bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of perioperative treatment (tx) among patients (pts) undergoing radical resection (RR) for muscle-invasive urothelial cancer (MIUC) in France, Germany, Italy, Spain, the United Kingdom, the United States, Canada, China, and Japan.
Authors: Broughton Edward I , Gschwend Jürgen E. , Witjes J. Alfred , Berry Mia , Kostikas Michael , Montgomery Rachel , Lambert Annabel , Teitsson Siguroli , Milloy Neil
Published: February 2022

467

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by RR is the standard of care in cisplatin-eligible pts with MIUC. Adjuvant chemotherapy (AC) with cisplatin-based tx may be offered to those not given NAC. The unmet need this survey tried to evaluate is the post-RR burden of disease, quality of life (QoL) and perioperative tx patterns among MIUC pts. Methods: Real-world descriptive data were drawn from Adelphi’s MIUC Disease-Specific Programme: A point-in-time survey conducted with clinical/medical oncologists/urologists and their pts in 9 countries between January and June 2021. Physicians completed a survey on their pts’ clinical characteristics and tx patterns, while pts voluntarily completed a series of patient-reported outcome measures. Results: Of 2178 pts (data provided by 320 physicians), 30% received NAC only, 26% received AC only, 38% received no NAC or AC tx, and 6% received both. 1744 pts had initial tumour in the bladder; 35% received NAC only, 24% AC only, 35% no NAC or AC tx, and 6% received both. Of 387 pts with upper-tract urothelial carcinoma (UTUC), 51% received no NAC/AC tx, 35% received AC only, and 12% NAC only. More pts with T3 disease received no NAC/AC tx (36%) or NAC (35%) than AC (24%). Of 734 pts with nodal disease, 36% received NAC only. Of all pts, 60% experienced symptoms at data abstraction: 50% in pts who received NAC only, 71% in pts who received AC only and 82% in pts of those who received both. Pts reported similar EQ-5D-5L utility index scores (mean = 0.86; range: 0.84 [AC only] to 0.89 [NAC only]). Overall, feeling pain (40%) and stress (39%) were the EQ-5D domains with the worst scores. Pts who received AC only reported nominally lower EQ-5D visual analogue scale scores (71.11) compared with pts who received no NAC/AC (73.17) or pts who received NAC only (75.05). EORTC QLQ-C30 Global Health Status scores were 60.0 in pts who received AC only, 64.1 in pts who received NAC only or no NAC/AC, and 66.7 for pts who received both NAC and AC. Conclusions: Nearly 40% of pts remain untreated in either NAC or AC setting in 9 countries. A higher proportion of pts with UTUC go untreated. AC was more frequently used in UTUC vs BC pts; and in pts with Tis. NAC was implemented more frequently in pts T3 disease and in those with N+ disease. Pts who received AC appear to have nominally worse QOL and more symptoms, further demonstrating the need for efficacious adjuvant tx that does not decrease post-RR QoL.[Table: see text]
Association of Medicaid expansion with racial disparities in timely neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC).
Authors: Jiang Changchuan , Perimbeti Stuthi , Deng Lei , Jatwani Karan , Roy Arya , Chatta Gurkamal S. , George Saby , Gopalakrishnan Dharmesh
Published: February 2022

472

Background: Timely initiation of NAC is critical to improve outcomes in MIBC. Medicaid expansion through the Affordable Care Act improved racial disparities in healthcare access for patients with advanced cancers. This study aimed to assess the association of Medicaid expansion with racial disparities in time-to-NAC in MIBC. Methods: This case-control study queried the National Cancer Database for 18-64 years old Black and White adults who were diagnosed with stage II&III bladder cancer and treated with NAC from Jan 1, 2008 to Dec 31, 2018. The primary endpoint was the timely receipt of NAC, defined as initiation within 45 days from the diagnosis of resectable MIBC. Racial disparity was defined as percentage-point (PP) difference for Black vs. White patients, adjusted for age, sex, income level, clinical stage, and year of diagnosis. Results: The study included 5053 patients (7.2% Black, n = 391). In states without Medicaid expansion, Black patients became less likely to receive timely NAC than their White counterparts (2008-2013: Black 59.6% vs White 63.8%, p = 0.53; 2014-2018: Black 47.9% vs White 61.2%, p < 0.01). In contrast, the racial disparity was narrowed in states with Medicaid expansion (2008-2013: Black 35.7% vs White 62.9%, p < 0.01; 2014-2018: Black 53.4% vs White 59.5%, adjusted PP difference -2.4; p = 0.20). The adjusted difference-in-differences estimate revealed a 26.0 PP reduction in racial disparity (95% CI, 8.1%-44.0%; p < 0.01). Conclusions: Medicaid expansion was associated with significant reduction in racial disparity between Black and White patients in the timely receipt of NAC for MIBC.
Long-term outcome and safety in patients treated with immune checkpoint blockade therapies for urothelial carcinoma: Experience from real-world clinical practice.
Authors: Tural Deniz , Arslan Cagatay , Selcukbiricik Fatih , Olmez Omer Fatih , Erman Mustafa , Ürün Yüksel , Karadurmus Nuri , Akar Emre , Kilickap Saadettin
Published: February 2022

