tbuckley/cabot-search huggingface dataset:
Patient factors associated with time to medication receipt of oral anti-cancer drugs.
Authors: Morgan RL Lichtenstein, Melissa Beauchemin, Sahil Doshi, Rohit Raghunathan, Cynthia Law, Melissa Kate Accordino, Elena B. Elkin, Jason Dennis Wright, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2021)

1519 Background: The past decade has seen a dramatic increase in the number of Food and Drug Administration approvals of oral anti-cancer drugs (OACDs). Most OACD prescriptions require coordination between providers, payers, specialty pharmacists, and financial assistance organizations, which can delay drug receipt. We evaluated median time to OACD receipt (TTR) from initial OACD prescription submission and assessed clinical and process-related factors associated with TTR. Methods: We prospectively collected data on all new OACD prescriptions for adult oncology patients at a large, urban outpatient cancer center from 1/1/2018 to 12/31/2019. We collected patient demographic, medical, and insurance data; prescription submission and delivery dates; and interactions with payers and financial assistance groups. TTR was defined as the number of days from OACD initial prescription to patient receipt of the drug. We estimated the median TTR across all patients and used multivariable logistic regression to identify factors associated with TTR above the median. Results: The cohort included 1080 patients who were prescribed 1269 new OACDs. Of these prescriptions, 84% (N=1069) were received, and 71% (N=896) required prior authorization. The median patient age was 66, 44% identified as Non-Hispanic White (White), 25% of patients had commercial insurance, 16% had Medicaid alone, and 58% had Medicare alone or in combination with another plan. The median TTR per patient was 7 days (IQR 0 – 142; 25% ≥ 14 days and 5% ≥ 30 days). In unadjusted analyses, insurance and race/ethnicity were associated with TTR. Compared with patients covered by Medicaid, those with Medicare and supplemental insurance (a partial, not free-standing plan) had nearly 2.5 times the odds of TTR &gt;7 days controlling for other factors. Race/ethnicity showed a trend toward longer TTR with Non-Hispanic Black (Black) patients having a longer TTR compared to White patients, controlling for other factors. We did not observe statistically significant effects of either comorbidity or prior authorization requirement on TTR. Conclusions: Though the majority of oncology patients prescribed OACDs receive the drug, 71% of prescriptions required prior authorization and a quarter of patients waited at least two weeks. Disparities in TTR are primarily driven by financial factors, specifically insurance type.[Table: see text]
Impact of social determinants of health on a late diagnosis and survival of patients with pancreatic cancer.
Authors: Jesus C. Fabregas, Miranda Lam
Journal: Journal of Clinical Oncology (2021)

e18530 Background: While disparities in pancreatic cancer (PC) are documented, it is unclear whether these inequities occur at the time of diagnosis or throughout treatment. We hypothesize social determinants of health (SDH) such as income, education, race and insurance status are a) associated with a late diagnosis of PC (Stage IV vs Stages 0-III) and b) associated with overall survival (OS) in Stage IV patients. Methods: The National Cancer Database 2017 version was accessed. Primary outcome: diagnosis of Stage IV PC. Secondary outcome: OS. Primary predictors: race, income, education, insurance. Confounders: Charlson comorbidity score, age, sex. Univariate and multivariate regression models evaluated the association between SDH and a late diagnosis of PC. Univariate and multivariate Cox proportional hazards model examined OS. 95% Confidence Intervals were used. Results: 230,877 patients were included. Median 68 yrs, mean 67.3 SD(12.1). In univariate analysis, education (&gt;93% high school completion (HSC) vs &lt;82.4%, OR 0.93 [0.91 – 0.95]), income (&gt;$63,333 vs&lt;$40,277, OR 0.94 [0.92– 0.96]), and insurance (Private vs No, OR 0.70 [0.66 – 0.73]), decreased the odds of Stage IV PC. Black race was associated with higher odds of Stage IV PC (vs White, OR 1.11 [1.08 – 1.14]). In multivariate analysis, education and having insurance decreased the risk of a late diagnosis, whereas black race increased it (table). In univariate Cox analysis, higher income (&gt;$63,333 (vs&lt;$40,277), HR 0.82 [0.81– 0.83]), insurance (Private vs No, HR 0.77 [0.73 – 0.76]) and education (&gt;93% HSC vs &lt;82.4%, HR 0.87 [0.86 – 0.88]) improved OS. Black race was associated with poorer OS (vs White, HR 1.03 [1.02 – 1.05]). In multivariate Cox analysis, only higher income (&gt;$63,333 (vs&lt;$40,277), HR 0.87 [0.85 – 0.89]) and having insurance (Private vs No, HR 0.77 [0.74 – 0.79]) were associated with improved OS. Conclusions: SDH impacted the continuum of pancreatic neoplasia care, from diagnosis to treatment. Expanding insurance coverage could be an effective public health intervention to improve early diagnosis and survival rates.[Table: see text]
VISTA is an activating receptor in human monocytes
Authors: Bryan M. Rogers, Laura Smith, Zoltan Dezso, Xu Shi, Enrico DiGiammarino, Denny Nguyen, Sunantha Sethuraman, Pingping Zheng, Donghee Choi, Dong Zhang, Andrew Nguyen, Kathleen McGuire, Wei Liu, Namjin Chung, Debra T. Chao, Shiming Ye, Gabriel R. Starbeck-Miller
Journal: The Journal of Experimental Medicine (2021)

