tbuckley/cabot-search huggingface dataset:
Unveiling the interplay of social factors in cancer survivorship: A comprehensive social determinants of health (SDOH) profile analysis.
Authors: Fangyuan (Chelsea) Chen, Ryan David Nipp, Xuesong Han, Samuel L. Washington, Robin Yabroff, Changchuan Jiang
Journal: Journal of Clinical Oncology (2024)

1536 Background: SDOHs contribute to patients’ cancer survivorship outcomes. While studies tend to focus on individual SDOH, understanding the interplay and collective impact of multiple SDOHs is vital for improving patient outcomes and access to care. Our study aims to understand SDOH profiles in cancer survivors and stratify social risks by analyzing relationships between SDOH profiles and health outcomes using a nationally representative dataset. Methods: We conducted an unsupervised clustering analysis using 2013-2018 National Health Interview Survey data, linked to NHIS Mortality Files, to examine 12 social determinants of health (SDOHs) in the general population. 12 SDOH included unmarried status, unemployment, less than high school education, material/psychological/behavioral financial hardship, transportation/food/housing insecurity, delayed care due to other reasons, and low income(less than federal poverty line), and low neighborhood cohesion. K-Modes clustering was used to identify optimal number of cluster. We estimated each cluster’s prevalence in younger (18-64 years) and older (65-79 years) cancer survivors, then used weighted Cox regression to assess the risk of overall (OS)in both age groups, adjusting for demographics. Results: We identified 5 distinct groups based their SDOH profiles, including group A (few SDOH barriers), B (unmarried but no other SDOH barriers), C (unemployed but no other SDOH barriers), D (unmarried, unemployed, occasionally having other SDOH barriers) and E (the highest rate of financial hardship/transportation/food/housing insecurity/low neighborhood cohesion/low income). Notably, group E, compared to all other groups, had the highest rate of racial minorities in both younger and older groups in both younger (71% vs 5-14%) and older populations (74% vs 1-8%). Older survivors in Group C (HR 2.48, 95% CI: 1.02-6.03), Group D (HR 4.09, 95% CI: 1.65-10.14), and Group E (HR 3.88, 95% CI: 1.44-10.46) had significantly lower OS rates compared to those in Group A. For younger survivors, Group D (HR 1.96, 95% CI: 0.97-3.96) and Group E (HR 1.40, 95% CI: 0.67-2.95) were associated with nonsignificant reductions in OS, possibly due to limited sample sizes. Conclusions: SDOHs form distinct clusters, each with profound on cancer survivorship especially among older survivors facing complex social challenges. This necessitates customized health interventions focused on these SDOH profiles, crucial for improving patient outcomes and addressing health disparities.
Geographic and racial disparities in bi-specific antibodies trials access for diffuse large B-cell lymphoma.
Authors: Moazzam Shahzad, Muhammad Fareed Khalid, Robin Park, Muhammad Kashif Amin, Iqra Anwar, Michael Vishal Jaglal
Journal: Journal of Clinical Oncology (2024)

1525 Background: The trials of bispecific antibodies to treat diffuse large B-cell lymphoma (DLBCL) have increased exponentially. However, there is a geographic limitation to offering these trials and universal access appears to be limited. Here, we investigate the geographical and racial disparities in accessing bispecific antibodies trials for DLBCL. Methods: We searched ClinicalTrials.gov using the terms for DLBCL and bispecific antibodies. A total of 13 out of 51 clinical trials with one or more open sites in the United States (US) were included in this systematic review. 2020 US Census Bureau data was used to obtain data on race and ethnicity. Analysis for this study was performed using SPSS version 26. Results: The majority of the included trials were Phase I (62%) followed by Phase II (23%), and Phase I/II (15%). A total of 885 participants were either enrolled or expected to enroll in these clinical trials. Nine (69%) clinical trials were only open in the US while 4 (31%) clinical trials were open in the US and other countries. The majority of the trials were funded by the pharmaceutical industry 62%. There were 50 unique study sites distributed over 24 states with a 2.4 (1-10) mean number of trials per state and 9.9 (1-39) mean number of sites per trial. Study sites were distributed in 24 different states. Midwestern states had the highest number of trials 28%, followed by Southern 26%, Northeastern 24%, and Western 22%. The highest number of study locations (10) and the highest number of open studies (10) were in California. Twenty-seven states had no open bispecific antibodies trials including three in the Northeast (Maine, Rhode Island, and Vermont), five in the Midwest (Illinois, Indiana, Nebraska, North and South Dakota), eight in the South (Delaware, Virginia, District of Columbia, West Virginia, Mississippi, Arkansas, Louisiana, and Oklahoma), and eleven in the West (Arizona, Colorado, Idaho, New Mexico, Montana, Nevada, Wyoming, Alaska, Hawaii, Oregon, and Washington). Using US Census Bureau data, only 20% of African Americans (AA) (8 349 699 of 41 104 200) lived in a county with a bispecific antibodies trial. There were only five states (21%) with 50% or more of the AA population living in a county with an open bispecific antibodies trial and seven states (29%) with 30-49.9% of their AA county residents. Five states (21%) had less than 10% of the AA population living in a county with an open bispecific antibodies trial. Nine (90%) out of ten states with the highest proportion of AA residents (18.6%-41.4%) have no (five states) or only one clinical trial site (four states). Conclusions: There is significant geographic and racial disparity in accessing bispecific antibodies trials for DLBCL. Strategies should be framed to address the causes of the observed disparities and to improve access to these trials.