474

Background: Anti-tumor activity and manageable safety profile of immune checkpoint blockade therapies (ICT) have been demonstrated in previous clinical trials in patients with metastatic urothelial carcinoma. To the best of our knowledge, very limited real-life data is available with the long follow-up time that confirms the durable antitumor activity and safety of ICT. In this study, we reported the real-life results of 56 months follow-up data of urothelial carcinoma patients who were treated with ICT. Methods: Metastatic urothelial carcinoma patients treated with at least one course of ICT included in the study. The primary endpoint was the overall response rate (ORR); secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of the ICT treatment, and safety. Median follow-up, PFS, and OS were estimated by using the Kaplan-Meier method. Results: Data of 185 eligible patients were analyzed, 11.9% of these patients received the ICT as the first line, 76.8 % as the second line, and 11.3 % as the third or more line of treatment. The median age of the patients was 66 years, and 156 (84.3%) were male (37-86). The majority of patients (93.5%) had ECOG PS scores of 0–1 and primary tumor in the bladder was predominant (86.7%). The median follow-up time was 47(1.15-56) months. The complete response rate to ICT, partial response rate, and ORR were 10.3% (n = 19), 19.5% (n = 36), and 29.8% (n = 55), respectively. The median duration of response was 33.1 months (95% CI, 16.5–49.7). Of the fifty-five patients who responded to treatment, 28 (51%) had an ongoing response at the time of the analysis. Median PFS and OS was 3.8 (2.6–5.1) months and 8.9 (6.8–11.1) months, respectively. 56-month PFS and OS rate was 9.2% and 11.4%, respectively. 56-month PFS and OS rate for CR and PR was 56.2% and 20%, respectively. Fifty-nine percent of patients experienced a treatment-related adverse event of any grade, and 32 (17.3%) of patients had a grade 3–4 treatment-related adverse event. Because of treatment-related side effects, treatment was discontinued in 8 (4.3%) patients and adverse event that required systemic steroid use was reported in only 13 (7%) patients. Four patients (2.2%) died due to treatment-related causes. Conclusions: This 56-month analysis of real-world data confirms the durable response and long-term survival with ICT in metastatic urothelial carcinoma patients. The safety profile was consistent with prior reports, and no new safety signals emerged.
Survival outcomes comparing radical nephroureterectomy versus endoscopic treatment in solitary kidney patients diagnosed with upper tract urothelial carcinoma.
Authors: Alam Ridwan , Cheaib Joseph G. , Biles Michael J. , Winoker Jared S. , Singla Nirmish , Bivalacqua Trinity , Pierorazio Phillip M. , Kates Max R. , Patel Sunil H.
Published: February 2022

477

Background: Solitary kidney patients who develop upper tract urothelial carcinoma (UTUC) present a significant management challenge. Radical nephroureterectomy (RNU) renders these patients anephric with a need for dialysis, which is associated with lower life expectancy and decreased quality of life. However, organ-sparing endoscopic treatment may result in undertreatment of the cancer process. We sought to compare survival outcomes between RNU and endoscopy in solitary kidney patients diagnosed with clinically localized UTUC. Methods: The Surveillance, Epidemiology, and End Results database was linked to Medicare records to identify patients diagnosed with UTUC through 2017. This data was then linked to the Medicare Provider Analysis and Review and National Claims History databases to identify patients with a solitary kidney. Only patients with an established diagnosis of solitary kidney prior to developing clinically node-negative and non-metastatic disease (cN0M0) UTUC were included. Patients were stratified by treatment with RNU versus endoscopy. Kaplan-Meier analysis was performed to estimate survival between the two groups. Results: A total of 2108 solitary kidney patients with cN0M0 UTUC were identified, with a median age of 75.3 years at diagnosis [IQR 69.3-81.1]. Median follow-up time was 2.8 years [IQR 1.7-4.4]. High-grade disease was present in 1531 patients (72.6%), of whom 1344 underwent RNU and 195 underwent endoscopy. Between the two treatments, there was no difference in either cancer-specific survival ( P=0.18) or overall survival ( P=0.10). When combining high- and low-grade UTUC patients, 1839 underwent RNU and 269 underwent endoscopy. Again, no difference was observed in cancer-specific survival ( P=0.31) or overall survival ( P=0.17). Patients with high-grade disease demonstrated higher rates of cancer-specific and overall mortality than those with low-grade disease (both P<0.001). Conclusions: Solitary kidney patients diagnosed with clinically localized UTUC demonstrate no difference in survival outcomes when comparing RNU to endoscopic treatment. This potentially suggests that, when weighed against the option of endoscopic treatment, the benefits of RNU in these patients may not outweigh the risks of becoming anephric and therefore dependent on dialysis.
Association of changes in albumin levels with survival and toxicities in patients (pts) with metastatic urothelial carcinoma (mUC) receiving enfortumab vedotin (EV).
Authors: El Zarif Talal , Riaz Irbaz Bin , Adib Elio , Freeman Dory , Madueke Ikenna C. , Davidsohn Matthew , McClure Heather , Nuzzo Pier Vitale , McGregor Bradley Alexander , Mantia Charlene , Ravi Praful , Sonpavde Guru P.
Published: February 2022

