bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALAN as an omic tool to build gene signatures and to stratify patients.
Authors: Bergom Hannah E. , Day Abderrahman , Shabaneh Ashraf , Ali Atef , Boytim Ella , Wang Jinhua , Hwang Justin 
Published: June 2023

1563 Background: Understanding aberrant gene behavior is critical towards devising clinical therapeutics or gene based diagnostic panels. Clustering and AI/ML have clinical utility, but they do not contextualize changes in gene behavior that result from differences in cell type, microenvironment, or prior treatments. Here, we developed the Algorithm for Linking Activity Networks (ALAN), an informatics algorithm that allows rapid functional comparisons of all detectable genes between clinically annotated patient cohorts. ALAN outputs quantify gene behavior without any additional inputs and can be applied on all forms of clinical omic data. We tested the utility of ALAN to identify the molecular features of resistance and novel precision therapeutics. Methods: We applied the ALAN algorithm in prostate tissue using whole-transcriptome sequencing (WTS) data from SU2C/PCF (n = 209, metastatic prostate cancer), TCGA (n = 493, primary prostate cancer), and GTEX (n = 245, benign prostate tissue). We conducted informatics analysis of whole-exome sequencing (WES) data from SU2C/PCF (n = 444 mPC), Fred Hutch (n = 130 mPC), and MCTP (n = 61 mPC) to identify mPC patients with amplifications in RSPO2. We scored an ALAN gene signature in a patient with single-cell RNA sequencing pre and post AR inhibition (n = 112, 83). We examined ChIP-seq data to evaluate binding of AR and Co-factors at the CD276 transcription regulatory sequences. Results: In mPCs, ALAN unbiasedly identified genes that prior studies have implicated as resistance mechanisms towards enzalutamide. In this process, ALAN nominated RSPO2, a secreted protein, as a potential resistant gene that has never been targeted in mPC. In recent studies, we found RSPO2 amplifications in 19.7-28.5% of mPC. We utilized ALAN outputs to build a novel gene signature that was exclusively enriched (p-value < 0.0001) in the transcriptome collected from single cells of a post-resistant mPC sample. We also utilized ALAN to stratify the optimal mPC patients in receiving precision therapies against B7-H3 ( CD276). B7-H3 is an immune regulatory molecule in the B7 superfamily that includes PD-L1 and CTLA-4 and has not been targeted in mPC. B7-H3 was unlike other B7 family members and exhibited robust association with AR co-factors and AR signaling. We confirmed ALAN findings as multiple B7-H3 transcriptional enhancers and promoters were bound by AR and AR-cofactors. Conclusions: ALAN is an algorithm that can be readily deployed on existing clinical omic data to build gene signatures, identify resistant genes, and risk stratify patients. ALAN nominated a novel therapeutic target, RSPO2, which is recurrently amplified in mPC patients. ALAN predicted that mPCs with high baseline levels of AR activity would be optimal candidates for B7-H3 precision therapeutics. Altogether, ALAN outputs should be considered for making clinical decisions that would benefit by comprehensive comparisons of all detectable genes.
The inclusion of health-related quality of life and other patient-reported outcomes in landmark trials for Food and Drug Administration oncology drug approvals: An analysis of cancer drug approvals between 2006 and 2022.
