bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the synergistic effects of cabozantinib (cabo) and a programmed cell death protein 1 (PD1) inhibitor in metastatic renal cell carcinoma (mRCC) with artificial intelligence (AI).
Authors: Costa Luis , Castellano Daniel , Puente Javier , Martin Lidia , Anido Urbano , Gómez Jessica , Duran Ignacio
Published: March 2021

336

Background: Nonclinical and clinical data suggest that cabo with a PD1 inhibitor provides synergistic antitumor activity in patients with mRCC, possibly by a cabo-induced switch to an immunopermissive tumor microenvironment. We used a complementary, unbiased, AI approach to gain a holistic view of the complex interplay between multiple pathways, cells and molecules and identify the mechanisms that may underpin this synergism. Methods: Biological targets associated with mRCC pathophysiology or drug actions were identified from proteomic, genomic and transcriptomic databases and literature. Using systems- and AI-based technology, the data were integrated using machine learning into mathematical models of the human mRCC protein network topology. The combined effects of cabo and a PD1 inhibitor on biological targets were simulated assuming target receptors were fully activated or fully inhibited. Relevant effects on known cancer processes (e.g. angiogenesis, metastasis, cell proliferation, immune evasion) were identified using artificial neural networks. Biologically plausible synergistic mechanisms were described with sampling methods. Results: Inhibition of VEGF/VEGFR and GAS6/TAMR axes by cabo enhanced the known effects of PD1 inhibitors on immune evasion mechanisms by modulating multiple humoral and cellular components of the innate and adaptive immune responses (Table). PD1 inhibitors further enhanced the anti-angiogenic and tumor pro-apoptotic effects of cabo by modulating pro- and anti-angiogenic factors and T cell cytotoxicity. Conclusions: These data provide a mechanistic rationale and further support for the beneficial combination of cabo and a PD1 inhibitor and may guide future nonclinical and clinical research. [Table: see text]
A dual drug therapy for sunitinib resistant RCC: An in vitro analysis.
Authors: Greenberg Jacob W. , Kim Hogyoung , Moustafa Ahmed A , Barata Pedro C. , Abdel-Mageed Asim , Krane L. Spencer
Published: March 2021

340

Background: Over the last decade, medical treatment for metastatic renal cell carcinoma has made significant advances through the development of tyrosine kinase inhibitors (TKI) like sunitinib. However, of patients initiated on TKI therapy, 70% respond well while 30% are believed to be primarily resistant to treatment. Additionally, 30% of patients who initially respond to treatment gain secondary drug resistance and present with increased tumor burden. In this study, we seek to develop a combination therapy of Tipifarnib + Sunitinib to target exosome conferred drug resistance. Methods: 786-O, 786-0 Sunitinib Resistant (SR), and 293-T cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2mM L-glutamine, and 1% penicillin/streptomycin (P/S). Exosomes were collected from conditioned media treated with Tipifarnib and isolated using differential ultracentrifugation. Exosomes were analyzed using the qNano IZON system. Colony forming units assay and Immunoblot analysis were used to further characterize or samples. Results: Exosomes collected from 786-O, 786-0 SR, and 293-T cells treated with 0.5 uM of Tipifarnib were compared using our qNANO IZON system. Exosome concentrations of all cell lines showed a decrease after Tipifarnib treatment. However, our 293-T cells showed a 16% decrease in exosome concentration while our 786-O and 786-0 SR lines displayed a 66% and 75% decrease respectively. To assess the pathway Tipifarnib used to decrease exosome concentrations, immunoblot assay was used after treating cells with 0, 0.1, 0.25, 0.5, 1 uM of tipifarnib. 293-T cells showed a dose dependent increase in ESCRT-dependent marker Alix and no change in either ESCRT-independent marker nSMase or trafficking marker Rab27a. Conversely, our 786-O and 786-0 SR cell lines showed a decrease in all 3 markers: Alix, nSMase, and Rab27a. Furthermore, a colony forming units assay was used to assess the drug combination of tipifarnib + sunitinib ability to alter cell growth. After 48hr, 293-T cell showed no decrease in colony forming units when compared to DMSO control. Our drug combination showed a synergistic ability to decrease colony forming units in the RCC 786-O cell line. 786-O SR cells were resistant to sunitinib treatment, showing comparable CFUs to DMSO control. When treated with the combination of sunitinib and tipifarnib, CTUs of 786-0 SR cells dropped significantly when compared to unaccompanied sunitinib and tipifarnib treatments. Conclusions: Tipifarnib has the ability to attenuate both the exosome ESCRT–dependent and –independent pathways. Our study also showed that when used injunction with sunitinib, tipifarnib is effective at decreasing cell proliferation. This drug combination is also pre-clinically useful in sunitinib resistance cancer cells. We believe this drug combination to be efficacious at decreasing tumor burden through blocking exosome biogenesis and secretion.
DNA damage repair (DDR) pathway alteration in advanced renal cell carcinoma (RCC) is association with good progression-free survival with tyrosine kinase inhibitor (TKI) therapy.
Authors: Zhai Wei , Wang Junyun , He Ning , Zhou Jiale , Wang Jianfei , Xue Yizheng , Yang Zhaolin , Chen Yonghui , Zhang Jin , Haung Jiwei , Kong Wen , Huang Yiran , Xue Wei
Published: March 2021

