bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection.
Authors: Albiges Laurence , Bex Axel , Suárez Cristina , Uzzo Robert , Tang Xiaobin , Assaf Zoe June , Dubey Sarita , Goluboff Erik T. , Carter Corey , Banchereau Romain , Huseni Mahrukh A , Pal Sumanta Kumar , Rini Brian I. 
Published: June 2024

4506 Background: In IMmotion010, adj atezo did not prolong investigator-assessed disease-free survival (DFS; primary endpoint) vs pbo after resection in pts with RCC (HR: 0.93, 95% CI: 0.75, 1.15; P=0.50; Pal Lancet 2023). This exploratory analysis of circulating protein biomarkers was performed to identify high-risk pts with minimal residual disease (MRD) who may show differential benefit from treatment (tx) with atezo. Methods: Pts with RCC with clear-cell or sarcomatoid component and increased recurrence risk post nephrectomy were randomized 1:1 to atezo 1200 mg or pbo IV q3w for 16 cycles or 1 year. A retrospective proteomics analysis was done with an affinity-based proximity extension assay (PEA) panel of ≈3000 analytes to identify circulating proteins with differential abundance patterns in matched serum samples (baseline vs at recurrence). A high sensitivity electrochemiluminescence (ECL) assay was then used to evaluate levels of KIM-1, a membrane glycoprotein overexpressed in clear-cell and papillary RCC, in all available baseline and post-tx serum samples. Outcomes in pts with KIM-1 high (≥86 pg/mL) vs low status at baseline were analyzed. Results: In pts with matched PEA samples (n=73), circulating KIM-1 was identified as the most significantly enriched protein at recurrence vs baseline. Of 778 pts enrolled in IMmotion010, 752 (97%) had baseline KIM-1 data (high: 300 [40%]; low: 452 [60%]). KIM-1–high status was associated with reduced DFS, and pts with KIM-1 high had better DFS with atezo vs pbo (Table). Longitudinal analysis of matched samples showed that in KIM-1–high pts, 9% (12/138) and 26% (36/141) of pts had a ≥30% increase from baseline in KIM-1 levels at Cycle 4 Day 1 with atezo vs pbo, compared with 16% (34/213) and 12% (25/207) in KIM-1-low pts, respectively. A ≥30% KIM-1 increase was associated with worse DFS in both KIM-1–high (atezo HR: 1.68, 95% CI: 0.77, 3.69; pbo HR: 3.53, 95% CI: 2.24, 5.58) and KIM-1–low (atezo HR: 3.56, 95% CI 2.21, 5.75; pbo HR: 3.22, 95% CI: 1.81, 5.70) subgroups. In pts with matched ECL samples (n=103), median KIM-1 levels were higher ( P<0.001) at recurrence (172 pg/mL) than at baseline (79 pg/mL). Conclusions: In IMmotion010, high baseline serum KIM-1 levels were associated with poorer prognosis but improved clinical outcomes with atezo vs pbo. Increased post-tx KIM-1 was associated with worse DFS. These data suggest that circulating KIM-1 may be a non-invasive marker of MRD and disease recurrence and be associated with benefit from atezo in adj RCC. Further investigation of KIM-1 in adj RCC is warranted. Clinical trial information: NCT03024996 . [Table: see text]
Long term cardiovascular adverse outcomes in testicular cancer survivors: Real-world U.S. population-based study.
Authors: Alkhatib Khalid Y. , Pluta John , Lee Daniel , Nathanson Katherine L. , Jacobs Linda A. , Guzzo Thomas J. , Adra Nabil , Gietema Jourik A. , Vaughn David J. , Pierorazio Phillip M. 