481

Background: EV is an anti-Nectin-4 antibody-drug conjugate that has been approved by the US FDA for mUC progressing on platinum and PD1/L1 inhibitor therapy and in cisplatin-ineligible pts following prior therapy. However, prognostic and predictive biomarkers in the setting of EV therapy are unclear. We aimed to investigate baseline and early changes in commonly available clinical and laboratory tests that could help predict survival and toxicities in patients with mUC treated with EV. Methods: Data from patients with mUC who were treated with EV at Dana Farber Cancer Institute between 2017 and 2021 were reviewed retrospectively. We assessed the association of demographic (age, sex), clinical (ECOG-performance status [PS], sites of metastasis) and laboratory variables (hemoglobin, RDW, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet count and serum albumin) at baseline as well as after 4-7 weeks of treatment with Overall Survival (OS) by constructing univariate and multivariable Cox proportional-hazards models. Any variables significantly associated with OS at the univariate level (using an alpha-level of 0.1 to determine statistical significance) were then entered into the multivariable model. Predictors were eliminated from the final multivariable models by a backward selection process, retaining only those with a p-value of ≤ 0.05. Results: A total of 49 patients who received EV were included in the analysis. The median age was 72 years (range 48-88) and 36 (73.5%) were male. The median OS was 13.3 months (range: 2.7-38.7) and grade 3-4 toxicities were seen in 11 pts (22.4%). In the final multivariable models, lower serum albumin at 4-7 weeks (HR = 0.18; 95% CI = 0.05-0.71; p = 0.015), and baseline ECOG-PS of 1 vs. 0 (HR = 2.56; 95% CI = 1.05-6.21; p = 0.038) were significantly associated with worse OS (Table). Patients with higher serum albumin levels at 4-7 weeks also had significantly lower odds of experiencing grade 3-4 adverse events on EV (OR = 0.05; 95% CI = 0.002-0.52; p = 0.02). Conclusions: Lower serum albumin appeared to predict worse survival and severe toxicities in mUC pts receiving EV. This information may guide therapy and assist in the prevention of toxicities. Additionally, ECOG-PS was prognostic while the location of metastatic disease was not prognostic in the setting of EV.[Table: see text]
Phase Ib study of avelumab and taxane based chemotherapy in platinum-refractory or ineligible metastatic urothelial cancer (AVETAX study).
Authors: Garje Rohan , Packiam Vignesh T. , Koski Amy , Milhem Mohammed M. , O'Donnell Michael A. , Zakharia Yousef
Published: February 2022

503

Background: Metastatic urothelial cancer is aggressive and associated with dismal 5-yr overall survival. Platinum-based chemotherapy and checkpoint inhibitors are standard first-line options with enfortumab vedotin, sacituzumab govitecan, and erdafitinib (in select FGFR altered tumors) subsequently utilized upon disease progression. However, despite these options, long-term outcomes remain poor, and novel strategies are needed to improve oncologic outcomes. We hypothesized that combining avelumab (anti-PD-L1 immunotherapy) with docetaxel is safe and will enhance cancer cell death by releasing neoantigens and potentiating anti-tumor immune-mediated cytotoxicity. Methods: This is a phase 1b, single-arm, open-label prospective clinical trial evaluating the combination of avelumab with docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. There are two phases. In Phase 1b, dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) aimed to establish the phase 2 dose in a standard 3+3 design. In dose-expansion, avelumab with the RP2D of docetaxel was evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles, and then avelumab alone is continued every 2 weeks. The primary endpoint is safety. Efficacy endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: At the cutoff date of 10/8/2021, 21 patients were enrolled in the study. Only one of the 6 patients treated with level 0 dose of docetaxel had dose-limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. An additional 15 patients were enrolled in the dose-expansion cohort. Of the 20 evaluable patients, ORR (CR+PR) was seen in 70% of subjects. (CR: 30%, PR: 40%, SD: 5%, PD: 25%, and 1 patient was not evaluable). The median PFS was 9.2 months (range: 1.5 – 25.8 months), and median OS was not reached. The most common Grade 3 or 4 AEs were febrile neutropenia, transaminitis, diarrhea, anemia, and neutropenia. No treatment-related deaths were noted. Conclusions: The combination of avelumab with docetaxel is safe with promising efficacy that is worth further studying in patients with platinum-refractory or ineligible metastatic urothelial cancer. Clinical trial information: NCT03575013.
Post hoc analysis of the efficacy of pembrolizumab retreatment after progression of advanced urothelial carcinoma (UC) in KEYNOTE-045 and KEYNOTE-052.
Authors: Castellano Daniel E. , Balar Arjun Vasant , O'Donnell Peter H. , Grivas Petros , Vaughn David J. , Powles Thomas , Vuky Jacqueline , Lee Jae-Lyun , Fradet Yves , Bellmunt Joaquim , Climent Miguel Ángel , Vogelzang Nicholas J. , Plimack Elizabeth R. , Gurney Howard , Hahn Noah M. , Sternberg Cora N. , Xu Jin Zhi , Imai Kentaro , Homet Moreno Blanca , De Wit Ronald
Published: February 2022