346

Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.
Sarcomatoid (srcRCC) versus clear cell (ccRCC) renal cell carcinoma: A comparative comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Spiess Philippe E. , Grivas Petros , Danziger Natalie , Huang Richard , Mata Douglas A , Decker Brennan James , Ross Jeffrey S.
Published: March 2021

349

Background: srcRCC is a well-described histologic entity often featuring rapid progression and aggressive clinical course when compared with classic ccRCC. We queried whether CGP would uncover opportunities for targeted and immunotherapy (IO) for srcRCC patients that could individualize their treatment and entry into clinical trials. Methods: Using a hybrid capture-based CGP assay to evaluate all classes of genomic alterations (GA), 160 cases of srcRCC and 1,664 cases of ccRCC were sequenced from FFPE tissue samples. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining set at 1-49% and high staining >50% expression. Results: Gender and age distributions for both tumor types were similar. srcRCC featured significantly higher GA/tumor than ccRCC (P < .0001). CGP revealed major differences with ccRCC associated more frequently with tumor suppressor gene (TSG) losses in VHL, PBRM1, TSC2 and SETD2 (all P < .0001). In contrast, srcRCC is associated with cell proliferation with increased inactivation of cell cycle regulatory genes including TP53, CDKN2A/B, MDM2 and TERT (all P < .0001). RB1 GA in srcRCC may reflect neuroendocrine differentiation occasionally found in these tumors. NF2 GA were more frequent in srcRCC (P < .0001). Conclusions: CGP reveals striking differences between srcRCC and ccRCC which may in part explain the differing histologic appearances and typical clinical course of these 2 aggressive malignancies. ccRCC is driven more by TSG loss and srcRCC is driven more by cell cycle dysregulation. Targeted therapy opportunities were uncommon for both tumor types although each featured biomarkers potentially predictive of mTOR inhibitor responses ( TSC2 in ccRCC and NF2 in srcRCC). Although the higher PBRM1 GA frequency in ccRCC may explain the IO benefit well-known for this tumor type, the srcRCC group features significantly increased TMB, CD274 amplification and PD-L1 staining which may also create IO opportunities for srcRCC patients. [Table: see text]
Distinct cytokines predict response to immunotherapy and targeted therapy in metastatic renal cell carcinoma (mRCC).
Authors: Chehrazi-Raffle Alex , Meza Luis A , Alcantara Marice , Salgia Nicholas , Dizman Nazli , Bergerot Paulo Gustavo , Hsu Joann , Kortylewski Marcin , Pal Sumanta K.
Published: March 2021

352

Background: Previous studies have suggested a link between plasma cytokines and mRCC outcomes with systemic therapy. In a prospective study, we assessed whether plasma cytokines could separately predict outcome with immunotherapy or targeted therapy. Methods: Eligible patients (pts) had histologically proven mRCC with intent to receive a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or an immune checkpoint inhibitor (ICI). Immunologic profiles were evaluated at several time points using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit (CB) was defined as complete response, partial response, or stable disease ≥ 6 months. Results: A total of 56 pts (40:16 M:F) were enrolled; 23 pts and 33 pts received VEGF-TKI and ICI, respectively. The most common VEGF-TKI was cabozantinib; the most common ICI was nivolumab. CB was similar between VEGF-TKI and ICI arms (65% vs 54%). Pts with CB from VEGF-TKIs had lower pretreatment levels of IL-6 (p = 0.02), IL-1RA (p = 0.03), and G-CSF (p = 0.02). Major shifts in plasma cytokines were seen as early as one month; these data will be presented. Conclusions: Distinct plasma cytokines predict benefit with VEGF-TKIs and ICIs. Ongoing work will incorporate analysis of pts receiving VEGF-TKI and ICI combination therapy.
Trends in the use of administrative databases in urologic oncology: 2000 – 2019.
Authors: Leopold Zev , Dave Priya , Menon Adarsh , Patel Hiren V. , Srivastava Arnav , Kim Isaac Yi , Jang Thomas L , Singer Eric A.
Published: March 2021

356

Background: Administrative databases (AD) provide investigators with nationally representative study populations to answer research questions using large sample sizes. We aimed to quantify the trends and incidence of AD use in published manuscripts in urologic oncology. We examined six commonly used databases: National Cancer Database (NCDB), Surveillance, Epidemiology and End Results Database (SEER), SEER-Medicare (SEER-M), Nationwide Inpatient Sample (NIS), National Surgical Quality Improvement Program (NSQIP), and Premier Healthcare Database (PHD). Methods: A literature review powered by PubMed and DistillerSR from 7/1/2000 to 6/30/2019 aggregated manuscripts that used the aforementioned databases to study a genitourinary malignancy. Included publications were categorized by database used, corresponding author department affiliation, organ, journal, year, and contribution – defined as temporal treatment trends, outcomes and survival, comparative effectiveness research, or cost-effectiveness. Results: There were 2,265 publications across 302 journals that met the inclusion criteria. Between 2000 and 2019 the compound annual growth rate of these publications was 18.7%. SEER contributed most heavily over the study period, with a 14.6% growth rate. NCDB use grew 75.6% annually starting in 2012. Prostate cancer comprised the majority of publications (51.3%), followed by kidney (23.1%) and bladder (22.5%) cancer. Journals publishing these manuscripts had a median impact factor of 3.28 (IQR = 1.84 – 5.74) in 2019. Urologists published 52.5% of AD manuscripts over the study period. Conclusions: Our results show substantial growth in the use of ADs for the study of urologic oncology. Given the broad use of ADs, investigators and specialty societies should advocate for continued improvement in the data captured by them.
Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).
Authors: Espinoza-Gutarra Manuel Ricardo , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: March 2021

