9 months, low FH expression was associated with a lower relapse rate (13% vs 50%; odds ratio for relapse 0.16; 95% confidence interval [CI] 0.04-0.62; P= .005), longer relapse-free survival (RFS) (5-years RFS rate 90% vs 50%; HR 0.20; 95% CI 0.06-0.63; P= .006) and a trend toward a better overall survival (OS) (5-years OS rate 100% vs 77.3%; HR 0.14; 95% CI 0.02-1.23; P= .07) when compared with normal FH expression. In the multivariable model including other characteristics associated with RFS, low FH expression confirmed an independent association with RFS (adjusted HR 0.25; 95% CI 0.06-0.91; P= .03). Conclusions: In our study, low intratumor FH, as detected by IHC, was associated with lower relapse rate, better RFS and a trend toward a better OS in patients with lccRCC when compared with normal FH levels. The role of FH expression as a prognostic biomarker in this setting warrants further investigation.
Nivolumab in second or third line setting for the treatment of metastatic renal cell carcinoma (mRCC): The real-world experience from Guy’s Hospital.
Authors: Le Ha Mo Linh , Josephs Debra Hannah , Chowdhury Simon , Rudman Sarah Maria , Enting Deborah
Published: March 2019

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Background: Nivolumab (Nivo) has been approved by the FDA for patients (pts) with mRCC who have received prior VEGF tyrosine kinase inhibition based on the Checkmate 025 study. However following various new anti-angiogenic therapies licensed over the past decade, optimal sequence of treatments in mRCC remains unknown. Methods: This is a retrospective review of mRCC pts who received nivo at Guy’s Hospital. Pts were divided based on treatment line setting. Clinical characteristics, response rate (RR), progression free survival (PFS), duration on treatment and safety are reported. Results: Between March 2016 and April 2018, 50 pts with mRCC received nivo, 25 as second line (2L) and 25 as third line treatment or beyond (3L+). In 2L setting, median age was 62 years and 68% were male. 76% had a nephrectomy, with a majority of clear cell (cc) histology (92%). 96% of pts had visceral metastases. 88% received pazopanib in the first line setting (1L). Median age for pts in 3L+ was 60 years and 88% were male. 60% had a nephrectomy and 80% had cc histology. 96% had visceral metastases. Pazopanib was given in 72% in 1L. RR was 28% and 16% in 2L and 3L+ respectively. Median duration of treatment was 4.3 months in 2L and 2.2 months in 3L+, with 11 patients (22%) still on treatment. Median follow-up time was 12.4 months in 2L and 9 months in 3L+. Median PFS was 4.8 months and 3.7 months respectively in 2L and 3L+ groups. Median OS was not reached in either group. Adverse events leading to treatment discontinuation occurred in 7 pts (14%). 5 pts experienced grade 3/4 toxicities (colitis, pneumonitis, hepatitis, arthritis and nephritis), with 4 pts in 3L+. Overall 22 pts received subsequent treatments: 8/25 (32%) had cabozantinib (cabo) and 4/25 (16%) were treated with axitinib following nivo given in 2L. For pts who received nivo in the 3L+ setting 7/25 (28%) received cabo and 2/25 (8%) had axitinib as subsequent therapy. Conclusions: Our real world data supports the efficacy and safety of nivo following VEGF inhibition for pts with mRCC. Nivo was associated with a trend towards superior clinical responses in the 2L setting. For the entire cohort no new safety signals were reported.
Prognostic value of loss of chromosome 10q in patients with localized renal cell carcinoma.
Authors: Lebacle Cedric Michel , Pooli Aydin , Rao Nagesh , Wood Erika Louise , Kroeger Nils , Liu Sandy , Faiena Izak , Chamie Karim , Belldegrun Arie S. , Shuch Brian , Drakaki Alexandra , Pantuck Allan J.
Published: March 2019

