bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic alterations and evolution in patients with prostate cancer with histologic evidence of neuroendocrine differentiation.
Authors: Barnett Ethan , Carbone Emily , Keegan Niamh M. , Vasselman Samantha E , Nweji Barbara , Zaidi Samir , Scher Howard I. 
Published: June 2022

5029 Background: The incidence of transformation to neuroendocrine prostate cancer (NEPC) has increased in castration resistant prostate cancer (CRPC) in parallel with treatment advances inhibiting androgen receptor signaling. The current understanding is that this occurs in ̃10-20% of CRPC cases. Missing is a determination of the timing of molecular events that drive the process. Methods: Under an IRB-approved protocol, retrospective annotation of all MSK-reviewed pathology reports was conducted for 1447 prostate cancer patients with MSK-IMPACT sequencing data. For patients with pathologically confirmed NEPC, the date of the first sample with unequivocally reported NEPC (described as “neuroendocrine carcinoma” or as having “neuroendocrine differentiation” or “neuroendocrine features”) was recorded. Patients with early signs of histologic transformation not specifically reported as NEPC (double negative prostate cancer or rare/focal staining for NE markers) were analyzed separately. Sequencing results were described by castration-status at collection (CRPC vs castration-sensitive) and, if applicable, the relationship to NEPC diagnosis (i.e. pre- vs post-NEPC). Genomic enrichment analysis was used to identify differentially altered genes between groups. Results: In total, 95 (6.6%) patients had pathologically confirmed NEPC during their disease course, from whom 150 samples with sequencing results were available: including 18 patients with matched pre- and post-NEPC samples. CRPC samples from patients with NEPC (n = 70) were significantly enriched for RB1 alterations (50% vs 12%, p < 10-10, q < 10-10). AR alterations were significantly enriched in CRPC samples from patients without NEPC (n = 380) (63% vs 21%, p < 10-10, q < 1.27*10-8). Further, alterations in numerous genes including TP53, AMER1, ARID5B, YAP1, SOX2, and NKX2.1 were enriched in NEPC patients at the 95% confidence interval (CI) without correction for repeat testing. Matched pre- and post-NEPC samples demonstrated that TP53 alterations in post-NEPC samples are detected in the majority of pre-NEPC samples (8 of 10 patients), but RB1 alterations in post-NEPC samples are detected in a minority of pre-NEPC samples (1 of 8 patients). 54 (3.7%) patients had evidence of early histologic transformation. CRPC samples from these patients (n = 29) were enriched for mutations in RB1, MAP2K2, MUTYH, and CTNNB1 at the 95% CI without correction. FOXA1 mutations were enriched in patients without transformation. Conclusions: RB1, consistent with previous findings, is enriched in NEPC. The inability to detect RB1 alterations in pre-NEPC samples supports divergent evolution, although technical limits of tissue panel sequencing make it difficult to rule out the presence of sub-clonal alterations. Further study of additional genes which contribute to histologic transformation and the development of NEPC is warranted.
Salvage high-dose chemotherapy (HDCT) for relapsed primary mediastinal nonseminomatous germ-cell tumors (PMNSGCT).
Authors: Taza Fadi , Abonour Rafat , Althouse Sandra K. , Ashkar Ryan , Abu Zaid Mohammad Issam , Hanna Nasser H. , Kessler Kenneth A. , Adra Nabil , Einhorn Lawrence H. 