Authors: Ojo Ademola Samuel , Ali Ahmed 
Published: June 2023

1569 Background: How patients feel and function are essential elements of the clinical benefit of interventions which is often not captured by traditional measures of clinical benefit such as progression-free survival and overall survival. Health-related quality of life, functional status, symptom burden, and other patient-reported outcomes (PROs) assess the impact of interventions from the patient’s point of view. The aim of this study is to assess the inclusion of PROs in landmark trials leading to FDA oncology drug approvals. Methods: This is a retrospective cross-sectional study of pivotal trials leading to FDA oncology approvals between January 2006 and December 2022 based on the FDA oncology approval notifications. The trial protocols of all pivotal trials were evaluated for inclusion of health-related quality of life or other PROs as an outcome measure. The approved therapies were classified into first-line, adjuvant/maintenance, and second or later line of treatment. Chi-square tests were used to assess the relationship between the line of treatment and the inclusion of PROs in the trial protocol. Results: There were 420 oncology approvals during the study period with the highest number of approvals in a single year in 2020 (56) and the least in 2007 (7). Lung cancer has the highest number of approvals (61, 14.5%) followed by lymphoma (50, 12%), leukemia (49, 11.7%), genitourinary malignancies (48, 11.4%), breast cancer (36, 8.6%), gastrointestinal malignancies (32, 7.6%), plasma cell disorders (30, 7.1%) melanoma (20, 4.8%), gynecological malignancies (20, 4.8%), hepatobiliary malignancies (14, 3.3%) and head/neck cancers (14, 3.3%). The approved therapies were first line (146, 34.8%), second or higher line (226, 53.8%), and adjuvant/maintenance therapies (48, 11.4%). PROs were included in 40.7% of the pivotal trials. There is a rising trend in the inclusion of PROs from 5.5% of pivotal trials in 2006 to 31% in 2022. Trials on first-line therapies are more likely to include PROs compared to second or higher-line therapies (44.5% vs 36.7%; p = 0.13). Conclusions: Although there is a rising trend in the inclusion of health-related quality of life and other PROs in pivotal trials for FDA oncology drug approvals, most pivotal trials did not include PROs as outcome measures.[Table: see text]
Endpoints reported in phase 3 randomized clinical trials at ASCO 2022.
Authors: Teuwen Laure-Anne Marie Nicole , Young Joanna Alyse , Bourlon Maria Teresa , Segelov Eva , Prenen Hans 
Published: June 2023

1570 Background: The goal of phase 3 randomized clinical trials (RCTs) is to show clinically meaningful benefit for patients. An analysis of phase 3 RCTs presented at the ASCO 2022 Annual Meeting (ASCO22) was undertaken to assess which endpoints were evaluated. Methods: A systematic analysis was undertaken of ASCO22 abstracts from phase 3 RCTs reporting primary, secondary, interim, updated, and subgroup analyses, as well as trials reporting methodology of currently enrolling studies. Trials that reported posthoc, exploratory, biomarker, and retrospective analyses of RCTs were excluded. Information from ASCO22 materials and clinical trial registration websites was recorded by two independent researchers. Results: In total, 166 RCTs were identified: 93 trials with 50,781 enrolled patients and 73 trials expected to enroll 52,098 patients. More trials reported on patients with locally advanced/metastatic cancer (64.5%) compared to localized cancer (35.5%). Funding source was pharmaceutical or biotechnology company in 62%. Within locally advanced/metastatic trials, overall survival (OS) was a primary endpoint in 40%, while progression-free survival (PFS) was a primary or co-primary endpoint in 45% and 13% respectively. Other primary endpoints included (invasive) disease-free survival ((i)DFS), event free survival (EFS), overall response rate and pathological complete response. In trials that did not include OS as a primary endpoint, OS was a secondary endpoint in 88% (n = 56/64). Within the localized group, trials were subdivided into adjuvant, neo-adjuvant, definitive and other categories. Within the adjuvant trials (n = 27), the most common primary endpoint was (i)DFS (37%), followed by OS (15%). Other primary endpoints included recurrence-free survival, invasive breast cancer free survival, metastasis-free survival, EFS, and PFS. Across all trials, quality of life (QOL) was never reported as a primary endpoint, however it was as a secondary or other outcome in 53% for locally advanced/metastatic trials and 42% for localized trials. When comparing the endpoints reported in the ASCO22 abstract and meeting materials with those listed on the trial registration website, discordance was noted in 14%. Conclusions: Phase 3 RCTs presented at ASCO22 represented participation from over 100,000 patients, however, fewer than half in locally advanced/metastatic cancer and fewer than one quarter in localized disease utilized OS as a primary endpoint. QOL was listed as an endpoint in roughly one half of all trials. Endpoints reported did not match registration data in a significant minority. Debate over which endpoints should be used for cancer RCTs should be informed by this data.
Global adoption of remote technologies to enable patient-centric oncology clinical trials: Analysis by the Bloomberg New Economy International Cancer Coalition.