Using an artificial intelligence platform to enhance cancer detection rates in primary care.
Authors: Bea Bakshi, Seema Dadhania, Peter Holloway, Claire Corbett, Miles Payling
Journal: Journal of Clinical Oncology (2024)

1560 Background: Patients with cancer who are diagnosed in a primary care setting have the best survival outcomes compared to any other route (e.g. Emergency department, routine referrals, incidental findings etc). This is primarily attributed to detection of cancer at an early stage. In the UK, the Cancer Detection Rate (CDR) metric serves as a measure of this, representing the percentage of cancer diagnoses originating from primary care referral routes. However, detecting cancer presents significant challenges, primarily due to the non-specific nature of cancer presentations, their tendency to overlap with symptoms of other conditions, and their relatively low prevalence. Artificial intelligence (AI) platforms may be able to support this endeavor but are yet to be established. C the Signs is an AI-enabled clinical decision support tool integrated into primary care practices to help clinicians stratify the risk of cancer and advise on which cancer pathway is most appropriate (if at all) for the patient’s presentation and history. Methods: An observational cohort study was undertaken between 1st May 2021 and 31st March 2022 where 35 practices (covering a population of almost 420,000) within the same geographic region in the East of England were offered the use of C the Signs, with the practices opting out as controls. All practices had the same access to referral and cancer diagnostic pathways within the region. The primary end point was to identify if C the Signs had a statistical impact on cancer detection rates in primary care through nationally linked data via Public Health England. Results: In practices utilizing C the Signs the CDR significantly increased from 58.7% in 2020-21 (prior to the implementation of C the Signs) to 66.0% in 2021-22, reflecting a significant increase of 12.3% (p &lt;0.05). In contrast, practices not using C the Signs maintained a stable CDR of 58.4% in both years. There was no statistically significant variance observed in the referral rate between the two groups, indicating no notable increase in diagnostic or referral activities. Conclusions: These findings underscore the importance of integrating cutting-edge technologies into primary care to improve cancer detection rates and facilitate early-stage diagnosis. Implementation of such advancements holds promise for reducing cancer-related mortality rates and enhancing overall patient outcomes.
A phase II trial to assess the impact of β2 adrenergic blockade in immune checkpoint inhibitor (ICI)– refractory metastatic triple negative breast cancer (mTNBC).