Published: June 2022

5032 Background: Patients with PMNSGCT have high relapse rates after first-line therapy. Historical outcomes in this subset with standard-dose salvage chemotherapy or HDCT+bone marrow transplant (BMT) have been poor. The use of peripheral-blood stem-cell transplant (PBSCT) has allowed for more rapid engraftment and the ability to start the 2nd course 3-4 weeks after the 1st course of HDCT. We report survival outcomes of salvage HDCT+PBSCT in relapsed PMNSGCT. Methods: Between 2004-January 2021, 32 pts with relapsed PMNSGCT were treated with HDCT+PBSCTx2 utilizing our institutional regimen: carboplatin 700 mg/m2 + etoposide 750 mg/m2, for 3 consecutive days, followed by PBSCT. Median time between cycle1 day1 to cycle2 day1 was 3.2 wks (range, 2.6-4.6). Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age was 30. At the start of HDCT, median AFP was 192 (range, 4-17130) and hCG 1.5 (range, 0.6-15711). First-line therapy was standard germ cell tumor chemotherapy such as bleomycin-etoposide-cisplatin (BEP) or etoposide-ifosfamide-cisplatin (VIP). HDCT was 2nd line in (26, 81.3%) and 3rd line in (6, 18.8%). Eighteen (56.3%) pts had platinum-refractory disease defined as progression within 4 weeks of 1st line chemo. Twenty-three (72%) patients had extra mediastinal metastases (mets) at the start of HDCT. Metastatic sites included pulmonary (17), lymph nodes (2), liver (3), bone (2), brain (1). Median follow-up time from start of HDCT was 1 yr (range, 0.02-14.1). Twenty-six (81%) pts completed both cycles, while 6 (19%) completed only one cycle due to toxicity or progression. The estimated 2-yr PFS was 30.7 (95% CI, 15.8-46.9) and 2-yr OS was 35.2 (95% CI, 18.9-51.9). At the most recent follow-up, 9 (28%) pts were continuously no evidence of disease (NED), including 2 pts who had surgical resection of teratoma following HDCT. Median follow-up from the start of HDCT for the NED pts was 4.6 yrs (range, 1-14.1). Five of the NED pts had extra mediastinal mets, and 2 had platinum-refractory disease. Among the 9 NED pts, HDCT was 2nd line in 7 (77.8%) and 3rd line in 2 (22.2%). These results compare favorably to historical data with standard-dose chemotherapy or HDCT+BMT in relapsed primary mediastinal GCT with salvage rates < 10% (Hartmann et al., JCO 19:1641-1648, 2001). Grade ≥3 toxicity, as previously described in our study (Adra et al., JCO 35:1096-1102, 2017), occurred in 8 (25%) pts. There were two treatment-related deaths. Conclusions: HDCT+PBSCT is a safe and effective salvage therapy in pts with relapsed PMNSGCT with curative potential. In our opinion, these complicated patients are best managed at tertiary centers with expertise in medical oncology, stem cell transplantation, and thoracic surgical oncology.
Final analysis of the phase 1b/2 study of sabizabulin in men with metastatic castration-resistant prostate cancer who progressed on an androgen receptor targeting agent.
Authors: Markowski Mark Christopher , Eisenberger Mario A. , Pieczonka Christopher Michael , Getzenberg Robert H. , Rodriguez Domingo , Barnette K. Gary , Steiner Mitchell S. , Saltzstein Daniel R. , Antonarakis Emmanuel S. , Tutrone Ronald F. 
Published: June 2022

5049 Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents. Methods: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose of 63 mg daily. Efficacy was assessed by bone/CT scans. A final analysis of the safety and efficacy data including the primary endpoint, the median progression-free survival was conducted. Results: Although the MTD was not reached in the Phase 1b, the recommended Phase 2 dose was set at 63 mg/day to maximize GI tolerability. The most common adverse events (> 10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher (n = 55) included an objective response rate of 6/29 (20.7%) in patients with measurable disease (1 complete, 5 partial). 14/48 (29.2%) of the patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (95% C.I. 29.63-65.79) (n = 55). Durable responses lasting > 2.75 years were observed with 14.5% (8/55) demonstrating a response greater than 12 months. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent. Clinical trial information: NCT03752099.
Activation of the AKT pathway and outcomes in patients (pts) treated with or without ipatasertib (ipat) in metastatic castration-resistant prostate cancer (mCRPC): Next-generation sequencing (NGS) data from the phase III IPATential150 trial.