Authors: Daly Robert Michael , Brawley Otis W. , Gospodarowicz Mary K. , Olopade Olufunmilayo I. , Fashoyin Ibilola , Wolodzko Smart Victoria , Chang I-Fen , Tendler Craig L. , Kim Geoff , Fuchs Charles S. , Zhang Lianshan , Legos Jeffrey J. , Duran Cristina , Kalidas Chitkala , Qian Jing , Finnegan Justin , Pilarski Piotr , Silverstein Amy , Wu Yi-Long , Li Bob T. 
Published: June 2023

1584 Background: Fewer than 5% of patients with cancer enroll in a clinical trial, partly due to the significant financial and logistical burden on patients, especially among underserved populations. The COVID-19 pandemic marked a significant shift in the adoption of remote technologies and decentralized trial operations by major pharmaceutical companies. We sought to determine the current global state of adoption of these technologies, understand factors that are driving or preventing adoption of them, and highlight aspirations and direction for industry to enable more patient-centric trials. Methods: The multi-stakeholder Bloomberg New Economy International Cancer Coalition composed of patient advocacy, industry, government regulators, and academic medical centers developed a survey directed to global biopharmaceutical companies of the Coalition with a focus on registrational clinical trials. The survey was organized into three main sections: 1) Impact of different remote monitoring and data collection technologies on patient-centricity; 2) Adoption of these technologies in oncology and all therapeutic areas; 3) Barriers/facilitators to adoption. Results: Administered from October 1 to December 31, 2022, a total of 8 companies completed the survey (response rate: 100%), representing 33% of oncology market by revenues in 2021. Across nearly all remote monitoring and data collection technologies, adoption in oncology trials lags that of all trials. In the current state, eDiary/eCOA is the most utilized technology with 56% and 51% adoption for all trials and oncology trials, respectively, whereas visits in local physician networks is the least adopted at 12% and 7%, respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 out of the 11 technologies (Table). Furthermore, respondents identified digitally enabled recruitment, local or mobile imaging capabilities, and local physician networks as those technologies that would be most impactful for improving patient centricity in the long term. Conclusions: This survey is the first by a coalition of global stakeholders to determine the current state and future aspirations for the use of remote technologies in oncology clinical trials. These efforts may galvanize momentum towards greater adoption of enabling technologies supporting a new paradigm of trials that are more accessible, less burdensome, and more inclusive.[Table: see text]
Association of state policies regulating short-term limited-duration insurance plans and cancer stage at diagnosis.
Authors: Barnes Justin Michael , Kirchhoff Anne C. , Yabroff Robin , Chino Fumiko 
Published: June 2023

1589 Background: In 2018, federal regulations expanded access to short-term limited duration insurance (STLD) plans. STLD plans generally limit coverage of medical services and have no cost-sharing caps, which can delay a cancer diagnosis. Furthermore, uptake of STLD plans can destabilize individual insurance markets, leading to increased prices and subsequent barriers to care for comprehensive insurance plan enrollees. Several states introduced legislation prohibiting and/or limiting STLD plans, but it is unclear whether STLD plans or policies restricting their proliferation have affected cancer stage at diagnosis. Methods: Individuals ages 18-64 years with staged first primary malignancies diagnosed 2016-2019 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Difference-in-differences (DID) analyses evaluated changes in early-stage (stages 0 [breast and bladder only] through II) diagnoses from pre- (2016-2017) to post- STLD expansion (2019; 2018 was excluded as washout/phase-in period) between states with policies prohibiting and/or limiting STLD plans vs. states with no policies regulating STLD plans. In some states limiting but not prohibiting STLD plans, insurers stopped selling STLD plans; we conducted additional analyses by state STLD plan availability in 2019. Linear probability models utilized cluster-robust standard errors (clustered at state level) and adjusted for fixed state and year effects, sociodemographic covariates, and cancer site. Sensitivity analyses excluded states that expanded and/or substantially changed Medicaid eligibility during the study period. The plausibility of the parallel trends assumption was tested in adjusted models restricted to the pre-policy period (2016-2017) and was satisfied for all analyses. Results: 398,190 individuals were included. In adjusted DID analyses, early-stage diagnoses increased 0.95 percentage points (95% CI = 0.53 to 1.38, p<.001) in states that prohibited vs. did not regulate STLD plans, but there was no relative change in early-stage diagnoses in states with other policies limiting STLD plans (p=.25). Relative to states where STLD plans remained available, there was a nonsignificant increase in early-stage diagnoses in states where legislation stopped the sale of STLD plans, with greater evidence for an increase after excluding states with Medicaid eligibility changes (1.03, 95% CI = 0.71 to 1.35, p<.001). There were no differential changes in early-stage diagnoses by state group in falsification tests limited to individuals >65 years-old, who were Medicare-age-eligible. Conclusions: State legislation prohibiting and/or leading to the cessation of STLD plans was associated with an increased rate of early-stage cancer diagnoses. Alternatively, the proliferation of STLD plans was associated with a differential decreased rate of early-stage cancers.