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Background: Several tumor-suppressor genes have been mapped to chromosome 10q, including PTEN. While loss of 10q is a frequently seen cytogenetic abnormality noted to occur in patients with renal cell carcinoma (RCC), little is known about its prognostic significance. We investigated the association of loss of 10q with pathological features and disease-free survival (DFS) in patients with localized RCC. Methods: All patients from UCLA with primary localized RCC who had tumor cytogenetic analysis were included. Alterations in chromosome 10q was specifically reviewed for this study. Logistic regression analyses were used to assess association of loss of 10q with ISUP grading, and T-stage. Cox proportional hazard modeling and Kaplan-Meier analyses were used to assess the impact of loss of 10q on DFS and OS. Recurrence was defined as any local recurrence or development of new metastasis after surgery. Results: A total of 886 patients were included in this study. Loss of 10q occurred in 68 (7.7%) patients and was more commonly seen in chromophobe subtype (24% vs. 6% in non-chromophobe RCC, p < .0001). Loss of 10q was associated with greater tumor size (mean 6.3 vs 5.1 cm, OR = 1.085 [1.024-1.150], p = .008), T3-stage (37% vs 23%, OR = 1.99 [1.17-3.39], p = .011), and ISUP 3-4 (61% vs 37%, OR = 2.64 [1.58-4.40], p < .0001). On survival analysis, after a mean follow-up of 55 months, these patients had a shorter time to recurrence (Log-rank p = .026) and a worse DFS (HR = 2.15 [1.32-3.50], p = .002) than those without loss of 10q. These findings were confirmed on clear-cell RCC subgroup with also a worse OS (HR = 2.00 [1.09-3.67], p = .026) with an estimated 34% risk of death at 5 years for patients with loss of 10q. Conclusions: Loss of chromosome 10q is a prognostic factor associated with larger tumor size, higher grade and T-stage, and worse survival in patients with localized RCC. Identifying patients with loss of 10q can provide additional prognostic information to clinicopathologic variables.
The UCLA Histo-Genetic Risk Classification (U-HGRC) to predict outcomes of localized clear cell renal cell carcinoma.
Authors: Lebacle Cedric Michel , Pooli Aydin , Rao Nagesh , Wood Erika Louise , Kroeger Nils , Kim Hyun J. , Faiena Izak , Liu Sandy , Chamie Karim , Belldegrun Arie S. , Shuch Brian , Drakaki Alexandra , Pantuck Allan J.
Published: March 2019

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Background: Thirty percent of patients with localized clear cell renal cell carcinoma (ccRCC) will ultimately develop recurrence (local or metastatic) after nephrectomy. Current risk stratification systems still misclassify patients. We have developed a novel classification integrating cytogenetic findings to better stratify the risk of recurrence and overall survival (OS) after surgery for localized ccRCC. Methods: A total of 646 patients from UCLA with ccRCC and tumor cytogenetic analysis, were included in this study. After a selection of histologic parameters using logistic regression and cytogenetic parameters using principal component analysis a CHAID decision tree and Kaplan Meier analysis were used to build the UCLA Histo-Genetic Risk Classification (U-HGRC). Survival analyses of the model were validated on two random samples of 323 patients. Recurrence was defined as any local recurrence or development of new metastasis after surgery. Results: The T-stage, tumor size, presence of sarcomatoid features, gain of chromosome 5q, loss 10q, or loss X/Y were used to stratify the risk of recurrence of ccRCC into three U-HGRC groups of low (1), intermediate (2) or high-risk (3). After a mean follow-up of 55 months, risk of recurrence (HR = 2.44, p = .001 for U-HGRC 2; HR = 9.90, p < .0001 for U-HGRC 3), disease-free survival (DFS) (Log-rank p < .0001), risk of death (HR = 1.72, p = .033 for U-HGRC 2; HR = 4.74, p < .0001 for U-HGRC 3) and OS (Log-rank p < .0001) were significantly different between groups. These findings were validated on two random samples. For high-risk group, median DFS and OS were 2.7 and 6.3 years, respectively. The 5-year risks of recurrence for U-HGRC group 1, 2 and 3 were 9%, 25% and 62%, respectively. The AUC of the model was significantly improved comparing to the current UISS system (0.72 for U-HGRC vs 0.65 for UISS, p = .008) with an accuracy of 82.8% for the U-HGRC high-risk group. Conclusions: The U-HGRC, which integrates genomic alterations with clinical and pathologic features, allowed a better stratification of recurrence risk and overall survival that could help to select appropriate patients for surveillance and adjuvant therapy protocols.
Are patients ready to participate in diet intervention trials in oncology? Experience from renal cell carcinoma (RCC) patients.
Authors: Colomba Emeline , Raynard Bruno , Guida Annalisa , Derosa Lisa , Escudier Bernard , Albiges Laurence
Published: March 2019

628

Background: Diet intervention in oncology is currently under investigation. Nevertheless, some cancer patients are increasingly using various diet interventions with the hope to optimize the anti-tumor response or to control the side effects of oncological treatment. Thus, well conducted prospective trials are required. In order to design such trials, we conducted a prospective study in order to estimate(a) the number of patients already using diet interventions on their own and (b) the percentage of patients who would agree to follow a restrictive diet in combination to antitumoral treatment within a prospective trial, if offered by their oncologist. Methods: Metastatic RCC patients seen at a single institution as outpatient clinic between April and May 2018, were offered to take part in an anonymous feasibility questionnaire. Questions included current treatment status for RCC, gender, height, and weight and explored (a) self diet restriction practices and (b) willingness to take part in trial(s) that would evaluate various diet interventions: fasting, ketogenic, vegetarian or vegan diets (each of them being explained). The proposed diet intervention was supposed to be for a minimum of 3 months. Results: Overall, 119 patients filled out the questionnaire. Median age was 61,5 years, 79(66.3%) were under systemic treatment. At time of data collection, 7.5% patients reported ketogenic diet practices, 0.9% fasting, none vegan or vegetarian diet. Regarding willingness to take part in “diet therapeutic trials”, 42.0% of patients claimed to agree to participate in a ketogenic diet trial, 29.4% of patients would agree to take part in a trial exploring fasting, 28.5% a vegetarian diet trial, and 14.2% of patients a vegan diet trial. No link between being under treatment and willingness to participate in trial was observed (p = 0.365). Conclusions: For the first time, we report feasibility of diet intervention within an homogenous population of patients with RCC. Almost half of patients are really keen in participating, with more interest for ketogenic diet and fasting. Such study raises the question of the feasibility of such trials, and obviously would make randomized trials very challenging.
A study of intense neoadjuvant testosterone lowering therapy with goserelin and enzalutamide (Enza) in high-risk prostate cancer (PC) with multiparametric MRI (mpMRI).
Authors: Karzai Fatima , Madan Ravi Amrit , VanderWeele David James , Chun Guinevere , Bilusic Marijo , Cordes Lisa M. , Carrabba Nicole , Wilkinson Scott , Ye Huihui , Harmon Stephanie , Sowalsky Adam G. , Turkbey Baris , Pinto Peter A. , Choyke Peter L. , Gulley James L. , Dahut William L.
Published: March 2019