Published: June 2024

5042 Background: The focus of Testicular Cancer (TC) has shifted towards survivorship due to the high cure rates. With the increase in TC survivors population, long-term cardiovascular disease (CVD) have been suggested to be strongly linked with earlier treatment for TC by various hospital based small studies. As it is crucial to investigate this relationship at a population level to develop early prevention strategies to improve TC survivors' overall quality of life (QoL), we analyzed the U.S. The Behavioral Risk Factor Surveillance System (BRFSS) to describe the long-term outcomes of TC survivors in a real-world random population sample. Methods: Using BRFSS cycles between 2014 and 2022, we pulled all patients who reported having a history of TC and compared them to the rest of the men's population sample who had no history of cancer diagnosis. Using national complex weights, we estimated each group outcomes proportions. Further, we evaluated several complex-weighted logistic regression models adjusted for different covariates to describe the association of high blood pressure, high cholesterol, diabetes, BMI of >25, angina, myocardial infarction (MI), and coronary heart disease (CHD). Results: Out of 3,077,806 participants, we identified 308 with a history of TC and 1,169,061 men with no history of cancer. After calculating descriptive demographics, our modeling analysis showed a consistent significant association in reporting history of Angina (OR range from 3.84 to 4.27), CHD or MI (OR range from 2.92 to 3.14). see table. Conclusions: Real-world data indicate alarming results of high prevalence CVD in TC survivors; our results confirm previously reported results from hospital-based cohorts. Our findings support immediate actions to develop and implement preventative strategies in TC survivors. [Table: see text]
Site versus central read discrepancy rates in PCWG3 evaluation for progression.
Authors: Phillippi Danielle , Marini Matthew , Bowman Erin 
Published: June 2024

5067 Background: Prostate Cancer Working Group-3 Criteria (PCWG3) is the standard for determining radiographic response assessments in Prostate Cancer (PC) Clinical Trials. PCWG3 accounts for soft tissue and bone responses by following RECIST and evaluation of metastatic bone disease, respectively. In PC, the determination of progressive disease (PD) by bone metastases is often challenging due to increased osteoblastic activity during drug treatment known as flare phenomenon. To account for this, PCWG3 uses the 2+2 rule during the flare window and requires persistence of bone lesions over a specified period. Protocols often require blinded independent central review (BICR) verification of PD (VOP) where sites request BICR confirm site suspected radiographic PD (rPD). This is often a challenge as BICR radiologists are required to follow the strict PCWG3 requirements for PD. Previous studies have shown a 32% site vs. central discordance in RECIST trials, yet there is limited data for PCWG3. Due to the complexity of PCWG3, we hypothesized that site vs central discordance is greater than that of RECIST. Thus, we aimed to examine site vs central discordance for PD by PCWG3 by analyzing archived data on site requested radiographic VOP. Methods: Aggregate data from metastatic PC trials requiring BICR VOP by PCWG3 was collected and retrospectively analyzed. Of the 6537 patient data reviewed, 3685 patients had at least one site requested VOP. For these patients with site suspected progression, a comparison between site submitted VOP requests and the BICR outcome of PD or non-PD was used for determination of discordance. The data was further categorized based on the number of times the site submitted a request and when BICR verified PD. Results: Analyses showed 50.91% of patients had BICR verified PD at the time of initial site request. The remaining 49.09% of patients had at least one instance of non-PD before PD was determined by BICR. For 33.3% of patients, central PD was never verified by BICR. In the remaining patients with VOP requests, 11.78% had verified PD following one Non-PD result, 4.03% had verified PD following two or more non-PD results. Conclusions: BICR verified rPD serves as an important endpoint in PC trials yet our analysis shows almost half of initial patient VOP requests from the site were not verified centrally. This is greater than the established discordance in RECIST trials and warrants further investigation. For over 15% of patients who did not have verified PD by BICR on the first request, PD was verified in a subsequent request. We postulate that these discrepancies are due site misinterpretation of PCWG3 or sites requesting VOP when insufficient time has passed to meet the persistence requirements. In addition, PCWG3s requirement for lesion persistence may differ from clinical practice in the assessment of PD. This preliminary analysis provides vital insight into site vs central discordance in BICR confirmation of PD in PC trials.
Dynamic androgen receptor alterations (ARa) ctDNA profiles and clinical outcomes in metastatic prostate cancer (mPC).
Authors: Jani Chinmay , Tran Eli , Zhang Nicole , Tsai Jill , Bucheit Leslie A , Pan Elizabeth , Panian Justine , McKay Rana R. 