Authors: Shipra Gandhi, Arya Mariam Roy, Hans Minderman, Spencer Rosario, Elizabeth A. Repasky
Journal: Journal of Clinical Oncology (2024)

TPS1141 Background: In PD-L1+ mTNBC patients (pts), the standard of care treatment is chemotherapy and pembrolizumab (P) in the first-line setting. It has been shown that acquired resistance to P occurs as a result of immune exhaustion. Further, our group and others have demonstrated that chronic β2-adrenergic receptor (β-AR) signaling suppresses CD8 + cytotoxic T lymphocytes (CTL) function, drives their exhaustion, and increases the numbers of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the tumor microenvironment (TME), thus supporting tumor proliferation. Consequently, abrogation of β-AR signaling using the pan β-blocker propranolol or β-AR - / - knockout mice increased the intratumoral frequency of CTLs and elevated the CTL:Treg ratio (Bucsek et al. Cancer Res. 2017; PMID: 28819022). Similarly, mouse tumor models also demonstrated decreased exhaustion markers (PD1, TIM3, LAG3) on CTLs when β-AR was blocked, via propranolol (Qiao G et al. Cancer Immunol Res. 2021, PMID: 33762351). Confirming this phenomenon, we have shown, in a prospective clinical trial in metastatic melanoma, that β-AR blockade with propranolol significantly increased response to P with an objective response rate (ORR) of 78%, as opposed to 30-40% with P monotherapy (Gandhi et al, Clin Cancer Res 2021, PMID: 33127652). Therefore, we hypothesize that using propranolol in an ICI refractory population should improve responses to ICIs. Methods: This is a phase II single-arm, non-randomized single-center study for mTNBC pts. Participants will bewomen &gt;=18 yrs with PD-L1+ mTNBC, who have progressed on treatment with chemotherapy and P in the upfront setting. They will continue P every 3 weeks in addition to 30 mg propranolol twice a day, based on our ongoing clinical trial in metastatic melanoma (NCT03384836) which has demonstrated safety with this combination. Treatment will continue until disease progression per irRECIST. The primary endpoint is ORR, defined as complete or partial response to treatment. The secondary endpoint is safety, 6-month progression-free survival and overall survival. As an exploratory endpoint, changes in tumor and blood immune markers will be assessed. In stage 1, n1=12 evaluable pts will be enrolled. If ≥ 1/12 response is observed, then the study will continue to enroll another n2=9 pts for a total of n=21, otherwise it will be suspended for futility. If ≥ 3/21 responses are observed, then the proposed therapy will be considered promising. Pre- and post-treatment tumor biopsies and sequential blood samples will be analyzed for changes in stress-induced biomarkers (epinephrine, norepinephrine, and frequency of CTL, MDSC, Treg) and expression of exhaustion markers (PD1, TIM3, LAG3). The study is currently open. Clinical trial information: NCT05741164 .
An exhaustive pre-clinical study of a circRNA drug candidate (cmRNA1210) encoding IL-12sc for anti-tumor therapeutics.
Authors: Shuhang Wang, Jiali Yang, Lixiang Wei, Yiling Tan, Jiaojiao Sun, Fan Wu, Lingkun Huang, Peiwen Ma, Jiawei Zhou, Guo Zhao, Yuning Wang, Qiyu Tang, Chijian Zuo, Ning Li
Journal: Journal of Clinical Oncology (2024)

e14569 Background: Circular RNA as emerging technology hasn't been approved of acceptance of any IND application. What’s the pharmacokinetics, pharmacodynamics and toxicity study of circular RNA drug candidate would be like is still unpublished. Here we provide an exhaustive pre-clinical study of a novel circular RNA drug candidate encoding IL-12sc, the immune stimulatory effector. Methods: Here, we performed an exhaustive pre-clinical study of a circular RNA drug candidate(cmRNA1210) encoding IL-12sc, including pharmacokinetics, pharmacodynamics, pharmacology and toxicology study. Meanwhile, we explored the bioactivity and cross reactivity of cmRNA1210 in vitro and the pharmacokinetics in vivo. Results: cmRNA1210 and its replace molecule exhibits robust therapeutic effect and good safety in syngeneic mouse tumor model and humanized human tumor mouse model. In situ administration of cmRNA1210 achieves abscopal effect and inhibits lung metastasis progression. Treatment with cmRNA1210 leads to cytokines change in plasma and tumor, cytotoxic immune cells accumulation in tumor and tumor tissue necrosis. Dynamic transcriptome profiling of tumor tissue post cmRNA1210 treatment. Combination with checkpoint inhibitor exhibits synergy effect and significantly decreases tumor relapse rate. Kaplan-Meier survival curve in TCGA dataset shows strong correlation of high IL-12A/B expression and long survival. Conclusions: The bioactivity and cross reactivity in rodents and primates of cmRNA1210 were validated in vitro. The advantage of pharmacokinetics of circular RNA was confirmed in vivo. cmRNA1210 exhibits robust anti-tumor effect in various tumor models, indicating its wild application situation in clinical. In situ treatment achieves abscopal effect and significantly inhibits lung metastasis progression. Systemic anti-tumor effect has been successfully initiated. The pharmacodynamics study reveals there are cytokine changes, immune cells activation or accumulation at tumor site and tumor tissue necrosis after cmRNA1210 treatment. cmRNA1210 as immune stimulatory effector works synergistically with checkpoint inhibitor. Kaplan-Meier survival analysis of IL-12 expression based on TCGA dataset shows there is a strong correlation of high expression and long survival. Overall, this pre-clinical study provides elaborate results of cmRNA1210 as anti-tumor therapeutics and demonstrates the great potential to enter clinical trial in the future.
