Despite increasingly stringent requirements from regulatory agencies, clinical trials often fail to recruit study populations representative of real-world demographics and disease prevalence and are ...often skewed away from racial/ethnic minorities. Consequently, data produced by such trials can result in treatment guidelines and outcome expectations that do not apply to racial/ethnic minorities, further widening health disparities. In this study, we describe a new tool, the TriNetX Diversity Lens ("Diversity Lens"), which augments the existing electronic health record querying functionality of TriNetX and allows clinical trial sponsors to rapidly evaluate the potential impact of inclusion and exclusion criteria on the eligibility rates of different racial and ethnic groups. We describe the development of Diversity Lens in collaboration with public and private stakeholders. Additionally, we feature examples of how Diversity Lens can bring to the surface insights into existing health disparities and prospectively explore the impact of study criteria on the eligibility of racial/ethnic minorities.
Clinical genomic testing of patient germline, tumor tissue, or plasma cell-free DNA can enable a personalized approach to cancer management and treatment. In prostate cancer (PCa), broad genotyping ...tests are now widely used to identify germline and/or somatic alterations in
and other DNA damage repair genes. Alterations in these genes can confer cancer sensitivity to poly (ADP-ribose) polymerase inhibitors, are linked with poor prognosis, and can have potential hereditary cancer implications for family members. However, there is huge variability in genomic tests and reporting standards, meaning that for successful implementation of testing in clinical practice, end users must carefully select the most appropriate test for a given patient and critically interpret the results. In this white paper, we outline key pre- and post-test considerations for choosing a genomic test and evaluating reported variants, specifically for patients with advanced PCa. Test choice must be based on clinical context and disease state, availability and suitability of tumor tissue, and the genes and regions that are covered by the test. We describe strategies to recognize false positives or negatives in test results, including frameworks to assess low tumor fraction, subclonal alterations, clonal hematopoiesis, and pathogenic versus nonpathogenic variants. We assume that improved understanding among health care professionals and researchers of the nuances associated with genomic testing will ultimately lead to optimal patient care and clinical decision making.
Proton beam therapy is an emerging radiotherapy treatment for patients with cancer that may produce similar outcomes as traditional photon-based therapy for many cancers while delivering lower ...amounts of toxic radiation to surrounding tissue. Geographic proximity to a proton facility is a critical component of ensuring equitable access both for indicated diagnoses and ongoing clinical trials.
To characterize the distribution of proton facilities in the US, quantify drive-time access for the population, and investigate the likelihood of long commutes for certain population subgroups.
This population-based cross-sectional study analyzed travel times to proton facilities in the US. Census tract variables in the contiguous US were measured between January 1, 2017, and December 31, 2021. Statistical analysis was performed from September to November 2023.
Drive time in minutes to nearest proton facility. Population totals and prevalence of specific factors measured from the American Community Survey: age; race and ethnicity; insurance, disability, and income status; vehicle availability; broadband access; and urbanicity.
Poor access to proton facilities was defined as having a drive-time commute of at least 4 hours to the nearest location. Median drive time and percentage of population with poor access were calculated for the entire population and by population subgroups. Univariable and multivariable odds of poor access were also calculated for certain population subgroups.
Geographic access was considered for 327 536 032 residents of the contiguous US (60 594 624 18.5% Hispanic, 17 974 186 5.5% non-Hispanic Asian, 40 146 994 12.3% non-Hispanic Black, and 195 265 639 59.6% non-Hispanic White; 282 031 819 86.1% resided in urban counties). The median (IQR) drive time to the nearest proton facility was 96.1 (39.6-195.3) minutes; 119.8 million US residents (36.6%) lived within a 1-hour drive of the nearest proton facility, and 53.6 million (16.4%) required a commute of at least 4 hours. Persons identifying as non-Hispanic White had the longest median (IQR) commute time at 109.8 (48.0-197.6) minutes. Multivariable analysis identified rurality (odds ratio OR, 2.45 95% CI, 2.27-2.64), age 65 years or older (OR, 1.09 95% CI, 1.06-1.11), and living below the federal poverty line (OR, 1.22 1.20-1.25) as factors associated with commute times of at least 4 hours.
