bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma.
Authors: Rosenberg Jonathan E. , Powles Thomas , Sonpavde Guru P. , Loriot Yohann , Duran Ignacio , Lee Jae-Lyun , Matsubara Nobuaki , Vulsteke Christof , Castellano Daniel E. , Mamtani Ronac , Wu Chunzhang , Matsangou Maria , Campbell Mary S. , Petrylak Daniel P. 
Published: June 2022

4516 Background: Enfortumab vedotin (EV), an antibody-drug conjugate directed against Nectin-4, demonstrated longer overall survival (OS) and progression-free survival (PFS) in the confirmatory phase 3, randomized, open-label EV-301 trial at the prespecified interim analysis. The longer-term clinical profile of EV is unknown. Data from 12 additional months of follow-up in EV-301 are presented. Methods: In EV-301 (NCT03474107), patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had received a prior platinum-containing chemotherapy and had disease progression during or after PD-1/L1 inhibitor treatment were randomized 1:1 to receive either EV 1.25 mg/kg on Days 1, 8, and 15 of each 28-day cycle or investigator-chosen standard chemotherapy with docetaxel, paclitaxel, or vinflunine. The primary endpoint was OS; secondary endpoints included investigator-assessed PFS per RECIST v1.1, as well as safety and tolerability. Efficacy and safety findings from July 30, 2021, approximately 1 year after the interim analysis (July 15, 2020), are reported. Results: Overall, 608 patients with la/mUC were randomly assigned to EV (n = 301) or chemotherapy (n = 307). As of July 30, 2021, 444 deaths had occurred (EV, n = 207; chemotherapy, n = 237). After a 23.75-month follow-up, median OS was significantly prolonged by 3.97 months with EV compared with chemotherapy (median OS: 12.91 vs 8.94 months, respectively; HR = 0.704 [95% CI: 0.581-0.852], 1-sided P= 0.00015). Additionally, the OS benefit of EV was retained in the majority of prespecified subgroups. PFS also was improved with EV (median 5.55 months) vs chemotherapy (median 3.71 months) (HR = 0.632 [95% CI: 0.525-0.762]; 1-sided P< 0.00001). Rates of treatment-related adverse events (TRAEs; 93.9% vs 91.8%), including serious TRAEs (22.6% vs 23.4%), were comparable between the EV and chemotherapy groups. Rates of grade ≥3 TRAEs were ̃50% in both groups. Conclusions: EV continues to show significant and consistent survival advantage over standard chemotherapy in patients with treatment-experienced la/mUC. No new safety signals were identified. With robust clinical benefit and a tolerable safety profile, EV maintains its place as a standard of care for this aggressive disease. Clinical trial information: NCT03474107.
Association of DNA damage response (DDR) gene mutations (mts) and response to neoadjuvant cisplatin-based chemotherapy (chemo) in muscle-invasive bladder cancer (MIBC) patients (pts) enrolled onto SWOG S1314.
Authors: Iyer Gopa , Tangen Catherine , Sarfaty Michal , Regazzi Ashley Marie , Lee I-Ling C. , Choi Woonyoung , Dinney Colin P.N. , Flaig Thomas W. , Thompson Ian M , McConkey David James , Rosenberg Jonathan E. 
Published: June 2022