512

Background: Pembrolizumab (pembro) has shown efficacy in advanced/unresectable and metastatic UC (mUC). There is interest in determining whether pts should be treated subsequently with checkpoint inhibitors such as anti–PD-1 therapy if mUC responds then later progresses. Pembro retreatment after disease progression has shown efficacy in melanoma and NSCLC. This post hoc exploratory analysis investigated the efficacy of pembro retreatment for pts with advanced UC or mUC enrolled in KEYNOTE-045 and KEYNOTE-052 with a best overall response (BOR) of SD or better and whose disease progressed after discontinuation or completion of 2 y of therapy. Methods: The phase 3 KEYNOTE-045 trial (NCT02256436) was designed to compare the efficacy and safety of pembro vs chemotherapy (chemo) in pts with mUC that recurred/progressed on platinum containing chemo; ≤2 prior lines of systemic chemo for mUC were permitted. The phase 2 KEYNOTE-052 trial (NCT02335424) was designed to evaluate the efficacy and safety of first-line pembro in cisplatin-ineligible pts with advanced UC. In both studies, pembro was administered for up to 2 y; pts were eligible for retreatment if they stopped pembro after CR or had a BOR of CR, PR, or SD and completed 2 y of treatment. Pts must have investigator-confirmed radiographic PD after therapy cessation, have ECOG PS score 0-1, and not have received anticancer treatment after the last pembro dose. BOR to retreatment is reported. Results: At data cutoff for KEYNOTE-045 (Oct 1, 2020), 11 pts were retreated: 5 (45%) achieved objective response to retreatment (3 CR; 2 PR; Table) and 6 had SD, for a disease control rate (DCR; CR+PR+SD) of 100%. Median treatment-free interval was 7.7 mo (IQR, 3.6-16.5); median duration of retreatment was 11.4 mo (IQR, 7.6-12.0). Seven pts (64%) were alive at cutoff. At data cutoff for KEYNOTE-052 (Sep 26, 2020), 10 pts were retreated; 5 (50%) had objective response to retreatment (1 CR; 4 PR) and 4 had SD, for a DCR of 90%. Retreatment BOR was PD for 1 pt (10%). Median treatment-free interval was 13.0 mo (9.2-16.6); median duration of retreatment was 6.0 mo (IQR, 4.9-9.2). Four pts (40%) were alive at cutoff. Conclusions: Although the number of pts who received retreatment was small, objective responses were observed. The findings are generally consistent with observations from retreatment in other tumor types (e.g., melanoma). Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]
Study RC48-C014: Preliminary results of RC48-ADC combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Zhou Li , Xu Huayan , Li Siming , Yan Xieqiao , Li Juan , Wu Xiaowen , Chi Zhihong , Si Lu , Cui Chuanliang , Kong Yan , Tang Bixia , Mao Lili , Lian Bin , Bai Xue , Wang Xuan , Guo Hongqian , He Zhisong , Guo Jun , Sheng Xinan
Published: February 2022

515

Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts) with metastatic urothelial carcinoma (mUC). Toripalimab is an anti-PD-1 antibody with a durable antitumor effect for mUC. The combination may have a synergistic antitumor effect. Initial RC48-C014 data was previously presented (ASCO 2021); here we reported an update on safety and ORR. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/kg toripalimab with the traditional 3+3 escalation design. In the expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS, stratified by HER2 and PD-L1 expression. Results: As of 23 Sep 2021 (data cutoff), 32 mUC pts (18 males; median age 67 y [52-76]) were enrolled since 20 Aug 2020. Fifty-three percent pts were systemic treatment naïve in the locally advanced or metastatic setting. The primary site was in upper tract UC in 56%; 53% had visceral metastases (mets), including 28% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 19% pts, and PD-L1 CPS≥1 in 56%. No dose-limiting toxicity was reported, and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, confirmed investigator-assessed ORR was 75% (95%CI: 50.9, 91.3), including 15% CRs; DCR was 95% (95%CI: 75.1, 99.9). The ORR for 1L previously untreated mUC pts was 80% and 75% for pts with liver mets. The ORR was 100% for pts with HER2 (3+), 77.8% for HER2 (2+), 66.7% for HER2 (1+), and 50% for HER2 (0) respectively. The ORR was 97.1% in pts with PD-L1 CPS≥1 and 50% in CPS < 1. Follow-up continues for PFS and OS. Most common treatment-related AEs were anorexia (72%), asthenia (56%, 8%≥G3), aminotransferase level increased (56%, 4%≥G3), peripheral sensory neuropathy (56%), alopecia (52%), nausea (36%), and anemia (32%). The most common immune-related AE was pneumonitis (20%). Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in pts with mUC and a manageable safety profile. Further evaluation of RC48 + toripalimab in mUC is ongoing. Clinical trial information: NCT04264936.
Impact of primary tumor location on efficacy and safety of pembrolizumab (pembro) in patients (pts) with locally advanced or metastatic urothelial carcinoma (UC) enrolled in the phase 2 KEYNOTE-052 and phase 3 KEYNOTE-045 trials.
Authors: O'Donnell Peter H. , Balar Arjun Vasant , Castellano Daniel E. , De Wit Ronald , Vaughn David J. , Powles Thomas , Vuky Jacqueline , Lee Jae-Lyun , Fradet Yves , Bellmunt Joaquim , Fong Lawrence , Petrylak Daniel P. , Gerritsen Winald R. , Quinn David I. , Culine Stephane , Bajorin Dean F. , Xu Jin Zhi , Imai Kentaro , Homet Moreno Blanca , Grivas Petros
Published: February 2022