376

Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p<0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P<0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]
Longer follow-up data of circulating miR371a-3p expression across the spectrum of germ cell tumors (GCT).
Authors: Nappi Lucia , Thi Marisa , Saxena Neetu , Soleimani Maryam , Eigl Bernhard J. , Chi Kim N. , Gleave Martin , So Alan I. , Black Peter C. , Daneshmand Siamak , Ahmadi Hamed , Hamilton Robert James , Nichols Craig R. , Kollmannsberger Christian K.
Published: March 2021

379

Background: miR371a-3p (miR371) is overexpressed in seminoma (S) and nonseminoma (NS) active germ cell malignancy (aGCM) and easily detectable in blood. We previously described1 a remarkably high accuracy of miR371 in detecting aGCM in early and advanced stages germ cell tumor (GCT) patients (pts). We here present the updated miR371 expression data with a longer follow-up, particularly relevant to assess miR371 clinical utility to predict GCT relapse in clinical stage I (CSI) and stage IIA pts. Methods:119 samples from 99 pts enrolled in the GU biobank program at the British Columbia Cancer – Vancouver were analyzed. The pts were divided according to their risk of aGCM in low (CSIA NS and CSI S), moderate (CSIB NS, stage IIA markers negative/low elevated S and NS), and high risk (definitively metastatic aGCM) groups. Blood of the low and moderate risk pts was collected post orchiectomy and at the time of the clinical relapse; prior to/post-chemotherapy in the high risk group. Plasma miR371 expression was evaluated by RT-PCR and quantified by ΔΔCT method. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC of the ROC curve were analyzed. Results: Five (2 moderate - 3 low risks) pts were lost at follow-up and 1 high risk pt had deceased. Overall, 113 samples (50, 36, 27 in the low, moderate, and high risk groups, respectively) were analyzed. The median follow-up from study entry was 30 (6-51), 28 (20-52), and 29 (7-53) months for the low, moderate and high risk, respectively. Seven more relapses occurred: 4 in the low risk (3 S and 1 NS) and 3 in the moderate risk groups (2 NS and 1 S). miR371 was found falsely negative post-orchiectomy in 4 pts and truly negative in 3 relapsed pts (2 pure teratoma and 1 unconfirmed relapse). Serial analysis of the false negative relapsed pts showed that miR371 became detectable at the time of clinical relapse. The operating characteristics of miR371 are summarized in the table below. Conclusions: Our follow-up has exceeded the expected time of relapse even in the low risk pts. The high accuracy of miR371 in detecting aGCM was confirmed with a longer follow up. However, the few false negatives in relapsed pts and the serial analysis suggest a lack of sensitivity in the detection of microscopic disease post-orchiectomy with the current methodology while miR371 high sensitivity was confirmed in presence of radiologic measurable disease (≥ 1 cm). The definitive operating characteristics of miR371 post-orchiectomy and during the follow-up of stages I/ IIA pts will be prospectively validated by the S1823 study that is actively recruiting pts. [Table: see text]
Phase II study of gemcitabine and split-dose cisplatin plus pembrolizumab as neoadjuvant therapy prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).
Authors: Rose Tracy L , Harrison Michael Roger , Deal Allison Mary , Osterman Chelsea K. , Ramalingam Sundhar , Whang Young E. , Brower Blaine Y , Bjurlin Marc , Smith Angela B. , Nielsen Matthew E. , Tan Hung-Jui , Wallen Eric M. , George Daniel J. , Zhang Tian , Drier Anthony , Kim William Y. , Milowsky Matthew I.
Published: March 2021