4522 Background: Neoadjuvant cisplatin-based chemo followed by radical cystectomy (RC) is a standard of care treatment for pts with MIBC. DDR gene mts, including within ERCC2, a DNA helicase implicated in cisplatin sensitivity in MIBC, have been associated with higher pathologic (path) downstaging ( < pT2) and complete response (pT0) at RC and improved overall survival (OS) in retrospective series. S1314 randomized pts to one of 2 chemo regimens (dose dense MVAC or Gem/Cis) followed by RC. We sought to correlate ERCC2 and other DDR gene mts with response and survival in MIBC pts enrolled onto this prospective trial. Methods: Tumor and matched germline DNA from evaluable pts enrolled onto S1314 underwent exon capture sequencing of 505 cancer-associated genes (MSK-IMPACT). Both deleterious (del) mts and any mts in 9 DDR genes (ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, ATM, ATR, RAD51C, FANCC) were correlated with clinical outcomes. The prespecified analyses included the association of mts with < pT2 and pT0 by logistic regression analysis and with progression-free survival (PFS) and OS by Cox proportional hazards regression. Results: 179 patients (median 61 years, 85% male, 87% white, and 87% clinical stage T2) who received >2 cycles of chemo and were evaluable for path response were included in the analysis. The pT0 rate was 28% and < pT2 was 41%. Del mts in ERCC2 were detected in 26 (14%) pts followed by ATM (n = 12, 7%), ATR (n = 3) and BRCA2 (n = 2). ERCC2 mts were associated with statistically significantly higher path responses with a 54% pT0 rate and 62% downstaging rate. Patients with any del mts had higher path response rates (51% pT0, 56% < pT2) and better PFS (Table) with a median follow-up of 53 months. There was a non-significant trend towards improved OS. Conclusions: In pts managed with neoadjuvant chemo and RC on S1314, both ERCC2 mts and del DDR gene mts correlated with pathologic response. Any del DDR gene mt was associated with improved PFS. These results are in line with retrospective analyses displaying a correlation between DDR gene mts and neoadjuvant chemosensitivity in MIBC and support ongoing genomically-informed organ sparing trials.[Table: see text]
Monitoring efficacy of neoadjuvant sunitinib in metastatic renal cell carcinoma using a personalized and tumor informed ctDNA assay.
Authors: Peterson Christine B. , Kalashnikova Ekaterina , Feeney Jordan , Koyen Malashevich Allyson , Sethi Himanshu , Aleshin Alexey , Jonasch Eric 
Published: June 2022

4525 Background: Approximately 30% of renal cell carcinoma (RCC) cases present as stage IV at the time of diagnosis. Metastatic RCC (mRCC) is associated with poor outcomes, with a five-year survival rate below 50%. Tools to evaluate the efficacy of novel systemic regimens are needed. Biomarkers like ctDNA can accurately and non-invasively assess molecular residual disease (MRD) in response to therapy and monitor disease status over time to predict disease progression. Here, we aimed to determine the feasibility of performing personalized and tumor-informed ctDNA testing in mRCC patients enrolled on a study integrating systemic therapy with surgical cytoreduction, as well as to measure patient response to sunitinib by assessing ctDNA dynamics. Methods: We analyzed a cohort of 21 mRCC patients with median age of 59.5 (43-76) years who were treated with sunitinib, and had planned cytoreductive nephrectomy during their second cycle of therapy. Baseline and post-first cycle ctDNA levels were measured using a personalized and tumor-informed ctDNA assay (SignateraTM bespoke mPCR NGS assay). Changes in ctDNA levels from baseline to the best response time point were correlated with disease status as assessed by radiological imaging. Results: In this cohort, baseline ctDNA was detected in 81% (17/21) of patients, with higher ctDNA concentrations observed in patients who presented with multiple distant metastases (n = 11) compared to the 10 cases with a single metastatic mass (median 5.8 vs 1.3 mean tumor molecules/mL, not statistically significant). Of those with baseline ctDNA measurement, 12% (2/17) cleared their ctDNA, 24% (4/17) had a decrease in ctDNA, and 59% (10/17) had an increase in ctDNA after 4 weeks of sunitinib. During the course of treatment, patients whose ctDNA concentration increased from baseline were more likely to experience a disease progression (HR: 3.9 95% CI 1.13-13.7; p = 0.032) compared to those whose ctDNA decreased. In addition, higher ctDNA concentration before surgery after initial treatment with sunitinib correlated with shorter time to progression (p = 0.04). Conclusions: Our results demonstrate the feasibility and prognostic value of personalized and tumor-informed ctDNA testing for determining response to systemic therapy in patients with mRCC. Early signs of unfavorable ctDNA kinetics can provide rationale for modification of systemic therapy in order to enhance response. Future work exploring the clinical utility of ctDNA testing in larger mRCC cohorts is warranted.
Estimating clear cell renal cell carcinoma transcriptomic signatures using machine learning and histopathology images.
Authors: Hassanpour Saeed , Tomita Naofumi , Kotecha Ritesh , Lee Chung-Han 
Published: June 2022