516

Background: Pembro showed antitumor activity in 1L and 2L for pts with UC in the single-arm, phase 2 KEYNOTE-052 study (NCT02335424) and the randomized phase 3 KEYNOTE-045 (NCT02256436) study, respectively. This post hoc exploratory analysis evaluated whether primary tumor location affected efficacy and safety of pembro (KEYNOTE-052; KEYNOTE-045) and chemotherapy (chemo; KEYNOTE-045). Methods: KEYNOTE-052 enrolled cisplatin-ineligible pts with advanced/metastatic UC who had not previously received systemic therapy; they received pembro (200 mg IV Q3W). KEYNOTE-045 enrolled pts with advanced/metastatic UC who had received platinum-containing chemo; pts were randomly assigned 1:1 to receive pembro (200 mg IV Q3W) or investigator’s choice of chemo (paclitaxel, docetaxel, or vinflunine). Both studies required pts to have measurable disease per RECIST v1.1. Upper tract (UT) UC included primary tumors in the renal pelvis or ureter; lower tract (LT) UC included primary tumors in the bladder or urethra. Pts with UT and LT disease (UT/LT) were classified as LT. Pts receiving pembro were treated until disease progression, unacceptable toxicity, or withdrawal of consent, for up to 2y. End points were PFS, ORR, and DOR per RECIST v1.1 by central radiology assessment and OS. Results: A total of 369 pembro-treated pts (68 UT; 301 LT [79 UT/LT]) from KEYNOTE-052 plus 270 pembro-treated pts (93 UT; 177 LT [33 UT/LT]) and 272 chemo-treated pts (94 UT; 178 LT) from KEYNOTE-045 were evaluated. Median follow-up from randomization to data cutoff (09/26/20 and 10/1/20, respectively) was ≥56 mo. Both studies enrolled a similar percentage of pts with PD-L1–positive tumors (25%-30%). PFS, ORR, DOR, and OS for pembro were consistent regardless of tumor location, although ORR for KEYNOTE-045 was lower for the UT group (Table). In the chemo arm of KEYNOTE-045, similar efficacy was observed regardless of tumor location or regimen. Grade 3-5 TRAEs occurred at similar rates in KEYNOTE-052 (19.1% UT; 21.6% LT) and KEYNOTE-045 (17.2% UT; 16.8% LT). Conclusions: In this exploratory analysis, pembro showed similar clinical activity and manageable safety regardless of primary UC tumor location. Clinical trial information: NCT02256436 and NCT02335424. [Table: see text]
Defining hereditary upper tract urothelial carcinoma: Implications for genetic testing and clinical management.
Authors: Truong Hong , Sheikh Rania , Kemel Yelena , De Jesus Escano Manuel , Khurram Aliya , Reisz Peter , Lenis Andrew Thomas , Goh Alvin C. , Cha Eugene K. , Bochner Bernard H. , Iyer Gopa , Rosenberg Jonathan E. , Bajorin Dean F. , Solit David B. , Stadler Zsofia Kinga , Latham Alicia , Offit Kenneth , Carlo Maria Isabel , Coleman Jonathan , Al-Ahmadie Hikmat A.
Published: February 2022

523

Background: Despite being a rare cancer, upper tract urothelial carcinoma (UTUC) is the third most common core cancer associated with Lynch syndrome (LS) after colorectal and endometrial cancers. Yet, there is no established guideline to identify patients with UTUC who are at risk of carrying germline mutations in LS-associated genes. The objective of this study is to define selection criteria for patients with UTUC for LS screening. Methods: We retrospectively identified patients with UTUC who underwent germline sequencing of ≥77 cancer susceptibility genes using next generation sequencing (NGS) as part of a prospective matched tumor-normal genomic profiling initiative from 04/2015 to 04/2021. Mismatch repair protein status was evaluated by immunohistochemical (IHC) staining for MMR genes MSH2, MSH6, MLH1, and PMS2. Microsatellite instability (MSI) status was determined using NGS. Diagnostic performance of clinical and tumor-based screening criteria was assessed by the presence of germline pathogenic/likely pathogenic variants (PGVs) in MMR genes. Results: A total of 232 patients with UTUC underwent germline testing; median age of diagnosis was 67 years (interquartile range 59 – 73). Of these patients, 70% were male, 43% had UTUC diagnosed before the age of 65, 85% had high grade UTUC,12% had bilateral UTUC, 11% had metastasis at diagnosis, 10% and 31% had personal and family history of LS-associated cancers, respectively. PGVs in moderate or high-penetrance genes were identified in 31 (13%) patients including 6 (3%) in BRCA1/ 2 and 21 (9%) in MMR genes (13 MSH2, 4 MSH6, 4 MLH1). A total of 10/21 (48%) patients with MMR PGVs developed UTUC as their first cancer diagnosis. Of patients with MMR PVGs, 15/16 (94%) had MMR-deficient tumors and 12/18 (67%) had MSI-high tumors. Personal and family history of LS core cancers (p < 0.001), age of diagnosis < 65 (p = 0.008), MSI-high (p < 0.001), and MMR-deficiency (p < 0.001) were associated with MMR carrier status. Female gender (p = 0.7), HG UTUC (p = 0.5), and bilateral UTUC (p = 0.7) were not associated with MMR PGVs. Current NCCN genetic referral criteria for Lynch syndrome has high specificity in identifying patients with LS (100%) but missed 11/21 (52%) patients with UTUC and MMR PGVs. Conclusions: Current genetic referral guidelines for Lynch syndrome may miss a significant portion of patients with LS-associated UTUC. UTUC tumor should be investigated for MMR protein and MSI status with IHC or next generation sequencing methods to augment LS-screening of patients with UTUC and inform systemic treatment selection.
Association between CD47 expression and clinicopathologic characteristics and survival outcomes in MIBC.
Authors: Myint Zin , Jayswal Rani , Chahine Zena , Bachert Sara E , McDonald Robert J , Allison Derek B.
Published: February 2022