Authors: Sweeney Christopher , Chi Kim N. , Bracarda Sergio , Sternberg Cora N. , Olmos David , Sandhu Shahneen , Massard Christophe , Matsubara Nobuaki , Nowicka Malgorzata , Selak Bienz Nives , Schenkel Fanny , Chen Geng , Wongchenko Matthew J. , Garcia Josep , De Bono Johann S. 
Published: June 2022

5056 Background: Ipat + abiraterone (abi) significantly reduced the risk of radiographic disease progression vs placebo (pbo) + abi in pts with mCRPC and PTEN loss tumors by immunohistochemistry (IHC; HR, 0.77; 95% CI: 0.61, 0.98; P=0.034) but not in ITT pts (HR, 0.84; 95% CI: 0.71, 0.99; P=0.043; Sweeney Lancet 2021). A greater risk reduction was seen in pts with PTEN loss by NGS (HR, 0.65; 95% CI: 0.45, 0.95). We describe the efficacy and safety of pbo + abi vs ipat + abi at the second interim analysis (IA) of overall survival (OS) and explore the impact of AKT pathway alterations. Methods: Pts with mCRPC were randomized 1:1 to ipat (400 mg/d) + abi (1000 mg/d) + prednisone (5 mg bid) or pbo + abi + prednisone. Coprimary endpoints were investigator-assessed radiographic progression-free survival by Prostate Cancer Working Group 3 (PCWG3) criteria in pts with PTEN loss tumors by IHC (PTEN loss in ≥50% of tumor cells) and in ITT pts. Secondary endpoints in both populations included OS, objective response rate (ORR) per RECIST 1.1 and PCWG3 and time to pain progression (TPP). Ad hoc analyses assessed pts with PIK3CA/ AKT1/ PTEN alterations by NGS vs wildtype (WT). Results: Median follow-up was 31 mo (cutoff: 2021 Sept 30). In PTEN loss by IHC pts, median OS was 35.8 mo (n=261) with pbo + abi and 36.8 mo (n=260) with ipat + abi (HR: 0.95; 95% CI: 0.74, 1.21; P=0.665); in ITT pts, median OS was 36.7 mo (n=554) with pbo + abi and 40.3 mo (n=547) with ipat + abi (HR: 0.90; 95% CI: 0.76, 1.07). With longer follow-up, the safety profile was consistent with that of the primary analysis. In the full NGS evaluable population (n=743), ipat + abi was associated with better outcomes in pts with PIK3CA/ AKT1/ PTEN alterations (Table). Among pts with PTEN loss tumors by NGS (205 of the evaluable 518 pts), median OS was 29.8 mo (n=102) with pbo + abi and 35.8 mo (n=103) with ipat + abi (unstratified HR: 0.82; 95% CI: 0.56, 1.19). Conclusions: At the second IA, no significant improvement in OS was observed with ipat + abi in pts with PTEN loss by IHC. Exploratory analyses in pts with PIK3CA/ AKT1/ PTEN alterations by NGS suggest that these patients have poorer prognosis but may derive greater benefit from ipat + abi. Clinical trial information: NCT03072238. [Table: see text]
Efficacy and safety of relugolix in men with advanced prostate cancer based on baseline body mass index (BMI): A subgroup analysis from the randomized, phase 3 HERO study versus leuprolide (LEU).
Authors: Saad Fred , George Daniel J. , Cookson Michael , Saltzstein Daniel , Tutrone Ronald F. , Garnick Marc B. , Brown Bruce , Lu Sophia , Fallick Mark , Hanson Sarah , Crawford E. David , Shore Neal D. 
