bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

50 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

55 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

59 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

71 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]