534

Background: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for these. CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. Methods: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) on transurethral resection of bladder tumor (TURBT) who subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by immunohistochemistry in both TURBT and matched RC specimens. Expression levels ≥1% were considered positive. The difference between CD47 expression levels between TURBT and RC were also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes were evaluated by Person’s chi-squared test and Kaplan-Meier method respectively. Results: A total of 87 MIBC patients were included. The median age was 66 (39-84) years. The majority of patients were Caucasian (95%), male (79%), and age > 60 (63%). Most patients (75%) underwent NAC prior to RC. Of those who received NAC, 35% were responders and 64% were non-responders. Responders includes those with a pathologic complete response (T0) or partial response (Tis or T1); non-responders included those with stage ≥ T2. The final reported stages for all patients were as follows: stage 0 (32%), stage I (1%), stage II (20%), stage III (43%), and stage IVA (5%). 60% of patients were alive, 40% died from bladder cancer, and 30% had disease recurrence at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients > 60 (p = 0.006), non-responders (p = 0.002), stage ≥ III (p < 0.001) were associated with worse OS by univariate analysis. There was no significance with multivariate analysis. There was a slight positive trend for decreased CD47 levels between TURBT and RC in patients who received NAC (p = 0.5), though this did not reach statistical significance. Conclusions: CD47 expression is not a prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore a potential role for anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend between decreased CD47 levels (from TURBT to RC) in patients receiving NAC. More research is needed to understand how NAC may or may not modify immune surveillance mechanisms in MIBC.
SWOG S1314: A randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer with overall survival follow up.
Authors: Flaig Thomas W. , Tangen Catherine , Daneshmand Siamak , Alva Ajjai Shivaram , Lucia M. Scott , McConkey David , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Bangs Rick , MacVicar Gary R. , Bastos Bruno R. , Fowles Jared , Gustafson Daniel , Plets Melissa , Thompson Ian Murchie , Lerner Seth P.
Published: February 2022

536

Background: This trial evaluated COXEN, a gene expression model, as a predictive biomarker in muscle-invasive bladder cancer (BC) patients randomized to Gemcitabine-Cisplatin (GC) or dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC). Primary results correlating COXEN with pathologic response at surgery have been reported. This secondary analysis includes progression-free (PFS) and overall survival (OS). Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. Cox regression was used to evaluate COXEN score or treatment arm association with PFS and OS, adjusting for stratification factors (stage and PS). Results: 167 patients were included in the primary COXEN analysis all having either at least 3 cycles of chemo and surgery within 100 days of last chemo or having progressed while receiving chemo. The COXEN scores were not significantly prognostic for OS or PFS in their respective arms; the COXEN GC score was a significant predictor for OS in pooled arms. OS and PFS data are shown for both scores in the table. In the intent to treat analysis (n=227), there was no significant difference in OS or PFS for ddMVAC versus GC (for OS, HR =0.87, 95% CI 0.54-1.40), p = 0.57); for PFS (HR= 0.76 95% CI 0.58-1.01, p = 0.055). Association of path response with OS will be presented. Conclusions: The COXEN GC score may be prognostic of survival in those receiving platinum-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and PFS for GC and ddMVAC that appear comparable, but this phase II trial is underpowered for definitive comparisons. The prospective data and correlative samples from S1314 will allow for further assessment of COXEN and other RNA and DNA based predictive and prognostic biomarkers. Clinical trial information: NCT02177695. [Table: see text]
Novel use of ctDNA to identify locally advanced and metastatic upper tract urothelial carcinoma.
Authors: Huelster Heather L. , Green Elizabeth A. , Soupir Alex C. , Katende Esther N. , Rose Kyle M. , Naidu Shreyas U. , Gilbert Scott Michael , Manley Brandon J. , Poch Michael Adam , Sexton Wade J. , Spiess Philippe E. , Yu Alice , Kim Youngchul , Du Pan , Jia Shidong , Kim Il-Jin , Tan Lu , Wang Liang , Li Roger
Published: February 2022

543

Background: Upper tract urothelial carcinoma (UTUC) is an aggressive cancer for which use of neoadjuvant chemotherapy (NAC) is limited by suboptimal clinical staging prior to nephroureterectomy. Detection of circulating tumor DNA (ctDNA) is associated with locally advanced and metastatic urothelial carcinoma of the bladder and may help identify UTUC patients who would benefit from NAC. Here we examine the feasibility and utility of plasma ctDNA in the diagnosis of non-organ confined high-risk UTUC. Methods: Patients with high-grade cTa-T2 UTUC without radiographic evidence of metastatic disease undergoing up-front radical nephroureterectomy (RNU) were prospectively accrued. Blood was collected preoperatively on the day of surgery, and plasma and buffy coat were processed for extraction of ctDNA. FFPE samples from RNU were used for tissue genomic DNA extraction. Next-generation sequencing (NGS) was used for variant profiling. Plasma and somatic tissue mutations were called by comparing with matched buffy coat samples. Detection of cancer variants with a mutation allele frequency (MAF) ≥ 0.25% and hotspot variants with a MAF down to 0.1% were reported for plasma samples targeted by a NGS panel (PredicineCARE). Variants with a MAF ≥ 5% and hotspot variants with a MAF down to 2% were reported for FFPE samples. Results: NGS analyses of matched FFPE and plasma samples were successfully performed for all 15 accrued UTUC patients. Alterations in MYC amplification (62%), TERT promoter (62%), TP53 (38%), FGFR3 (31%), ERBB2 (25%), ARID1A (19%), and PIK3CA (19%) were demonstrated in urothelial tumor tissue. Matched plasma ctDNA showed prevalent alterations in the TERT promoter (47%), TP53 (30%), ARID1A (20%), ERBB2 (20%), FGFR3 (20%), and PIK3CA (17%). Five patients (33%) had detectable plasma ctDNA mutations concordant with tumor-based genotypes using the targeted NGS panel. All patients with detectable preoperative ctDNA had advanced staging (≥pT2 or ≥pN1) and lymphovascular invasion on final pathology, resulting in a 71.4% sensitivity. The panel was 100% specific with no patients with pTis, pTa, or pT1 and pN0 having detectable concordant ctDNA mutations. Conclusions: Prospective ctDNA analysis using a targeted NGS panel is a feasible nonsurgical approach to prediction of high-risk UTUC and has the potential for identification of upper tract urothelial cancer patients that may benefit from NAC.
Prognostic impact of serum cytokeratin 19 fragments in patient with metastatic urothelial cancer treated with immune checkpoint inihibitors.
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Takeda Hayato , Yanagi Masato , Mikami Hikaru , Ikuma Shunsuke , Toyama Yuka , Kondo Yukihiro
Published: February 2022