Published: June 2024

5069 Background: The AR plays a pivotal role in PC pathogenesis and ARa, including ligand binding domain mutations and amplifications, can evolve under the selective pressure of androgen deprivation therapy and androgen receptor signaling inhibitors (ARSi). Next-generation sequencing of circulating tumor DNA (ctDNA) enables non-invasive, longitudinal monitoring of AR dynamics in patients (pts) undergoing systemic therapies. This study aims to explore the dynamic changes in ctDNA profiles, particularly focusing on the AR gene and its association with clinical outcomes. Methods: We utilized GuardantINFORM, a clinical-genomics database containing de-identified ctDNA test results and commercial payer-claims data. Eligible pts had a diagnosis of mPC and underwent ctDNA testing pre (within 3 months prior to initiation) and post (within 3 months of discontinuation prior to initiating subsequent treatment) ARSi, poly ADP‐ribose polymerase inhibitors (PARPi), and taxane chemotherapy. The primary endpoint was to characterize changes in molecular alterations pre- and post-therapy. Secondary endpoints included overall survival (OS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) for pts receiving with ctDNA testing within 3 months prior to 1L ARSI for mCRPC. Results: From a database of 21,682 pts with PC, 145 had ctDNA collected pre/post ARSI, 54 pre/post PARPi, and 115 pre/post taxane chemotherapy. We observed increased ARa across the three treatment groups (%pre/%post): ARSi (17/35), PARPi (39/43), and taxanes (44/58) (Table). In the ARSi group, most common (%pre/%post) ARa included AR amplifications (11/23), AR T878A (5/9), AR L702H (2/6) and AR H875Y (0.7/1.4). In the PARPi group, the most prevalent (%pre/%post) ARa comprised AR amplifications (24/32), AR L720H (15/15), AR T878A (11/9) and AR F877L (2/6). In the taxane group, notable (%pre/%post) ARa consisted of AR amplifications (33/44), AR L702H (4/10), AR H875Y (3/9) and AR T878A (7/8). 1294 pts had ctDNA testing prior to 1L ARSi for mCRPC and were included in the outcomes analysis. Pts with ARa showed worse TTD (2.8 vs 4.3, p<0.0001), TTNT (6.9 vs 4.8, p<0.0001) and (OS (15.3 vs 49.3, p<0.0001). Conclusions: Our study elucidates evolving changes in AR in mPC using ctDNA profiling. We observed an increase in ARa following ARSi, PARPi, and taxane treatment in mPC. Furthermore, our findings highlight associations between ARa and clinical outcomes, emphasizing the potential for personalized treatment strategies in mPC pts based on molecular profiling. [Table: see text]
Abiraterone with discontinuation of gonadotropin-releasing hormone (GnRH) analogues in patients (pts) with metastatic prostate cancer (PC): A single arm, phase II study.
Authors: Makrakis Dimitrios , Goel Sanjay , O'Sullivan Darciann , White Monique , Gartrell Benjamin Adam 
Published: June 2024

5086 Background: Abiraterone acetate (AA) is approved in metastatic PC. AA inhibits CYP17, required for androgen biosynthesis. A first in human trial suggested that AA monotherapy was inadequate to maintain castrate testosterone (T) in non-castrate men and AA development required continued GnRH analogues. However, T recovery is often delayed post GnRH analogue cessation; the need for their ongoing use to maintain castrate T with AA use is unclear and studies are limited. We present a single arm, phase II trial of pts with metastatic PC treated with AA+Prednisone (AAP) after GnRH discontinuation. Methods: We conducted a single arm, phase II study for pts with metastatic PC treated with AAP with GnRH analogue discontinuation. Entry criteria required metastatic PC treated with AAP and GnRH analogue & baseline T of <50 ng/dl without previous orchiectomy. After enrollment AAP was continued with GnRH analogue discontinuation. Primary endpoint was the pt proportion with castrate T (<50 ng/dl) at 6 months. Secondary endpoints included time to LH normalization, PSA response, radiographic progression-free survival (rPFS) and overall survival (OS). T, PSA & LH levels were monitored at 12-week intervals. We used descriptive statistics to assess the time to non-castrate testosterone levels, LH normalization time & mean T, LH & PSA levels at each monitoring timepoint. Results: We enrolled 31 pts; 27 were evaluable at 6 months. Median age was 69 years. Race/Ethnicity included 21 (68%) non-Hispanic black (68%) and 10 (32%) Hispanic pts. Sixteen (52%) had castration-resistant disease as AAP indication. Mean duration of ADT and AAP prior to enrollment were 29.1 (3-204) and 9.2 (1-38) months, respectively. Median follow up was 28 months. At 6 months, 25/27 (92%) patients had castrate T as did 22/26 (85%) at 12 months, 18/23 (78%) at 18 months, 16/22 (73%) at 24 months and 11/17 (65%) at 30 months. There were no treatment discontinuations due to toxicity Mean T, LH and PSA values at timepoints are reported. rPFS and OS will be reported later. Conclusions: Pts with metastatic PC treated with AAP after GnRH analogue discontinuation often remain castrate with AAP monotherapy even 30 months after GnRH analogue cessation. Phase III trials showing benefit of AAP required continued GnRH analogue; this small phase II study does not change standard of care but does suggest that further evaluation of AAP monotherapy may be warranted; AAP without use of GnRH inhibitors successfully suppressed T levels. Further randomized clinical trials are needed to assess the role of AAP monotherapy without GnRH analogues in metastatic PC. Clinical trial information: NCT03565835 . [Table: see text]
Germline gene-specific associations in a large prostate cancer cohort.