Clinical practice guideline descriptions of oncologic drugs granted FDA accelerated approval: A cross-sectional study.
Authors: Mooghali Maryam , Wallach Joshua David , Mitchell Aaron Philip , Skydel Joshua J , Ross Joseph S. , Ramachandran Reshma 
Published: June 2023

1590 Background: The Food and Drug Administration’s (FDA's) accelerated approval (AA) pathway allows drugs to be approved using surrogate endpoints, while requiring that sponsors complete postmarketing requirement (PMR) studies verifying clinical benefit. Subsequently, FDA determines whether AA can be converted to standard approval or be withdrawn. It is unclear whether clinical practice guidelines reflect PMR results or FDA regulatory decisions. As most drugs granted AA are cancer therapies, we investigated whether and how National Comprehensive Cancer Network (NCCN) guidelines reflect underlying evidence supporting AAs and subsequent FDA decisions. Methods: In this cross-sectional study, we used Drugs@FDA to identify drug indications granted AA by FDA for oncologic indications from 2016-2018, PMR status and results, and whether AA was converted to regular approval or withdrawn. We excluded pediatric and tumor-agnostic indications. PMR studies were classified as positive if the results from primary efficacy endpoint were statistically significant ( P<0.05) favoring the drug. For each AA indication, we searched relevant NCCN guidelines for their recommendations and examined if AA status, PMR results, and updated FDA decisions were reflected. Results: Among 36 oncology drug indications granted AA from 2016 to 2018, 29 (81%) NCCN guidelines did not mention that the drug was approved via AA pathway or had not yet verified clinical benefit. For all 36 (100%) indications, NCCN guidelines did not state that approval was based on surrogate endpoints. As of December 31, 2022, among 16 drug indications that were converted to standard approval, 13 (81%) guidelines reflected FDA’s updated decisions. Among 8 indications withdrawn after AA, 5 (63%) guidelines reflected the withdrawn status. Of 6 drug indications with negative PMR study results that were withdrawn, 2 (33%) were still recommended in NCCN guidelines thereafter. Conclusions: NCCN guidelines do not consistently reflect FDA regulatory status or PMR study results, highlighting the need for more up-to-date and accurate information to guide clinical practice.[Table: see text]
Trends in new and persistent opioid use in older adults with cancer.