Published: June 2022

5073 Background: BMI has been correlated with adverse prostate cancer outcomes, such as risk of biochemical failure, mortality and androgen deprivation therapy complications. Relugolix is a FDA-approved, once-daily oral GnRH receptor antagonist that has demonstrated superior continuous suppression of testosterone (T) to castrate levels through Week 48 compared to LEU (96.7% vs 88.8%, respectively; Shore N, NEJM 2020;382:2187) in men with advanced prostate cancer (APC). This HERO subgroup analysis looks at the impact of baseline BMI on efficacy and safety. Methods: HERO was a phase 3 randomized, open-label study to evaluate relugolix vs LEU in 930 men with APC. This analysis looked at all men enrolled and treated in the HERO study divided by baseline BMI (BMI subgroups: <25.0 [underweight and healthy weight]; 25.0 – 29.9 [overweight]; and >29.9 [obese]). Assessments included sustained T suppression to castrate levels (<50 ng/dL) from Day 29 through 48 weeks, early T suppression to castrate levels (Day 4 and Day 15), prostate specific antigen (PSA) response (>50% decrease from baseline) at Day 15 with confirmation at Day 29, and profound castration rate (<20 ng/dL) at Day 15. T recovery subset analysis was not included due to low patient numbers. All analyses performed were descriptive. Results: Of the 930 men (relugolix:622; LEU:308) treated in HERO, 287 (30.9%) men had BMI <25, 424 (45.6%) were 25 – 29.9, 219 (23.5%) were >29.9. Sustained castration rates through 48 weeks were higher for the relugolix group than the LEU group and results for select key secondary endpoints were generally consistent across BMI categories, although PSA response proportions were lower in obese patients (table). No differences were noted in the incidence or types of adverse events within treatment groups in the subgroups analyzed. Conclusions: In this HERO study subgroup analysis, relugolix demonstrated greater continuous T suppression than LEU regardless of baseline BMI. Although higher BMI has been associated with poorer outcomes, we did not observe a similar trend with T responses. A numerically lower PSA response was seen in obese patients. Additional research with longer follow-up is warranted. Clinical trial information: NCT03085095. [Table: see text]
Effect of docetaxel (D) use on survival outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with novel hormonal therapies (NHTs): A meta-analysis.
Authors: Guven Deniz Can , Sayegh Nicolas , Tripathi Nishita , Erman Mustafa , Agarwal Neeraj , Swami Umang 
Published: June 2022

5079 Background: ARASENS and PEACE-1 trials have shown that the addition of NHTs to D + androgen deprivation therapy (ADT) improves overall survival (OS) outcomes in mCSPC. However, whether a true synergism is present with using NHT+ADT+D is unknown due to the lack of a trial testing the efficacy of adding D to the NHT+ADT backbone. Our objective was to evaluate the survival outcomes with NHTs according to D use in mCSPC. Methods: The literature search was done from PubMed and Embase databases to identify published studies until February 12th, 2022 for meta-analysis. The MeSH search terms were “castration-sensitive prostate cancer” OR “hormone-sensitive prostate cancer” OR “hormone-naïve prostate cancer” AND “abiraterone” OR “apalutamide” OR “enzalutamide” OR “darolutamide”. The target outcome measures were progression-free survival (PFS) and OS. Generic inverse-variance method with a fixed-effects model was used, with hazard ratios with 95% two-sided confidence intervals (CI) as the principal summary measure (Review Manager software, version 5.3, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). P values below 0.05 were considered statistically significant. Results: The literature search retrieved a total of 2565 records. Six phase III studies encompassing 6701 patients evaluating survival outcomes with NHTs in mCSPC (TITAN, ARCHES, ENZAMET, LATITUDE, STAMPEDE Abi- M1, and PEACE-1) were included after filtering of the available records. Results summarized in below table. In the combined analysis, the addition of NHTs to standard of care (SOC) improved PFS and OS. PFS benefit with NHTs was similar in studies (or study subgroups) with or without D use. However the relative OS benefit with a NHT was higher in studies (or study subgroups) without D than studies permitting D (concurrent or sequential). Conclusions: In this meta-analysis, the PFS and OS benefit with NHT in mCSPC was observed independent of D use. A randomized phase III study comparing D+NHT+ADT with NHT+ADT is needed to evaluate the contribution of D to survival outcomes in patients with mCSPC receiving treatment with NHT+ADT. [Table: see text]
Transcriptomic profiling of patients (pts) with de-novo metastatic castration-sensitive prostate cancer (DN-mCSPC) versus those with mCSPC that have relapsed from prior localized therapy (PLT-mCSPC).