Authors: Khan Hiba M , Nielsen Young Sarah M. , Russell Emily M. , Esplin Ed , Korn W. Michael , Cheng Heather H. 
Published: June 2024

5102 Background: Identification of pathogenic germline variants (PGV) in patients (pts) with prostate cancer (PC) enables precision therapy and cascade testing. Equitable advances in precision PC management require more detailed understanding of gene-level associations. Herein we describe PC gene-specific demography in a large cohort of PC pts. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare Map) data were linked for PC pts from 2015-2023. ICD/CPT codes were used to define PC personal and family history and disease stage (early-stage = codes for active surveillance or definitive local treatment; advanced = remaining pts). PC genes analyzed were those in NCCN PC guidelines with >100 PGV+ pts: ATM, BRCA1, BRCA2, CHEK2, HOXB13 and mismatch repair (MMR) genes ( EPCAM, MLH1, MSH2, MSH6, PMS2). Two sample t-tests were used for age and chi-square tests were used for other variables, with a Bonferroni correction for post hoc analysis. Results: 14,979 pts had GGT: 68% with advanced disease (enriched for BRCA2) and 32% with early-stage. Mean diagnosis age was 64, and significantly younger for ATM/ BRCA2/ HOXB13+ pts (p<0.04) (Table). BRCA2was the most common PGV but was not enriched in any clinician-reported race/ethnicity. CHEK2/MMR+ pts were more likely to be White ( post hoc p<0.001). The Midwest had the highest frequency of PGV (12%). A lower proportion of CHEK2+ pts resided in the South ( post hoc p<0.001). 26% of PGV+ pts had documented PC family history, which was significantly associated with BRCA2/HOXB13, and negatively correlated with MMR (p<0.02 for both). Conclusions: In this cohort of ~15,000 PC pts, gene-specific associations were detected that warrant further study. Three-quarters of pts with PGV had no claims for family PC history, highlighting the importance of GGT in all pts meeting criteria, independent of family history. Further analysis of linked data will assess real-world treatment decisions and outcomes by GGT result. [Table: see text]
Willingness of patients with biochemically recurrent prostate cancer (BCR) with positive 18F-dcfpyl PET/CT PSMA to monitor without treatment.
Authors: Williams Monique , Hankin Amy , Hausler Megan , Mena Gonzalez Esther , Lindenberg Liza , Aragon-Ching Jeanny B. , Sena Laura , Arlen Philip M. , Karzai Fatima , Choyke Peter L , Madan Ravi Amrit 
Published: June 2024

5104 Background: For patients that have a rising PSA and negative CT and bone scan after surgery or radiation, there are no therapies that have been shown to improve survival. This fact has not been changed by the approval of DCFPyL PET/CT PSMA, which can now define subclinical disease in patients with bone and CT scans that are otherwise negative. Treatment and outcome data in BCR is not equivalent to metastatic castration sensitive prostate cancer (mCSPC). Despite the lack of data for the optimal management for prostate cancer that is PSMA positive (ppBCR), many providers feel they must treat patients because patients are unwilling to monitor ppBCR over time. Methods: The NCI is currently accruing to a study (NCT05588128; goal n=250) designed to monitor patients with BCR to understand the evolution of PSMA imaging over time. Eligible patients have BCR and underwent definitive treatment (surgery and/or radiation therapy) > 6 months prior to enrollment. Required PSA minimum 0.5 ng/mL; Testosterone minimum 100 ng/dL. Baseline CT and Tc-99m bone scans must be negative. Initial PSMA assessments occur within 8 weeks of confirmed eligibility. Positive PSMAs will be repeated every 6 months and negative PSMAs are repeated every 12 months for up to 5 years. PSAs are collected every 3 months. Following each PSMA scan, patients are counseled on the results. Radiation and intermittent systemic therapies (for 6 months or less) are allowed on this trial. Results: 57 patients have enrolled on the study and have been evaluated with PSMA PET thus far. Median PSA value at enrollment is 3.65 ng/mL (range, 0.5-71.6 ng/mL). Median PSA doubling time is 11.3 months (range, 1.2-132.4 months). Median patient age is 71 years (range, 54-92 years old). Self-reported race/ethnicity as follows: 75% White, non-Hispanic, 12% Black, non-Hispanic, 3.5% White, Hispanic, 3.5% Other, Hispanic, 2% Asian, 4% Unknown. Of the first 57 patients enrolled who have had PSMA PET scans, 52 patients (91%) were found to have positive findings. Among these, 49 patients (94%) with ppBCR elected to monitor their disease until the next scan. Conclusions: This study (NCT05588128) is the first prospective trial to monitor ppBCR patients to better define the natural history of BCR in the PSMA era. This preliminary data from the ongoing study thus far suggests that with appropriate counseling and a follow-up plan, the majority of patients are willing to monitor ppBCR. Given that no data has demonstrated a survival advantage for BCR or ppBCR, it is important for providers to have balanced conversations with patients about the implications of ppBCR, which often results in an indolent disease course. Clinical trial information: NCT05588128 .
Trends in phase 3 gynecological clinical trials of targeted therapies: Study oversight and pharmaceutical involvement in the past 12 years.
Authors: Ruan Qiao , Johnson Caitlin Ruth , Kapp Daniel Stuart , Chan John K 
Published: June 2024

5503 Background: To determine the trends, progress, and pharmaceutical sponsorship of clinical trials in targeted therapy treatments for gynecologic cancers. Methods: From January 1st, 2011, to May 31st, 2023, all phase III gynecological clinical trials in targeted therapy treatment were identified from clinicaltrials.gov and reviewed using peer review publications. Characteristics of demographics and authorship were analyzed for comparison using Chi-square analyses and Fisher’s exact tests. P-values <0.05 were considered statistically significant. Results: Over the 12-year period, we identified 18,424 patients enrolled across 30 clinical trials studying targeted therapy treatments for gynecologic cancers. Of these trials, 86.7%, 10.0%, and 3.3% involved ovarian, cervical, and endometrial cancers, respectively. Of patients enrolled in these trials, 77.0% identified as White, 13.3% as Asian, and 2.4% as Black; only 3.0% identified as Hispanic. Approximately 46.7% of first authors of publications for these trials were from the U.S. and 43.3% were from Europe. Furthermore, 23.4% of co-authors served or consulted on a committee board, 15.2% received grants/honoraria, and 10.0% were pharmaceutical employees. 73.3% of dedicated medical writers were funded by pharmaceutical groups. Additionally, 83.3% of trials were led by the pharmaceutical industry while 16.7% mainly funded by cooperative groups. 70.0% of clinical trials employed pharmaceutical group funding for study design, and 66.7% of trials had data analyzed by pharmaceutical groups. Clinical trials were then divided into three time periods based on time of publication (2011-2015, 2016-2019, and 2020-2023). Over these periods, diverse patient enrollment increased. There were statistically significant decreases in the proportion of White (80.7% vs. 82.6% vs. 70.3%; p<0.0001) and Black (2.8% vs. 2.5% vs. 2.1%; p<0.0001) patients while increases were found among Asians (6.4% vs. 10.3% vs. 20.5%; p<0.0001) and Hispanics (2.3% vs. 0.7% vs. 12.3%; p<0.0001). The proportion of authors receiving grants/honoraria support increased from 8.0% to 14.2% to 18.2% (p<0.0001). Authors serving as industrial employees rose from 6.3% to 7.1% to 13.1% (p=0.02). Conversely, the proportion of authors acting as pharmaceutical advisory board members or consultants changed from 31.3% to 30.1% to 16.5% (p<0.0001). However, authors without pharmaceutical affiliation remained stable at 49.1% to 53.6% to 48.9% (p=0.004). Conclusions: The number of trials over the last 12 years sponsored by industry increased, as well as pharmaceutical employee participation and grant support. Additionally, Asian and Hispanic participant enrollment significantly increased. Balancing the benefits of pharmaceutical partnership with study oversight and disclosure is important in protecting the interests of our patients.