396

Background: Cisplatin-based neoadjuvant chemotherapy is standard of care in MIBC with improved pathologic response and overall survival (OS) compared to RC alone. Pembrolizumab (pembro) is active in high-risk non-muscle invasive and metastatic bladder cancer and is generally well tolerated. This phase II trial evaluated the safety and efficacy of gemcitabine and split-dose cisplatin (GC) + pembro as neoadjuvant therapy prior to RC (NCT02690558). Methods: Patients with clinical T2-4a N0/X M0 urothelial carcinoma of the bladder eligible for RC were enrolled. Patients received pembro 200mg on day 1 with cisplatin 35mg/m2 and gemcitabine 1000mg/m2 on days 1 and 8 every 3 weeks for 4 cycles, followed by RC within 4-8 weeks. The first 6 patients received full-dose cisplatin (70mg/m2 on day 1) and a lead-in pembro dose; this schedule was discontinued for excess toxicity. Primary endpoint was pathologic downstaging rate ( < pT2) with the null and alternative hypothesis rates = 35% and 55%, respectively. Secondary endpoints were toxicity, pT0 rate, event free survival, and OS. Exploratory objectives include association of response with molecular subtype and post-treatment changes in immune microenvironment (predicted neoantigens, immune gene expression, and T cell receptor repertoire). Results: Between May 2016 and July 2020, 39 patients were enrolled (72% cT2, 23% cT3, 5% cT4a) with a median age of 66 and 82% male. Patients received a median of 4 cycles of therapy. All patients underwent RC except one who declined but is included in intention to treat analysis. Rate of < pT2N0 was 56% (22/39) and pT0N0 rate was 36% (14/39). Most common adverse events (AEs) of any grade were thrombocytopenia (29/39; 74%), anemia (27/39; 69%), neutropenia (26/39; 67%), and hypomagnesemia (26/39; 67%). Most common grade 3/4 AEs were neutropenia (16/39; 41%), thrombocytopenia (13/39; 33%), febrile neutropenia (5/39; 13%), and anemia (4/39; 10%). One patient had new onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab and no patients required steroids for immune-related AEs. Nine patients (23%) discontinued GC + pembro due to AEs, including 4 of the 6 patients who received full-dose cisplatin with pembro lead-in. Survival data are not yet mature and correlative studies are ongoing. Conclusions: Neoadjuvant GC + pembro was generally safe and met its primary endpoint for improved pathologic downstaging. Correlative analyses are ongoing. Additional investigation of this combination is warranted. Clinical trial information: NCT02690558.
Sapanisertib, a dual mTORC1/2 inhibitor, for TSC1- or TSC2-mutated metastatic urothelial carcinoma (mUC).
Authors: Kim Joseph W. , Milowsky Matthew I. , Hahn Noah M. , Kwiatkowski David J. , Morgans Alicia K. , Davis Nancy B. , Appleman Leonard Joseph , Gupta Sumati , Lara Primo "Lucky" N. , Hoffman-Censits Jean H. , Quinn David I. , Shyr Yu , LoRusso Patricia , Sklar Jeffrey , Petrylak Daniel Peter
Published: March 2021

431

Background: A mammalian target of rapamycin (mTOR) inhibitor, everolimus, showed activity in patients with metastatic urothelial carcinoma (mUC) including an exceptional objective response in a patient with a deleterious TSC1 mutation. Sapanisertib is a potent inhibitor of mTOR complex 1 and 2. Here, we present the data from a phase II study of sapanisertib in patients with TSC1- or TSC2-mutated mUC. Methods: Eligible mUC patients with a TSC1 or TSC2 mutation received sapanisertib 3mg po daily on days 1 through 28 every 28 days. Primary endpoint was the overall response rate. Tumor samples were submitted for central confirmation of the mutation. A prescreening test for TSC1/2 mutation was available at a central lab for those with unknown mutational status. Results: Tumor samples from 41 patients were submitted for either prescreening (n=24) or confirmation (n=17). Of 24 prescreening patients, 4 (16%) had TSC1 mutation; 2 (8%) had TSC2 mutations. Of 17 confirmatory testing, 16 were confirmed by the central lab. Of 23 potentially eligible patients with a TSC1 or TSC2 mutation, 17 (14 TSC1 and 3 TSC2) were enrolled. Baseline characteristics of these 17 patients are shown. Four patients with TSC1- mutated mUC were deemed non-evaluable for response; two withdrew consent before starting sapanisertib to pursue an alternative therapy, and the other two withdrew consent with an adverse event before completing the first cycle. Of 13 evaluable patients, no objective response was observed. Although 4 patients had stable disease (SD) at their first restaging scan, none were confirmed to have SD with a subsequent scan. Median overall survival is 3.4 months. Four patients withdrew consent due to adverse event. Most common adverse events were hyperglycemia (80%), Cr elevation (53%) and AST increased (46.7%). No treatment-related death was observed. Conclusions: Sapanisertib did not result in any objective response in 13 patients with TSC1- or TSC2-mutated mUC. Given the lack of clinical activity, and problems with tolerance of sapanisertib, the trial was terminated early for futility. Future studies of an mTOR inhibitor or other targeted agent in the mTOR pathway should examine molecular alterations beyond TSC1 or TSC2. Clinical trial information: NCT03047213 . [Table: see text]
A longitudinal study for the effect of frailty on the quality of life and lower urinary symptoms following robot-assisted radical prostatectomy.
Authors: Hatakeyama Shingo , Togashi Kyo , Hamaya Tomoko , Kojima Yuta , Yamamoto Hayato , Okamoto Teppei , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: March 2021