4533 Background: Gene expression signatures derived from RNA sequencing data have been associated with treatment outcomes for renal cell carcinoma (RCC) patients. Incorporating these RNA biomarkers into clinical practice is promising, yet its real-world applicability is heavily limited as RNA profiling is expensive, time-consuming, and requires specialized expertise for data analysis. In this study, we applied a deep neural network framework to identify the correlation between standard pathology images and underlying RNA signatures using hematoxylin and eosin (H&E) stained formalin-fixed paraffin-embedded (FFPE) whole slides of clear cell kidney tumors from The Cancer Genome Atlas (TCGA). Methods: We collected 496 H&E stained FFPE clear cell RCC whole-slide images and the RNA gene signatures for 496 patients from the TCGA database. We partitioned 496 slides into training (N = 245, 50%), development (N = 49, 10%), and test (N = 202, 40%) sets. We used this dataset to train and evaluate our weakly-supervised deep learning model. The model was iteratively trained using extracted patches from a slide and processed the patches through a convolutional neural network (CNN), pre-trained for the RCC subtypes classification task, to represent features. The features were aggregated and summarized to predict angiogenesis, myeloid infiltration, and adenosine gene signature (AdenoSig) scores. Performance was assessed by computing Pearson’s correlation coefficients. 95% confident intervals (CI) are computed using the Fisher Z transformation. Results: The median angiogenesis score was 6.98 (range: 1.77-8.40), the median myeloid score was 0.54 (range: -4.59-5.96), and the median AdenoSig score was 268.31 (range: -4988.71-7621.57). A total of 202 slides were included in the test set. On this test set, the results of our weakly supervised method achieved a Pearson’s correlation of 0.65 (95% CI: 0.57-0.73), 0.10 (95% CI: -0.04-0.23), and 0.10 (95% CI: -0.04-0.23) with angiogenesis, myeloid, and AdenoSig scores from gold-standard RNA sequencing data, respectively. Conclusions: We proposed using deep learning-based AI techniques to process digitized histopathological images and estimate actionable signatures of angiogenesis, myeloid, and AdenoSig from H&E stained slides. Our model showed promising results for predicting angiogenesis scores compared to myeloid and AdenoSig scores. These results suggest the feasibility of this approach for estimating digital biomarkers from H&E histopathology images and offering a rapid and cost-effective alternative to conventional RNA sequencing.
Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with non-chromophobe RCC (nonchrRCC): Impact of FLCN genomic alteration (GA) status.
Authors: Bratslavsky Gennady , Necchi Andrea , Grivas Petros , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Danziger Natalie , Ross Jeffrey S. 
Published: June 2022

4550 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with nonchrRCC. Methods: 109 chrRCC and 5,862 nonchrRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female (37 [34%] vs. 1,817 [31%]) and younger than pts with nonchrRCC (median age 58 vs 62 years, p <.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in the nonchrRCC cases only at 2.3% with 37% of the GA being germline. 1/109 (0.9%) of chrRCC featured a germline FLCN GA. GA/tumor were slightly higher in nonchrRCC vs chrRCC (3.6 vs 2.4; NS). There were no significant differences in gLOH, genomic signatures or ancestry between the groups. GA more frequent in chrRCC included TP53, RB1, PTEN. GA more frequent in the nonchrRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Biomarkers of immune checkpoint inhibitor (ICPI) drug response revealed higher mean TMB, TMB ≥10 mutations/Mb and PBRM1 inactivating mutation frequencies in the nonchrRCC than the chrRCC indicating possible differences in IO drug response. Conclusions: FLCN mutations that are associated with familial incidence of chrRCC are rarely associated with sporadic chrRCC. Sporadic chrRCC has a substantially different genomic profile from nonchrRCC and appears to harbor fewer opportunities for both targeted and immunotherapies. [Table: see text]
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in subgroups defined by response to 1L chemotherapy.
Authors: Pérez-Valderrama Begoña , Powles Thomas , Sridhar Srikala S. , Caserta Claudia , Loriot Yohann , Gupta Shilpa , Bellmunt Joaquim , Sternberg Cora N. , Wang Jing , Costa Nuno , Laliberte Robert J , Di Pietro Alessandra , Park Se Hoon , Grivas Petros 
Published: June 2022