Authors: Baum Laura Van Metre , KC Madhav , Soulos Pamela R. , Jeffery Molly , Ruddy Kathryn Jean , Leapman Michael , Jairam Vikram , Dinan Michaela Ann , Lerro Catherine , Woods Corinne , Lee Hana , Ho Amy , Graham David J. , Liberatore Mark , Rivera Donna , Gross Cary Philip , Park Henry Soo-Min 
Published: June 2023

1592 Background: While ongoing efforts to decrease opioid use have dramatically altered the prescribing landscape, the impact on patients with cancer is not well understood. We examined trends in new and persistent opioid use in opioid-naïve older patients with and without cancer in the United States. Methods: This retrospective cohort study used SEER-Medicare linked data for patients with solid tumors malignancies diagnosed from 2012 through 2017, and a random sample of patients without cancer. We included patients who did not receive opioids for 3 months prior to the diagnosis or randomly assigned index date. We identified new opioid use (claim in 0-90 days after diagnosis/index date), early persistent opioid use (claims in days 0-90 and 91-180), and long-term persistent opioid use (claims in days 0-90 and 91-180 and months 13-15). Further analysis focused on 4 clinical strata: non-cancer, metastatic cancer, cancer treated with surgery alone, and cancer treated with surgery plus chemotherapy and/or radiotherapy ("surgery+"). We calculated relative changes in the predicted probability of opioid use from 2012 to 2017 based on a logit model adjusted for patient demographics. Results: We identified 238,470 eligible patients with cancer (mean age 76.3 years). Among patients with cancer, 46.4% had new opioid use; use was higher among those receiving surgery+ (70.6%), those treated with surgery alone (58.8%) and those with metastatic cancer (50.0%), compared to patients without cancer (6.9%). From 2012 to 2017, the predicted probability of new opioid use declined in all groups, with lower relative decline in the cancer subgroups (6.8% surgery+; 9.5% surgery alone; 10.2% metastatic cancer) compared to the non-cancer comparator (24.7%). For instance, in patients with metastatic cancer, predicted probability of new use decreased from 52.4 to 47.1% (10.2%) vs. 8.0 to 6.0% (24.7%) in patients without cancer. Relative decline in predicted probability of long-term persistent opioid use was lower in the surgical cancer strata (44.2% surgery+; 46.1% surgery alone) vs. the non-cancer comparator (54.0%). Conclusions: While opioid use remains common in patients with cancer, new and persistent opioid use declined over time in all patients, though with steeper relative declines in non-cancer compared to cancer populations. Our study suggests important but tempered effects of the changing opioid climate on patients with cancer.[Table: see text]
Data transparency and demographic representation in approval packages of FDA-approved oncology drugs from 2012-2021.
Authors: Liu Jingyi , Jayaram Gowri , Varma Tanvee , Sammut Stephen , Guerra Carmen , Miller Jennifer E. 
Published: June 2023

1594 Background: Over the past decade, the U.S. Food and Drug Administration (FDA) has leveraged regulations and guidance documents to accelerate improvements in demographic reporting and encourage adequate representation of minorities in clinical trials. This cross-sectional study aims to assess the impact of these interventions by characterizing demographic data reporting and representation by sex, age, and racial and ethnic identity in pivotal trials supporting novel cancer therapeutics approved by the FDA from 2012 through 2021. Methods: Study demographic data were abstracted from FDA drug approval packages and US cancer population demographic data was abstracted from US Cancer Statistics. The percentages of trials reporting sex, age, racial and ethnic identity of participants in drug approval packages were calculated and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of participants in each demographic by the percentage of the US cancer population in each group. PPRs were constructed for each pivotal trial by cancer type. Adequate representation was defined as PPR 0.8-1.2 and the proportion of trials which were adequately representative of each demographic was calculated and trended over time. Results: From 2012 through 2021, the FDA approved 118 cancer therapeutics, based on 131 pivotal trials. For drugs approved 2012-2016, the majority of associated pivotal trials reported participation based on sex (100% of trials), age (100%) and White (98%), Black (75%) or Asian (84%) racial identity, but not American Indian or Alaskan Native racial identity (18%) or Hispanic ethnic identity (41%). For drugs approved 2017-2021, there were no significant improvements in demographic data reporting, although there was a trend towards increased reporting on Hispanic ethnic identity from 2012-2016 (41%) to 2017-2021 (65%) (p= 0.06). For drugs approved 2012-2016, most pivotal trials adequately represented female participants (78% of trials) and participants identifying as White (87%), but few pivotal trials adequately represented older adults (7%), participants identifying as Black (11%), American Indian or Alaskan Native (0%), Asian (18%) or Hispanic (5%). Representation in pivotal trials did not significantly improve for any demographic for drugs approved 2017-2021 (p>0.05). Conclusions: This study found that the last decade’s efforts to improve demographic data transparency and representation in clinical trials have not yet borne fruit for novel cancer therapeutics. More consequential FDA regulations may be necessary. Beyond the FDA, demographic data transparency and adequate minority representation in oncology clinical trials is an all-stakeholder responsibility. A more just clinical trial infrastructure requires greater collaboration between the FDA, sponsors, enrollers, contract research organizations and cooperative groups.