45

Background: We aimed to evaluate the effect of frailty on health-related quality-of-life (HRQOL) and lower urinary symptoms (LUTS) following robot-assisted radical prostatectomy (RARP) in patients with prostate cancer (PC). Methods: We longitudinally evaluated geriatric 8 (G8), HRQOL, and LUTS for 12 months in 118 patients with RARP from January 2017 to April 2020. Patients were divided into frail (G8 ≤14) and nonfrail (G8 > 14) groups. We compared the effect of frailty on HRQOL and LUTS between the frail and nonfrail groups before and 12 months after RARP. Results: The median age of patients was 68 years. The number of patients in the frail and nonfrail groups were 41 and 77, respectively. No significant difference in patients’ background was observed between the groups, except for the presence of cardiovascular disease (22% vs. 7.8%, p = 0.041). There was no significant difference in HRQOLs and LUTS between the groups at baseline. Similarly, HRQOLs, LUTS, and pad-free continence rates were not significantly different between the groups at 12 months after RARP. In the nonfrail group, LUTS at 12 months following RARP significantly improved compared to those at the baseline, but it did not significantly improve in the frail group. Multivariable logistic regression analysis demonstrated that frailty was not significantly associated with LUTS worsening. Conclusions: Frailty was not significantly associated with the worsening of HRQOL, LUTS, and pad-free continence rates in patients treated with RARP.
A pilot clinical trial of genomic-based therapy assignment with co-expression extrapolation (COXEN) in advanced/metastatic urothelial carcinoma.
Authors: Niglio Scot Anthony , Nadal Rosa Maria , Cordes Lisa M. , Steinberg Seth M. , Davarpanah Nicole N. , Costello Rene , Mallek Marissa , Girardi Daniel da Motta , Merino Maria , Wang Yonghong , Mannheimer Joshua , Edelman Daniel , Walling Jennifer , Meltzer Paul S. , Theodorescu Dan , Gustafson Daniel , Apolo Andrea B.
Published: March 2021

452

Background: We investigated the Co-eXpression ExtrapolatioN (COXEN) algorithm to select “next best therapy” for patients with advanced/metastatic urothelial cancer based on gene expression profiles. Methods: This is a single-arm, open label pilot study, that investigates the COXEN algorithm’s ability to use patients’ tumor gene expression models to predict sensitivities to 75 FDA-approved anticancer agents. The COXEN results were reviewed and discussed in a multi-disciplinary molecular tumor board. From that a treatment plan was chosen based on monotherapy clinical efficacy data in urothelial carcinoma, combination safety data (combinations of agents were allowed provided phase I data were available), side effect profile/tolerability, response or resistance to prior therapies, therapy contraindications, and feasibility of therapy. The objective of this study was to determine the feasibility of using COXEN as a clinical decision algorithm to make a real-time treatment decision within 21 days of specimen collection in patients with advanced/metastatic urothelial carcinoma. Results: A total of 8 patients enrolled and underwent tumor biopsy for COXEN analysis. Five out of 8 patients received COXEN therapy within 21 days of biopsy with various regimens including: vorinostat and etoposide; doxorubicin; sunitinib; doxorubicin and paclitaxel; erlotinib and nab-paclitaxel. There were no objective responses. The 5 patients treated with COXEN therapy had a median potential follow up of 36 months, median overall survival of 8.4 months (95% CI: 5.2 months – not estimable), and median progression free survival of 2.2 months (95% CI: 1.4 – 3.9 months). Grade 3 or 4 adverse events included: febrile neutropenia (n=2), hypophosphatemia (n=1) and hyponatremia (n=1). This trial was terminated early due to a lack of treatment responses. Conclusions: The COXEN algorithm is a unique personalized method for selecting therapy for patients with advanced urothelial carcinoma. Although the COXEN method was feasible, it did not demonstrate clinical efficacy in this small cohort of patients. Clinical trial information: NCT02788201.
Enfortumab vedotin in FGFR3-mutated advanced urothelial carcinoma.
Authors: Teo Min Yuen , Ratna Neha , Regazzi Ashley Marie , Zimmerman Danielle Elise , McHugh Deaglan Joseph , Laccetti Andrew Leonard , Xiao Han , Lee Chung-Han , Aggen David Henry , Funt Samuel Aaron , Bajorin Dean F. , Iyer Gopa , Rosenberg Jonathan E.
Published: March 2021

458

Background: Enfortumab vedotin (EV) and, for those with FGFR3 mutations (FGFR3+), erdafitinib, are established therapeutic options for refractory advanced urothelial carcinoma. However, optimal sequencing of these agents remains undefined. Here, we report our experience of EV monotherapy with focus on patients (pts) with FGFR3 alterations. Methods: Pts who were treated with EV were identified. Clinical data and outcomes were extracted. Tumor genomic profiles by the MSK-IMPACT assay as part of standard of care were reviewed for FGFR3 and other commonly altered gene mutations and tumor mutation burden (TMB). Progression-free (PFS) and overall survival (OS) were measured from start of EV therapy and compared with unadjusted log-rank test. Results: 89 patients received EV on completed monotherapy studies (n = 37) or as standard of care. Median age was 62 years (IQR: 62 – 78), 71% were male (n = 63), 28% had liver metastases. Distribution per Bellmunt score (0 – 3) was: 12%, 42%, 37% and 9%. For the entire population, PFS and OS were 5.2 and 11.4 months, respectively, with response rate of 52% among 75 evaluable patients. MSK-IMPACT was available for 80 patients. Overall genomic profile was similar to TCGA cohort except for fewer DNA damage response/repair gene alterations – 15% (ERCC2: 2; ATM: 4, BRCA1: 2, BRCA2: 3, RAD51C: 1) and FGFR3+ rate of 33%. Median TMB was 8.9/Mb (IQR: 5.2 – 13.3). Of the 26 FGFR3+ pts, 8 and 1 received an FGFR3 inhibitor (FGFR3i) before and after EV, respectively. 17 pts have not been exposed to FGFR3i; 13 of whom have progressed on EV and 9 died. Compared to FGFR3- pts, FGFR3+ pts with no prior FGFRi had significantly shorter median PFS on EV (2.5 vs. 6.8 months; HR 0.33 [0.14 – 0.80] p < .01) and trend towards shorter median OS (4.9 vs. 14.6 months; HR 0.42 [0.16 – 1.08] p > .05). PFS on EV among FGFR3+ pts with prior FGFR3i exposure was 6.7 months, similar to FGFR3- pts (HR 0.77 [0.30 – 1.96] p = .6). Response rates for FGFR3+ with and without prior FGFRi, and FGFR3- pts on EV were 4/7 (50%), 5/13 (38%) and 29/48 (60%). Conclusions: In this retrospective study, FGFR+ patients who receive EV first appear to have shorter PFS and lower ORR than those who have received prior FGFRi. Prospective studies on the sequence of EV and FGFR3i in FGFR3+ pts are warranted.
Superior molecular pathology of urothelial bladder cancer using urinary cell-free DNA.
Authors: Zhang Ruiyun , Xie Feng , Zhang Yue , Wang Yiqiu , Zhao Zhixin , Du Pan , Jia Shidong , Chen Haige , Zhuang Guanglei , Wang Yiqiu
Published: March 2021