This cross-sectional study of drive-time access to proton beam therapy found that disparities in access existed among certain populations in the US. These results suggest that such disparities present a barrier to an emerging technology in cancer treatment and inhibit equitable access to ongoing clinical trials.
An important obstacle to cancer research is that nearly all academic cancer centers maintain substantial collections of highly duplicative, poorly quality-assured, nonintercommunicating, ...difficult-to-access data repositories. It is inherently clear that this state of affairs increases costs and reduces quality and productivity of both research and nonresearch activities. We hypothesized that designing and implementing a multipurpose cancer information system on the basis of the Biomedical Research Integrated Domain (BRIDG) model developed by the National Cancer Institute and its collaborators might lessen the duplication of effort inherent in capturing, quality-assuring, and accessing data located in multiple single-purpose systems, and thereby increases productivity while reducing costs.
We designed and implemented a core data structure on the basis of the BRIDG model and incorporated multiple entities, attributes, and functionalities to support the multipurpose functionality of the system. We used the resultant model as a foundation upon which to design and implement modules for importing preexisting data, capturing data prospectively, quality-assuring data, exporting data to analytic files, and analyzing the quality-assured data to support multiple functionalities simultaneously. To our knowledge, our system, which we refer to as the Cancer Informatics Data System, is the first multipurpose, BRIDG-harmonized cancer research information system implemented at an academic cancer center.
We describe the BRIDG-harmonized system that simultaneously supports patient care, teaching, research, clinical decision making, administrative decision making, mandated volume-and-outcomes reporting, clinical quality assurance, data quality assurance, and many other functionalities.
Implementation of a highly quality-assured, multipurpose cancer information system on the basis of the BRIDG model at an academic center is feasible and can increase access to accurate data to support research integrity and productivity as well as nonresearch activities.
Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease ...progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.
The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1 -mediated cell cycle regulation. For multiple tumor types, loss of RB function ...is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects distinct from cell cycle control. Mechanistically, RB loss led to E2F1 cistrome expansion and different binding specificity, alterations distinct from those observed after functional RB inactivation. Additionally, identification of protumorigenic transcriptional networks specific to RB loss that were validated in clinical samples demonstrated the ability of RB loss to differentially reprogram E2F1 in human cancers. Together, these findings not only identify tumor-suppressive functions of RB that are distinct from cell cycle control, but also demonstrate that the molecular consequence of RB loss is distinct from RB inactivation. Thus, these studies provide insight into how RB loss promotes disease progression, and identify new nodes for therapeutic intervention.
Abstract
Background
The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk ...group for coinfection.
Methods
We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality.
Results
Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio OR, 1.61; 95% CI, 1.33–1.95) and fungal (OR, 2.20; 95% CI, 1.28–3.76) coinfections.
Conclusions
Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.
Prostate cancer (PCa) remains the most highly diagnosed, noncutaneous malignancy in men in the United States, and is the third leading cause of mortality within this category. As PCa is typically ...reliant on signaling of the ligand dependent transcription factor the androgen receptor (AR) throughout all stages of disease, PCa treatment targets the AR signaling axis. However, while these therapies are initially effective, patients typically relapse in 36-48 months and progress to the ultimately fatal stage of disease, termed castration-resistant prostate cancer (CRPC), for which there remains no cure. As such, defining both the molecular mechanisms underlying AR signaling and the associated networks that contribute to PCa maintenance and progression is vital. Studies herein describe AR activity in proliferating cells as a function of cell cycle phase, illuminating expanded AR binding and identifying a novel, cell cycle specific AR target associated with development of metastases and lethal disease. Additionally, data in the present study validate loss of the cell cycle regulator retinoblastoma protein (RB) as the major mechanism of RB pathway disruption in CRPC. Further, studies here nominate expansion of E2F Transcription Factor 1 (E2F1) activity as the underlying molecular mechanism of RB loss-driven CRPC, as determined through genome-wide interrogation of cell culture systems and in vivo tumor samples. Utilizing data herein, it will be concluded that cross-talk between the cell cycle machinery and PCa signaling axes drive advanced PCa phenotypes, mediated through expanded activity of transcriptional regulators and novel gene networks that drive late stage disease.
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