Trends in the providers’ uptake of advance care planning from 2016 to 2021.
Authors: Nan Wang, Changchuan Jiang, Xin Hu
Journal: Journal of Clinical Oncology (2024)

1538 Background: Advance care planning (ACP) facilitates meaningful discussions and preparation for future medical decisions. This person-centered approach has been recognized for its potential to improve care quality and reduce unnecessary aggressive care at the end of life, especially among cancer patients. We examined the trends in ACP visits across specialty groups that may involve cancer care and between rural and urban areas. Methods: We used publicly available data from the Centers for Medicare &amp; Medicaid Services, the Provider Utilization and Payment Data Physician and Other Practitioners Dataset – By Provider and Service files (2016-2021). We included providers in 3 specialty groups that may encounter cancer patients needing ACP: Cancer-Related Specialties, Hospice and Palliative Medicine (HPM), and Midlevel Providers. The primary outcome was billing for any ACP services each year, identified through Healthcare Common Procedure Coding System codes (99497 and 99498). Geographical areas were classified using Rural-Urban Commuting Area codes into metropolitan and non-metropolitan areas. Trends in the percent of providers billing any ACP and average ACP service volumes were described, with Wilcoxon tests used for statistical comparisons. Results: The primary analytic sample consists of 1,280,656 provider-years from 2016 to 2021 (Cancer-Related Specialties: 113,012, HPM: 7,320, and Midlevel: 1,160,324). The percentage of providers billing ACP visits tripled from 1.0% in 2016 to 3.3% in 2021. The highest uptake was among HPM physicians (12.8% to 36.9%) compared to cancer-related specialists and midlevel providers (Table). Average ACP service volume was higher in non-metropolitan areas among Cancer-Related Specialties (53.6 vs. 142.9). However, the average ACP service volume by metropolitan status was similar among HPM (75.0 vs. 66.7, P=0.65) and higher in metropolitan areas among Midlevel providers (70.2 vs. 54.8, P&lt;.001). Conclusions: The proportion of physicians billing ACP codes increased including those in HPM and cancer-related specialties, but adoption remained low. Rural-urban disparities in average ACP service volume among cancer-related specialties might reflect a shortage of specialty-trained HPM physicians to provide ACP services. Particularly noteworthy is the absence of HPM specialty in non-metropolitan areas. A comprehensive strategy involving education, awareness, enhanced training capacity, innovative care models for advanced practice nurses, and increased resources, is needed to promote APC use and patient-centeredness in cancer care.[Table: see text]
Medicaid expansion and cancer stage at diagnoses during the COVID-19 pandemic in the United States.
Authors: Xuesong Han, Nuo Nova Yang, Qinjin Fan, Leticia M Nogueira, Robin Yabroff
Journal: Journal of Clinical Oncology (2024)

1526 Background: Substantial cancer underdiagnosis, especially for early-stage diseases, occurred during the COVID-19 pandemic in the US in 2020. The Affordable Care Act expanded Medicaid to nonelderly adults with income up to 138% Federal Poverty Level in states that opted in, potentially facilitating residents’ access to care during pandemic-related financial and employment instability, thus aiding in timely detection of cancer. This study examines the association of Medicaid expansion with changes in cancer stage at diagnosis during the COVID-19 pandemic. Methods: Adults aged 18-64 years newly diagnosed with cancer in 2019 and 2021 were identified from the National Cancer Database. Year 2020 was excluded to avoid confounding from distinct geographic patterns of COVID-19 infections. A difference-in-differences (DD) approach was used to compare the changes in proportions of patients diagnosed at stage I/II in 2021 vs 2019 between Medicaid expansion states and non-expansion states. Adjusted DD estimates were calculated with linear probability models and stratified by key sociodemographic factors and cancer type. Results: A total of 427,368 adults newly diagnosed with cancer in 2019 and 393,961 in 2021 were identified. Patients diagnosed with stage I/II decreased nationwide, however, decreases were larger in non-expansion states (from 58.3% in 2019 to 56.9% in 2021) compared to expansion states (61.4% in 2019 to 60.7% in 2021), leading to a DD of 0.92 percentage points in early-stage cancer diagnosis associated with Medicaid expansion (95% CI =0.46-1.38). The association was strongest among individuals aged 18-44 years (DD=1.46, 95% CI=0.42-2.49), men (DD=1.46, 95% CI=0.73-2.19), those living in most socioeconomically deprived areas (DD=1.40, 95% CI=0.41-2.40) and nonmetropolitan areas (DD=1.82, 95% CI=0.56-3.09). When stratified by cancer type, the largest associations were seen for esophageal cancer (DD=3.86, 95% CI=0.26-7.45) and prostate cancer (DD=2.81, 95% CI=1.43-4.18). Conclusions: Substantial cancer underdiagnosis and declines in proportion of early-stage diagnoses continued nationwide in 2021, the second year of the COVID-19 pandemic. However, the pattern was worse in non-expansion states, suggesting a protective effect of Medicaid expansion on cancer early diagnosis during the public health emergency. Findings may inform policy makers and the public in the 10 states that have yet to expand Medicaid eligibility.