491

Background: Both urinary and blood cell-free DNA (cfDNA) have been implicated in noninvasive detection and surveillance of urothelial bladder cancer (UBC). However, a direct comparison of their diagnostic performance in the real-world setting is lacking. Methods: 59 eligible cases with pathologically confirmed disease and accompanying tissue/urine pairs were prospectively enrolled and consented to Institutional Review Board-approved protocols. Baseline peripheral blood mononuclear cell (PBMC) and plasma specimens were collected during clinic visit. The 180-gene Predicine liquid biopsy assay was applied for ultra-deep targeted sequencing and somatic alteration identification in tumor tissue-based DNA (tDNA), urinary cfDNA (ucfDNA) and blood cfDNA (bcfDNA). Results: The 59 studied subjects constituted a natural UBC cohort of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), including 48 (81.4%) NMIBC and 42 (71.2%) male patients. Diverse quantitative metrics such as VAF (variant allele frequency) and TMB (tumor mutational burden) were invariably concordant between tDNA and ucfDNA, but not bcfDNA. The mutational landscape captured by tDNA or ucfDNA highly resembled each other and mirrored previously described genomic panorama of UBC, whereas a significant proportion of bcfDNA aberrations stemmed from clonal hematopoiesis. Using tDNA-informed variants as the ground truth, ucfDNA assays achieved a specificity of 99.3%, a sensitivity of 86.7%, a positive predictive value (PPV) of 67.2%, a negative predictive value (NPV) of 99.8%, and a diagnostic accuracy of 99.1%, which were generally lower in the case of bcfDNA analysis. Conclusions: Urine-based molecular pathology provides valid and complete genetic information about neoplastic lesions, and represents a faithful surrogate for genotyping and monitoring UBC.
Geographic variation in systemic therapy in men age 66 years and older with de novo metastatic castration-sensitive prostate cancer: A population-based study in a single payer health-system.
Authors: Wallis Christopher J.D. , Malone Shawn , Cagiannos Ilias , Morgan Scott Carlyle , Hamilton Robert James , Basappa Naveen S. , Ferrario Cristiano , Gotto Geoffrey , Fernandes Ricardo , Niazi Tamim , Noonan Krista , Saad Fred , Hotte Sebastien J. , Hew Huong , Chan Katherine , Park-Wyllie Laura , Shayegan Bobby
Published: March 2021

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Background: Significant developments in the standard of care for patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) have been reported over the past decade. Treatment intensification with systemic therapies in addition to androgen deprivation therapy (ADT) alone is guideline recommended for most patients. We studied the geographic variation in the use of systemic therapy for de novo mCSPC in Ontario, Canada, a single-payer health system. Methods: We performed a population-based study of men aged 66 years and older diagnosed with de novo mCSPC between 2014-2019. We linked population-based healthcare databases, as administered at the level of Local Health Integration Networks (LHINs) in Ontario, to examine treatment patterns following diagnosis of de novo mCSPC. We categorized initial mCSPC treatments as those begun within 60 days preceding and 6 months following diagnosis and examined the proportion of patients receiving LHRH alone, first generation anti-androgen (AA) alone, combined androgen blockade (CAB; LHRH + 1st gen AA), ADT + abiraterone acetate + prednisone (AAP), and, ADT + docetaxel (D). In aggregate, we considered LHRH alone, AA alone and CAB as “standard ADT”, and ADT + AAP and ADT + D as “ADT-plus”. Multinomial logistic regression analyses were used to examine the association between receiving systemic treatment intensification (“ADT-plus”) or no prostate cancer pharmacotherapy relative to ADT across geographic regions, while adjusting for baseline patient and disease characteristics. Results: We identified 3,556 men over 66 with de novo mCSPC. Overall, 2794 (78.6%) received standard ADT, 311 (8.7%) did not receive prostate cancer-directed pharmacotherapy, and 451 patients (12.7%) of patients received “ADT-plus”. Utilization of AAP increased from 0.5% to 3% following the LATITUDE data release in 2017, while D decreased from 12% to 10%. There was significant variation in treatment strategies between geographic regions in use of “ADT-plus” ranging from 7 to 20% (p < 0.0001), a difference which persisted after accounting for patient demographics, comorbidity, rurality, and disease characteristics (p = 0.036). Conclusions: Despite proven survival benefits in randomized controlled trials, intensified treatment with docetaxel or abiraterone in addition to ADT was infrequently utilized in this population-based study of men age 66 years and over with mCSPC.
Quality of life of prostate cancer (PCa) patients aged 60 years and older: Changes in QLQ-ELD14 dimensions after a six-month gonadotropin-releasing hormone agonist (GnRHa) therapy, according to age groups–Primary analysis of PRISME study.
Authors: Rozet Francois , Hennequin Christophe , Mongiat-Artus Pierre , Pello Leprince Ringuet Nathalie , Grandoulier Anne-Sophie , Roupret Morgan
Published: March 2021