4559 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based chemotherapy. We report exploratory analyses in subgroups defined by response to 1L chemotherapy (complete response [CR], partial response [PR], or stable disease [SD]) after ≥2 years of follow-up. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC (n = 350) or BSC alone (n = 350), stratified by best response to 1L chemotherapy (CR/PR vs SD) and visceral vs nonvisceral disease at start of 1L chemotherapy. Results: At data cutoff (June 4, 2021), median follow-up in both arms was ≥38 months. OS and PFS were longer in the avelumab + BSC vs BSC alone arm in all subgroups (Table). Median duration of study treatment and incidence of grade ≥3 treatment-emergent adverse events (TEAEs) in subgroups are shown in the Table. In the avelumab + BSC vs BSC alone arm, respectively, subsequent second-line anticancer drug therapy was received by: CR subgroup, 50.0% vs 74.2%; PR subgroup, 58.3% vs 71.8%; and SD subgroup, 46.4% vs 70.4%. Conclusions: Long-term follow-up from JAVELIN Bladder 100 continues to show prolonged OS and PFS with avelumab + BSC vs BSC alone irrespective of response (CR, PR, or SD) to 1L chemotherapy and despite a higher proportion of pts in the BSC alone arm receiving subsequent therapy. Long-term safety was consistent across subgroups. These findings further support avelumab 1L maintenance as standard of care for all pts with aUC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Real-world treatment patterns and clinical outcomes with first-line therapy in cisplatin-eligible and ineligible patients with advanced urothelial carcinoma.
Authors: Sonpavde Guru P. , Galsky Matt D. , Wright Phoebe , Hepp Zsolt , Chang Nancy N. , Willmon Candice , Sesterhenn Steven , Liu Yutong , Morgans Alicia K. 
Published: June 2022

4565 Background: Advanced urothelial carcinoma (aUC) has a poor long-term prognosis. Despite new clinical trial data for novel therapies including PD-1/L1 inhibitors, data on real-world (RW) treatment patterns and overall survival (OS) in aUC patients (pts) treated with first line (1L) therapy are limited. Methods: This retrospective observational study describes the contemporary RW 1L treatment patterns and OS in aUC pts stratified by cisplatin (cis)-eligibility (based on accepted criteria) and treatment. Data were from the nationwide Flatiron Health longitudinal electronic health record-derived database, comprising de-identified patient-level structured and unstructured data. Eligible pts were adults diagnosed with aUC from May 2016-Oct 2020 and followed until death or end of data availability in July 2021. OS was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. Results: Of 4,300 aUC diagnosed pts, 3,311 (77.0%) received 1L treatment; 1836 (55.5%) cis-ineligible, 1475 (44.5%) cis-eligible. Differences between cis-ineligible and cis-eligible pts were observed, with cis-ineligible more likely to be older (mean age, 75.0 vs 69.0 yrs), have lower CrCl (median, 45.3 vs 80.7 mL/min), and worse ECOG-PS (2+, 29.2 vs 0%). Only 44.4% received 2L therapy: 38.3% cis-ineligible vs 52.0% cis-eligible. Median OS in all 1L treated pts was 11.0 (95% CI, 10.3 – 11.5) mo and was shorter in cis-ineligible than cis-eligible pts (8.6 [95% CI, 8.1 – 9.2] vs 14.4 [95% CI, 13.4 – 16.4]; hazard ratio [HR], 0.8 [0.7 – 1.0]). A number of cis-ineligible pts received cis, and many cis-eligible pts did not (Table), suggesting physicians consider clinical factors beyond conventional criteria to determine cis-eligibility. Cis + gemcitabine (gem) or MVAC was associated with longer OS vs other treatments regardless of cis-eligibility (Table). Conclusions: Clinical outcomes in 1L aUC pts were poor, particularly for cis-ineligible pts, which may be partly driven by the specific regimen administered. Many aUC pts did not receive 1L treatment and among those who did, less than half received 2L therapy. These data highlight the need for more effective and tolerable 1L therapy for all aUC pts. [Table: see text]
A phase 3 trial of SHR3680 versus bicalutamide in combination with androgen deprivation therapy (ADT) in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Ye Ding-Wei , Gu Weijie , Han Weiqing , Luo Hong , Zhou Fangjian , He Dalin , Ma Lulin , Guo Hongqian , Liang Chaozhao , Chong Tie , Jiang Jun , Chen Zhiwen , Wang Yong , Zou Qing , Tian Ye , Xiao Jun , Huang Jian , Yang Xinfeng , Li Junliang , Jin Chunlei 
Published: June 2022