555

Background: Recent clinical trials such as Keynote-045, EV-201 and Javelin bladder100 have provided new therapeutic agents for metastatic urothelial carcinoma (mUC). However, the only tool that can evaluate the therapeutic responses is a radiological criteria, Response Evaluation Criteria in Solid Tumors (RECIST) in mUC. In the clinical practice, biomarkers that can predict the efficacy and prognosis of various agents are essential to treat these patients, and the search for such biomarkers is urgently needed. We reported that Performance status ≥ 1, liver metastasis and elevated serum cytokeratin 19 fragments (sCYFRA) are the prognostic factors for first-line cytotoxic cheomotherapy (CTC) for mUC. In this study we evaluated pretreated clinical biomarkers including sCYFRA that can predict overall survival (OS) in patients with mUC treated with immune-checkpoint inhibitors (ICI). Methods: Thirty four patients with mUC received pembrolizuab (PB) from February 2018 to July 2020 at our institution. We retrospectively collected performance status, metastasis site, blood neutrophil-lymphocyte ratio (NLR), hemoglobin (Hb), and serum levels of lactose dehydrogenase (LD), alkaline phosphatase (ALP), C-reacted protein (CRP), total protein, albumin, corrected calcium (Ca), carbohydrate antigen19-9, sCYFRA before PB was administered. OS rate were analyzed by Kaplan-Meier curves and log-rank test. Multivariate analysis was carried out using the Cox hazards model. Objective Response rate (ORR) was evaluated based on RECIST (version 1.1). Results: Of 34 patients (Pts), with median age of 73(31-86), during the median follow-up period of 25 (7-126) months, 21patients (65%) had died. Median OS was 9.2 months (0.2-33.4), A 1-year OS rate was 33%. ORR was 33% and 9 Pts was SD (27%) and 14 pts (40%) was progressive disease. On univariate analysis, bone metastasis (p=0.028), LD (p=0.003), ALP (p=0.001), Ca (p=0.003) and sCYFRA (p=0.001) were the significant prognostic factor for OS. On multivariate analysis, ALP (HR9.2, 95%CI [2.89-135.9], p=0.002), Ca (HR7.3, (95%CI [2.36-22.49], p=0.001), sCYFRA (HR 5.0, 95%CI [1.63-15.55], p=0.005) were the significant prognostic factor for OS. Based on these 3 factors we divided pts into three groups, good risk (G1,0 factor), intermediate risk (G2, 1 factor) and poor risk (G3, 2-3 factors)3. There was a significant difference between the three groups for OS on K-M curve (G1 vs G2, p=0.001, G2vs G3, p=0.009). Conclusions: sCYFRA, ALP and Ca were the independent prognostic factors for OS in patients with mUC treated with ICI. sCYFRA was the independent prognostic factor for OS in the 1st line CTC and 2nd line ICI and it can be a prognostic factor though those therapies.
Prognostic value of HER2 expression levels for upper tract urothelial carcinoma.
Authors: Li Siming , Wu Xiaowen , Yan Xieqiao , Zhou Li , Xu Huayan , Li Juan , Liu Yiqiang , Tang Bixia , Chi Zhihong , Si Lu , Guo Jun , Sheng Xinan
Published: February 2022

557

Background: HER2 expression is an adverse prognostic factor of bladder urothelial carcinoma (UBC) while the prognostic value of HER2 expression in upper tract urothelial carcinoma (UTUC) remains to be explored. This study aims to investigate the prognostic value of different HER2 expression and gene amplification levels in UTUC. Methods: The baseline clinicopathological data of 130 patients with UTUC were reviewed. The expression level of HER2 was detected by immunohistochemistry (IHC) staining ( Anti-Her2/neu, Cat.4B5, Ventana ) from formalin-fixed paraffin-embedded (FFPE) tumor tissue of patients. The HER2 gene amplification level was detected by second-generation sequencing (NGS) (HER2 gene copy number [CN]) or Fluorescence in situ hybridization (FISH) from FFPE tumor tissue of patients. HER2 negative was defined as IHC 0. HER2 low expression was defined as IHC 2+ but CN- or FISH-, while HER2 overexpression included IHC 3+, and IHC 2+ but CN+ or FISH+. The correlation between HER2 expression levels or other clinicopathological characteristics and overall survival (OS) were analyzed. The Cox proportional-hazards model was used to analyze the independent prognostic factors of UTUC. Results: All the 130 patients provided FFPE tumor slides for the IHC detection of the HER2 expression levels including: IHC 0 (n = 47), IHC 1+ (n = 28), IHC 2+ (n = 41) and IHC 3+ (n = 14), the median OS were 27.5 months, 48.7 months, 67.3 months, and not reached, respectively, with significantly difference ( P = 0.014). Among the 41 patients with HER2 IHC 2+, 15 patients received the detection of the HER2 gene amplification level by NGS or FISH while the other 26 patients whose HER2 gene amplification levels were unknown were excluded from the analysis. The patients of HER2 negative, low expression, and overexpression had a median OS of 27.5 months, 58.0 months, and 60.0 months, respectively, but the difference was not significant ( P = 0.184). Cox proportional-hazards model also verified that the HER2 IHC expression is an independent prognostic factor on the survival, while the prognostic value of the HER2 gene amplification levels was not found. Conclusions: HER2 IHC expression is an independent factor for the prognosis of patients with UTUC. However, HER2 gene amplification levels have no impact on the prognosis of UTUC patients. HER2 expression especially the HER2 gene amplification level in UTUC needs to be explored further.
Association between TERT promoter mutations and clinical outcome with immune checkpoint inhibitor therapy for advanced urothelial cancer.
Authors: Chawla Neal Shiv , Tripathi Nishita , Sayegh Nicolas , Govindarajan Ameish , Dizman Nazli , Zengin Zeynep Busra , Meza Luis A , Muddasani Ramya , Chehrazi-Raffle Alex , Salgia Sabrina , Malhotra Jasnoor , Hsu Joann , Philip Errol James , Bergerot Cristiane Decat , Lyou Yung , Swami Umang , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Pal Sumanta K.
Published: February 2022