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Background: PCa mostly affects elderly men and impacts their health-related quality of life (HRQOL). Our purpose was to compare the evolution, between age groups, of HRQOL measured through EORTC QLQ-ELD14 instrument, specific to the elderly cancer patients, after a 6-month GnRHa therapy. Methods: Between March 2018 and February 2020, a prospective, multicenter, non-interventional study was conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited patients aged 60 years and older, with PCa, initiating a GnRHa therapy. 1000 patients were planned to be included 1:2:1 in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). They reported HRQOL using ELD14 (7 dimensions, each scored 0-100): “Maintaining purpose”, “Family support” (higher scores represent better functioning), “Mobility”, “Worries about others”, “Future worries”, “Burden of illness” and “Joint stiffness” (higher scores represent worse functioning). Analyses of covariance (ANCOVA) were performed to compare evolution of each of the 7 dimensions of ELD14 between subgroups of ages, adjusted on baseline scores. Level of significance was set to 0.002 because of the multiplicity testing on the 7 dimensions (Bonferroni). Results: After enrollment of 814 patients by 138 investigators, enrollment was stopped because of a slow recruitment in the [70-75[ group. The final analysis included 652 patients (full analysis set population). Mean (±SD) age was 72.5±6.2 years. There were 193, 269 and 190 patients, in the [60-70[, [70-75[ and ≥75y age groups, respectively. 71.6% had at least one comorbidity at baseline and 65.0% were receiving at least one concomitant systemic treatment. Main reasons for GnRHa initiation were high risk PCa in 65.3%, metastatic stage in 18.4%, biochemical recurrence in 13.3%. For each dimension, ANCOVA analyses showed that changes from baseline, adjusted on baseline values, were not significantly different between age groups. For example, least square (LS) means (SE) changes in “Mobility” scores from baseline were 3.01 (1.13), 3.14 (0.95) and 6.13 (1.15) in the [60-70[, [70-75[ and ≥75y age groups, indicating a worsening in all groups, but without significant differences between groups (Table). Conclusions: In this large observational cohort of PCa men with prespecified age groups, HRQOL changes after a 6-month GnRHa therapy didn’t depend on age group. Clinical trial information: NCT03516110. [Table: see text]
Association of circulating tumor cells (CTC) with survival outcomes in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in a real-world cohort.
Authors: Swami Umang , McFarland Taylor Ryan , Haaland Benjamin , Kessel Adam , Nussenzveig Roberto , Sayegh Nicolas , Hahn Andrew Warren , Rathi Nityam , Sirohi Deepika , Esther John , Li Haoran , Kohli Manish , Maughan Benjamin Louis , Goldkorn Amir , Agarwal Neeraj
Published: March 2021

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Background: In mCSPC, baseline CTC counts have been shown to correlate with PSA responses and progression free survival (PFS) in small studies in the context of androgen deprivation therapy (ADT) without modern intensification with docetaxel or novel hormonal therapy. Similar correlation of CTC count with PSA responses and PFS was recently reported from an ongoing phase 3 trial in mCSPC setting (SWOG1216) without reporting the association in the context of ADT intensification. Furthermore, none of these studies correlated CTCs with overall survival (OS). Herein we evaluated whether CTCs were associated with outcomes including OS in a real world mCPSC population treated with intensified as well as non-intensified ADT. Methods: Eligibility criteria: new mCSPC receiving ADT with or without intensification and enumeration of baseline CTCs by FDA cleared Cell Search CTC assay. The relationship between CTC counts (categorized as: 0, 1-4, and ≥5/7.5 ml) and both PFS and OS was assessed in the context of Cox proportional hazards models, both unadjusted and adjusted for age, Gleason, PSA at ADT initiation, de novo vs. non-de novo status, and ADT intensification vs. non-intensification therapy. Results: Overall 99 pts were identified. Baseline characteristics are summarized in Table. In unadjusted analyses, CTC counts of ≥5 as compared to 0 were strongly associated with inferior PFS (hazard ratio [HR] 3.38, 95% CI 1.85-6.18; p < 0.001) and OS (HR 4.44 95% CI 1.63-12.10; p = 0.004). In multivariate analyses, CTC counts of ≥5 as compared to 0 continued to be associated with inferior PFS (HR 5.49, 95% CI 2.64-11.43; p < 0.001) and OS (HR 4.00, 95% CI 1.31-12.23; p = 0.015). Within the ADT intensification subgroup also, high CTC counts were associated with poor PFS and OS. For PFS, the univariate HR for CTC ≥5 vs. 0 was 4.87 (95% CI 1.66-14.30; p = 0.004) and multivariate HR for CTC ≥5 vs. 0 was 7.43 (95% CI 1.92-28.82; p = 0.004). For OS, the univariate HR for CTC ≥5 vs. 0 was 15.88 (95% CI 1.93-130.58; p = 0.010) and multivariate HR for CTC ≥5 vs. 0 was 24.86 (95% CI 2.03-304.45; p = 0.012). Conclusions: To best of our knowledge this is the first study to show that high baseline CTC counts are strongly associated with inferior PFS as well as OS in pts with newly diagnosed mCSPC, even in those who received intensified ADT therapy. Identifying these pts at highest risk of progression and death can help with counselling and prognostication in clinics as well as design and enrollment in future clinical trials. [Table: see text]
Referral patterns and treatment preferences in patients with advanced prostate cancer (aPC): Differences between medical oncologists and urologists.
Authors: Gajra Ajeet , Hime Skyler , Jeune-Smith Yolaine , Russell Amy , Feinberg Bruce A.
Published: March 2021