5005 Background: Both TITAN and ARCHES studies have demonstrated significant clinical benefits of second-generation androgen receptor inhibitors (ARIs) plus ADT versus placebo plus ADT in the treatment of mHSPC. However, first-generation ARIs plus ADT is also widely used in clinic and how superior second-generation ARIs is to first-generation ones remains to be determined. Here, we evaluated the efficacy and safety of SHR3680, a novel oral ARI, versus bicalutamide (Bica) in high-volume mHSPC. Methods: CHART is a randomized, open-label, phase 3 study (NCT03520478). Patients (pts) with mHSPC were randomized 1:1 to ADT plus either SHR3680 (240 mg/d) or Bica (50 mg/d). All pts had high-volume disease adapted from the CHAARTED study. The primary endpoints were radiographic progression-free survival (rPFS) assessed by independent review committee (IRC) and overall survival (OS). As of May 16, 2021, 209 rPFS events per IRC and 153 deaths occurred and a preplanned interim analysis for rPFS was done. Results: 654 pts were randomized to receive SHR3680 (n = 326) or Bica (n = 328). At data cutoff, the median follow-up duration was 22.1 mo in SHR3680 group and 20.4 mo in Bica group. SHR3680 significantly reduced the risk of radiographic progression or death than Bica (HR, 0.44; 95% CI, 0.33-0.58; p < 0.0001; median, not reached vs 25.1 mo). OS data were immature but an improved OS was observed in SHR3680 group compared to Bica group (HR, 0.58; 95% CI, 0.42-0.80; p = 0.0009). All secondary efficacy endpoints favored SHR3680 plus ADT (Table). Frequencies of adverse events of any cause in any grade were similar between groups. Grade ≥3 treatment-related adverse events occurred in 19.2% and 13.9% of pts in SHR3680 and Bica groups, respectively. No seizure occurred in SHR3680 group. Conclusions: SHR3680 plus ADT significantly improved rPFS versus Bica plus ADT in pts with high-volume mHSPC, with a desirable safety profile. New drug application has been submitted to seek approval based on the data presented here. Clinical trial information: NCT03520478. [Table: see text]
Defining germline genetics of germ cell tumor: Implications for genetic testing and clinical management.
Authors: Truong Hong , Ravichandran Vignesh , Kemel Yelena , Knezevic Andrea , Gleeson Jack Patrick , Benfante Nicole , Bromberg Maria , Bolos Mary , Joseph Gabriella , Matulewicz Richard , Sheinfeld Joel , Funt Samuel Aaron , McHugh Deaglan Joseph , Bajorin Dean F. , Donoghue Mark , Stadler Zsofia Kinga , Feldman Darren R. 
Published: June 2022

5007 Background: Epidemiologic studies on germ cell tumors (GCT) in men have shown GCT has a high heritability. Yet, the genetic mechanisms underlying development of GCT in men remain unknown. We sought to determine the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in cancer predisposition genes in men with GCT and identify clinical and pathologic factors associated with the presence of P/LP variants. Methods: We retrospectively identified men with testicular (T) or mediastinal (M) GCT who underwent matched tumor--germline sequencing of ≥ 310 genes as part of an institutional genomic profiling initiative from 04/2015 to 12/2020. Presence of germline variants in clinically actionable genes associated with hereditary cancer syndromes were analyzed. Clinicopathologic characteristics, including primary site, histology and family history were assessed by the presence of P/LP variants and compared using Fisher’s exact test. Results: The study included 480 men, 70 (15%) with M-GCT and 410 (85%) with T-GCT. The median age of diagnosis was 30 years (interquartile range 24 – 39). A total of 81% had non-seminoma; 5% had localized disease; 46%, 14%, and 34% had good, intermediate, and poor risk advanced disease, respectively; 6% had family history of GCT. Among men with T-GCT, 4% had bilateral T-GCT. P/LP variants in clinically actionable genes were identified in 58 (12%) men in the entire cohort. Men with M-GCT had higher frequency of P/LP variants compared to those with T-GCT (15/70 [21%] vs 43/410 [10%], p = 0.02). A total of 7 (10%) men with M-GCT and 20 (5%) with T-GCT had P/LP variants in moderate or high penetrance cancer predisposition genes (p = 0.09). Most P/LP variants in both M-GCT (11/15, 73%) and T-GCT (33/43, 77%) were in genes involved in DNA damage repair pathways. The spectrum of moderate or high penetrance DNA damage repair genes identified is shown in the Table 1. Family history and histology (seminoma vs. non-seminoma) were not associated with the presence of a P/LP variants in the overall cohort (p = 0.8 and 0.7, respectively). Bilateral disease was not associated with the presence of P/LP variants in men with T-GCT (p = 0.4). Conclusions: Approximately 1 in 5 men with M-GCT carried a P/LP variant in a clinically actionable cancer susceptibility gene and 10% had a P/LP variant in a high-risk gene such as TP53 and PMS2. As men with GCT tend to develop disease in early adulthood, identification of germline P/LP variant has significant implications for enhanced cancer screening and surveillance, cascade testing for at-risk family members, and potential preconception genetic counseling. [Table: see text]