Authors: Sayegh Nicolas , Chigarira Beverly , Hernandez Edgar Javier , McFarland Taylor Ryan , Li Haoran , Sahu Kamal Kant , Tripathi Nishita , Kumar Shruti Adidam , Nordblad Blake , Goel Divyam , Tandar Clara , Yandell Mark , Nussenzveig Roberto , Sirohi Deepika , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: June 2022

5080 Background: Pts with DN-mCSPC have been reported to experience worse prognosis and outcomes compared to those with PLT-mCSPC. We hypothesized that gene expression profiling of pre-treatment primary prostate tumors from PLT-mCSPC pts would be distinct from those with DN-mCSPC. Methods: Eligibility criteria: histologically confirmed mCSPC and available RNAseq profiling performed by a CLIA certified lab using primary prostate biopsies collected prior to start of treatment. Pts were categorized into two cohorts: PLT-mCSPC versus DN-mCSPC. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Ninety-seven (97) patients met eligibility (52 PLT, 45 de novo). Characteristics of the overall eligible pts: median age = 65, median baseline PSA = 12.6, Gleason score ≥8 = 71%, and high volume of disease = ̃30%. Differential expression and pathway enrichment between cohorts: upregulation of cell-cycle signaling pathways (G2-M checkpoint, E2F) in pts with DN-mCSPC, and upregulation of androgen signaling and immune pathways (inflammatory response, NFKB-mediated TNF-alfa signaling) in pts with PLT-mCSPC (Table). Conclusions: These hypothesis-generating data, upon external validation, may provide the rationale for personalized therapy in men with mCSPC, such as the use of CDK4/6 inhibitors in addition to standard of care intensified ADT in men with DN-mCSPC. [Table: see text]
Diagnosed with advanced prostate cancer: A population-based cohort from national oncology practices.
Authors: Kim Simon P. , Kiani Kayvon , Konety Badrinath , Bronsert Michael , Candelario Nellowe , Kessler Elizabeth R , Gershman Boris , Tyler Robin , Flaig Thomas W. 
Published: June 2022

5087 Background: Clinical trials can provide access to novel systemic agents and possible improved survival for men diagnosed with regional and metastatic prostate cancer. Although clinical trials should be accessible to all patient populations, racial disparities to enrollment of clinical trials and its outcomes remain an important unknown outcome. Herein, we sought to elucidate the racial disparities in clinical trial enrollment and survival amongst advanced prostate cancer patients from a large community-based medical oncology consortium. Methods: Using CancerLinQ, we identified all patients who were diagnosed with regional (N1+) and/or metastatic (M1) prostate cancer from 2011 – 2021. Enrollment into a clinical trial and overall survival constituted the primary outcomes in this study. Multivariable logistic regression and Cox proportional hazard regression were used to identify covariates associated with each outcome. Results: Amongst the 160,888 patients with regional/metastatic prostate cancer, only 1.5% patients were enrolled in a clinical trial (n = 2,368). On multivariable analysis, patients with worse ECOG performance status were associated with lowers odds of clinical trial enrollment (p < 0.001). Relative to white patients, African-American men (AAM) also had lower odds of clinical trial enrollment (OR: 0.67; p < 0.001). For the entire cohort, clinical trial enrollment correlated with higher survival (HR: 1.19; p < 001) and lower survival for AAM men (HR: 0.85; p < 0.001) compared to white men after adjusting for other covariates. In the subgroup analysis of patients enrolled in clinical trials, AAM demonstrated similar survival to white patients (HR: 0.96, p = 0.95). Conclusions: Although African-American men with regional/metastatic prostate cancer face barriers to clinical trial enrollment, racial disparities in survival appear to resolve for patients who enroll in clinical trials. Increased attention is needed to address barriers to communication and access to clinical trials.