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Background: With the advent of newer non-cytotoxic therapies for aPC, early integration of hormonal therapies (HT), and expansion of services within urology practices [e.g., radiation therapy (RT) and immunotherapy], urology practices are playing a larger role in the management of patients with aPC. In this descriptive study, we sought to assess the differences between medical oncologists (oncs) and urologists (uros) as they pertain to referral patterns and treatment decisions of men with aPC. Methods: Virtual meetings held in August 2020 convened oncs and uros of diverse US regions and practice types with experience treating prostate cancer (PC) to better understand perceptions around the management of patients with PC. Participants submitted responses via web-based pre-meeting surveys and real-time polling. All responses are summarized using descriptive statistics. Results: 66 oncs and 69 uros participated. The advisors were mostly community-based and see on average 20+ patients per day. 75% of uros estimated they refer ≤25% of all of their patients with PC to oncs and 75% of oncs reported that > 50% of their patients with PC referrals are from uros. Other referring physicians identified include primary care (76%), radiation oncs (46%), or hospitalists (40%). Uros perceive oncs as co-managers (86%) for their patients with aPC and rarely (9%) transfer the care of their patients completely to oncs. Referrals from uros to oncs are driven by the need for chemotherapy (chemo) (52%) or progression to metastatic castration-resistant PC (mCRPC) (22%). Oncs reported that upon referral, these patients with PC have already been exposed to HT (75%), RT (66%), and/or surgery (43%). For second-line treatment of asymptomatic patients with mCRPC, oncs most commonly prescribe HT (60%) and chemo (23%), while uros most commonly prescribe sipuleucel-T (45%) and HT (38%). For second-line treatment of patients with mCRPC and symptomatic bony disease, oncs most commonly prescribe chemo (44%) and radium-223 (34%), while uros most commonly prescribe radium-223 (47%) and HT (22%). Conclusions: Uros refer patients with aPC to oncs for chemo. Uros prefer to treat with non-chemo options when possible and retain oncologic care for most of the patients’ cancer journey. The need for chemo is a major reason for referral from uros to oncs. The impact of these provider preferences upon patient outcomes in the real world needs further research. [Table: see text]
Enzalutamide plus androgen deprivation therapy (ADT) versus flutamide plus ADT in men with castration-resistant prostate cancer (CRPC): AFTERCAB.
Authors: Uemura Hiroji , Kobayashi Kazuki , Yokomizo Akira , Hinotsu Shiro , Horie Shigeo , Kakehi Yoshiyuki , Naito Seiji , Nonomura Norio , Ogawa Osamu , Oya Mototsugu , Suzuki Kazuhiro , Saito Atsushi , Uno Satoshi , Akaza Hideyuki
Published: March 2021

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Background: Enzalutamide has been approved for the treatment of CRPC in Japan since 2014. This study compared the efficacy and safety of enzalutamide + ADT and flutamide + ADT in the treatment of men with CRPC who progressed despite combined androgen blockade with bicalutamide + ADT. The sequential order of treatment was also investigated. Methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016–March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC (metastatic or nonmetastatic) and an Eastern Cooperative Oncology Group performance status of 0 or 1 who progressed despite bicalutamide + ADT. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375 mg/day [125 mg 3 × daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: 206 men were randomized, stratified by study site and disease stage. Baseline demographics and disease characteristics were similar between treatment arms. Median treatment exposure was 14.3 months (range 0.8–35.9) with enzalutamide first and 5.6 months (range 0.3–37.7) with flutamide first. 133 patients transitioned to second-line therapy (n=48 for enzalutamide first and n=85 for flutamide first). TTPP1 was significantly improved with enzalutamide first versus flutamide first; numerically longer TTPP2 was observed with enzalutamide first versus flutamide first (Table). With first-line therapy, 92.2% (n=94) of patients reported treatment-emergent AEs (TEAEs) and 28.4% (n=29) reported serious TEAEs for enzalutamide first. Corresponding numbers for flutamide first were 76.0% (n=79) for TEAEs and 14.4% (n=15) for serious TEAEs. Conclusions: Treatment with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT as first-line therapy. Both treatments were generally well tolerated, with AEs consistent with the known safety profiles. Clinical trial information: NCT02918968. [Table: see text]