561

Background: Recently published data suggests that the presence of a TERT promoter mutation is predictive of superior overall survival (OS) in patients (pts) with advanced/metastatic bladder cancer (mUC) treated with an immune checkpoint inhibitor (ICI) (Kouchkovsky et al, JITC 2021). We aim to validate the results of this study in a large independent cohort. Methods: Pts with mUC treated at two tertiary cancer centers with available genomic data collected in the course of routine clinical care were identified retrospectively. Pts that had received at least one line of ICI therapy in the metastatic setting were selected. Demographic and treatment data were collected, with pts divided into two groups based on the presence or absence of TERT mutation status ( TERTm or TERTwt, respectively). We evaluated OS from diagnosis of at least muscle invasive disease, progression free survival (PFS), and objective response rate (ORR) with ICI therapy across the two groups. OS in our cohort was compared with findings from pts with bladder cancer in The Cancer Genome Atlas (TCGA) database. Results: From our combined data sets, a total of 166 pts had available genomic data, with 64 TERTm pts (52:12 M:F) and 58 TERTwt pts (32:26 M:F) meeting criteria for inclusion. Median age at diagnosis was 67 in both groups. The site of primary disease was bladder in 54 (84%) TERTm vs. 41 (71%) in TERTwt; 10 (16%) and 17 (29%) had upper tract disease, respectively. 47 (73%) TERTm pts and 40 (69%) TERTwt pts had pure urothelial disease; 17 (27%) and 18 (31%) pts had mixed/pure variant histology, respectively. 37 (58%) and 42 (72%) pts received first-line ICI therapy whereas 27 (42%) and 16 (28%) received subsequent-line therapy in TERTm and TERTwt, respectively. At the time of analysis, there were 24 (38%) patients alive in TERTm, and 23 (40%) patients alive in TERTwt. OS was 35 vs. 36 mos (95% CI 0.62-1.51, P=0.66) in TERTm and TERTwt, respectively. PFS on ICI therapy was 4.6 vs. 5.3 mos (95% CI 0.58-1.34, P≥0.99) in TERTm and TERTwt, respectively. ORR was 75% in TERTm and 50% in TERTwt (P=.004). OS in the TCGA database was 35 mos in TERTm and 47 in TERTwt (P=0.19) from a total of 311 and 127 pts, respectively. Conclusions: In contrast to previously published data, our data show no difference in OS and PFS on the basis of TERT mutational status in pts with mUC treated with ICI therapy. Further analysis from larger datasets is needed to reconcile the role of TERT mutations within this patient population.
Genomic characterization and identification of actionable variants in patients with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Stecca Carlos , Selvarajah Shamini , Jiang Di Maria , Abdeljalil Osama , Zhang Tong , Bedard Philippe L. , Hansen Aaron Richard , Fallah-Rad Nazanin , Sridhar Srikala S.
Published: February 2022

562

Background: Next generation sequencing (NGS)-based molecular profiling has been widely used across various tumor types including genitourinary malignancies to better understand and potentially predict tumor behavior. The goal of this study was to determine the feasibility of using NGS to characterize mUC and to identify potentially actionable variants. Methods: Patients with locally advanced or metastatic urothelial carcinoma (mUC) treated at the Princess Margaret Cancer Center were prospectively recruited for the OCTANE study, which collects archival tumor samples to provide genomic characterization through NGS with a custom hybridization capture DNA-based panel (555 genes) or a targeted DNA/RNA amplicon panel (Oncomine Comprehensive Assay v3, 161 driver gene panel). Variants were annotated using a somatic variant scheme [PMID: 25880439] or the oncoKB database. Comprehensive clinical information including patient, disease and treatment characteristics was collected using electronic patient records. Kaplan-Meier and cox regression were used for survival analysis. Results: Of the 73 patients, median age was 65 (23-83), majority were men (69%), most had lower tract disease (80%) and 41% had de novo metastatic disease. NGS was deemed feasible, based on availability of tumor samples, and performed in 67 (92%) patients. Overall, 61 (91%) had at least one oncogenic variant, including 34 (56%) with a potentially "druggable" target. The most frequent genomic alterations found were TP53 (44%), FGFR (18%), TERT (18%), ARID1A (18%) and PIK3CA (16%), all classified as "pathogenic/likely pathogenic". Only 2 patients received targeted treatment, one as part of clinical trial and one as standard of care. mOS was numerically longer among patients with genomic mutations compared to the ones without: 55 vs 31 months (HR: 0.87, CI 95% 0.3-2.4; p:0.7). No specific mutation was shown to significantly impact survival (table). Conclusions: Use of NGS technology in characterizing the genomic profile of patients with locally advanced or metastatic UC was feasible in most cases. Oncogenic variants were detected in the majority of patients, and more than half of them harbored a potentially "druggable" target, which may lead to future therapeutic advances.[Table: see text]