63

Background: Neoadjuvant therapy with novel androgen receptor inhibitors, like enza, offer an opportunity to improve cure rates in men with high risk PC but also emphasizes the need for improved imaging techniques and genomic studies to evaluate treatment (trt) responses. We conducted a feasibility study using mpMRI to evaluate tumor responses and resistance in newly diagnosed, high-risk PC. Methods: Patients (pts) were treated with androgen deprivation therapy (ADT) + enza 160 mg po qdaily for 6 months (mos). Pts underwent 2 mpMRI: baseline and post 6 mos of therapy. Post-trt mpMRI was followed by radical prostatectomy (RP). Primary endpoint was feasibility of mpMRI for localization and detection of PC before and after therapy with ADT + enza. Results: 31 out of 33 pts completed 6 mos of therapy and underwent RP. Median on-study PSA was 9.58 (1.18-984.72 ng/dL). Median PSA post 6 mos of ADT + enza was <0.02 (0.02-0.35 ng/mL). No pt was taken off-trt for adverse events. Median residual cancer burden (RCB) defined as volume of tumor corrected by tumor cellularity was 0.1584 (0.0001-12.32 cc). Using RCB of <0.05 cc, 12 patients had minimal residual disease of which 4 pts were pathologic complete responses. Post-trt mpMRI volume correlated with final pathology in all cases. Conclusions: Neoadjuvant enza + ADT is tolerable and shows activity in a newly-diagnosed, high-risk population. mpMRI can be utilized to assess responses to trt. Analysis of genomic characteristics and resistance mechanisms is on-going. Clinical trial information: NCT02430480.
Comprehensive molecular and genomic characterization of pancreatic tropism in metastatic renal cell carcinoma.
Authors: Singla Nirmish , Choi Jacob , Onabolu Oreoluwa , Woolford Layton , Stevens Christina , Tcheuyap Vanina , McKenzie Tiffani , Xie Zhiqun , Wang Tao , McKay Renee , Christie Alana , Kapur Payal , Rini Brian I. , Brugarolas James
Published: March 2019

633

Background: Patients with metastatic renal cell carcinoma (mRCC) involving the pancreas have been shown to exhibit a relatively indolent course, yet the biologic explanation is unclear. We sought to characterize the genomic landscape of patients with mRCC harboring pancreatic metastases to identify molecular drivers of pancreatic tropism. Methods: mRCC patients harboring pancreatic metastases from UTSW and Cleveland Clinic were identified. Clinicopathologic data and oncologic outcomes were analyzed. Samples were obtained from primary tumors, metastatic sites (including pancreatic or other distant metastases), and matched normal tissue. Whole exome (WES) and RNA sequencing of tumors was conducted. Patient-derived xenograft (PDX) models were generated from a subset of patients, and the engrafted tumors were analyzed. Results: 31 mRCC patients with pancreatic metastases were included with 54 tumor samples derived from the primary tumor or thrombus (24), pancreatic metastasis (21), or other metastatic sites (9). Median follow-up was 101 months. Clinicopathologic characteristics were similar between the two institutional cohorts, and all but one patient were favorable or intermediate IMDC risk. All patients had clear cell histology. 8 patients (26%) were metastatic at diagnosis, and median time to metastasis in the remaining patients was 74 months (IQR 32-120). Overall (OS) and cancer-specific (CSS) survival did not vary by IMDC risk group. Morphologically, tumors largely displayed low-grade acinar patterns. WES with matched normal tissue and RNAseq were completed with adequate quality for 48 and 30 samples, respectively. 14 PDX lines were generated, of which 5 (36%) engrafted stably (≥2 passages). WES from 2 tumorgraft specimens revealed preservation of specific mutations in the corresponding human samples. Conclusions: mRCC patients with pancreatic metastases exhibit remarkably favorable survival outcomes. The relatively indolent biology of these tumors is reflected histologically and genomically and can be recapitulated in PDX models. Understanding tumor heterogeneity may help refine prognostic models for mRCC and hold implications for improved personalization of therapy.