Expression of alternatively spliced PD-L1 RNA with skipping of transmembrane domain.
Authors: Ahmad Charifa, Alfonso Lam, Hong Zhang, Jeffrey Estella, Sally Agersborg, Arash Mohtashamian, Maher Albitar
Journal: Journal of Clinical Oncology (2024)

e14596 Background: Programmed death-ligand 1 (PD-L1) is a transmembrane ligand for the programmed cell death protein 1 (PD-1), a receptor that inhibits T-cell activity. The PD-L1/PD-1 immune checkpoint axis has been successfully targeted to enhance antitumor immune responses. This gene is composed of seven exons. Exons 1-4 are responsible for the extracellular domain, exon 5 for the transmembrane domain, and exons 6-7 for the intracellular domain. Emerging data indicates that alternative splicing in genes is an important mechanism for expression of different isoforms that may influence antibody-based therapies. We explored the potential of the presence of alternative splicing in PD-L1 transcripts via sequencing of PD-L1 RNA in patients with various type of solid tumor cancers. Methods: RNA was extracted from 3443 FFPE solid tumor samples including lung, colon, pancreas, breast, and other cancer types. In addition, cfRNA was extracted from 532 peripheral blood plasma samples from patients with solid tumor cancers. RNA was sequenced using a hybrid capture targeted RNA panel on FFPE samples and peripheral blood with analysis focused on PD-L1 gene transcript. Quantification of RNA transcript was done using Salmon algorithm. Results: Of the 3443 FFPE samples, 38 (1.2%) samples showed alternative splicing involving deletion of exon 5 (PD-L1∆Ex5). The alternative splicing was in 2.10% of lung cancer, 2% of colon cancer, 0.70% of pancreatic cancer, 1.40% of gastric cancer, 0.38% of breast cancer, 0.30% of ovarian cancer, 1.10% of sarcoma cases, 1.50% of glioblastomas, 3.30% of thyroid cancer and 2% of urothelial cancer. Of the 532 cfRNA samples, 20 (3.7%) showed PD-L1∆Ex5. The median percentage of PD-L1∆Ex5 transcripts was 2.2% of total PD-L1 transcripts in tissue samples as compared with 6.6% in cfDNA samples. In tissue samples, there was a correlation between levels of PD-L1 and PD-L1∆Ex5 (r = .567, p &lt; .001). In contrast, cfRNA showed no significant correlation between levels of PD-L1 and levels of PD-L1∆Ex5 (r = .268). Conclusions: PD-L1 exon 5 skipping was detected in a number of patients with different types of solid tumor cancers. The percentage of skipping transcripts is low in cells and relatively higher in cfRNA. Since exon 5 skipping deletes the transmembrane domain, the PD-L1 protein may remain in the cytoplasm or perhaps is secreted as cell-free PD-L1 protein. The demonstration of relatively higher levels of PD-L1∆Ex5 in cfRNA is likely reflecting higher turnover of cells and raises the possibility that cells with this isoform of PD-L1 are more aggressive than cells without the expression of this isoform. Further studies are needed to explore the clinical relevance of the expression of such abnormal PD-L1 protein on treatment with immune checkpoint inhibitors.