As indicated by its name, V-domain Ig suppressor of T cell activation (VISTA) is thought to serve primarily as an inhibitory protein that limits immune responses. VISTA antibodies can dampen the effects of several concomitantly elicited activation signals, including TCR and TLR activation, but it is currently unclear if VISTA agonism could singly affect immune cell biology. In this study, we discovered two novel VISTA antibodies and characterized their effects on human peripheral blood mononuclear cells by scRNA/CITE-seq. Both antibodies appeared to agonize VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. We also used pentameric VISTA to identify Syndecan-2 and several heparan sulfate proteoglycan synthesis genes as novel regulators of VISTA interactions with monocytic cells, adding further evidence of bidirectional signaling. Together, our study highlights several novel aspects of VISTA biology that have yet to be uncovered in myeloid cells and serves as a foundation for future research.
An international multicenter matched cohort analysis of incidental meningioma progression during active surveillance or after stereotactic radiosurgery: the IMPASSE study
Authors: Jason Sheehan, Stylianos Pikis, Abdurrahman I Islim, Ching-Jen Chen, Adomas Bunevicius, Selcuk Peker, Yavuz Samanci, Ahmed M Nabeel, Wael A Reda, Sameh R Tawadros, Amr M N El-Shehaby, Khaled Abdelkarim, Reem M Emad, Violaine Delabar, David Mathieu, Cheng-Chia Lee, Huai-Che Yang, Roman Liscak, Jaromir Hanuska, Roberto Martinez Alvarez, Dev Patel, Douglas Kondziolka, Nuria Martinez Moreno, Manjul Tripathi, Herwin Speckter, Camilo Albert, Greg N Bowden, Ronald J Benveniste, Lawrence Dade Lunsford, Michael D Jenkinson
Journal: Neuro-Oncology (2021)

The optimal management of patients with incidental meningiomas remains unclear. The aim of this study was to characterize the radiologic and neurological outcomes of expectant and stereotactic radiosurgery (SRS) management of asymptomatic meningioma patients.Using data from 14 centers across 10 countries, the study compares SRS outcomes to active surveillance of asymptomatic meningiomas. Local tumor control of asymptomatic meningiomas and development of new neurological deficits attributable to the tumor were evaluated in the SRS and conservatively managed groups.In the unmatched cohorts, 727 meningioma patients underwent SRS and were followed for a mean of 57.2 months. In the conservatively managed cohort, 388 patients were followed for a mean of 43.5 months. Tumor control was 99.0% of SRS and 64.2% of conservatively managed patients (P < .001; OR 56.860 [95% CI 26.253-123.150]). New neurological deficits were 2.5% in the SRS and 2.8% of conservatively managed patients (P = .764; OR 0.890 [95% CI 0.416-1.904]). After 1:1 propensity matching for patient age, tumor volume, location, and imaging follow-up, tumor control in the SRS and conservatively managed cohorts was 99.4% and 62.1%, respectively (P < .001; OR 94.461 [95% CI 23.082-386.568]). In matched cohorts, new neurological deficits were noted in 2.3% of SRS-treated and 3.2% of conservatively managed patients (P = .475; OR 0.700 [95% CI 0.263-1.863]).SRS affords superior radiologic tumor control compared to active surveillance without increasing the risk of neurological deficits in asymptomatic meningioma patients. While SRS and active surveillance are reasonable options, SRS appears to alter the natural history of asymptomatic meningiomas including tumor progression in the majority of patients treated.
Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer.
Authors: Justin Wayne Wong Tiu-lim, Jun Yin, Joanne Xiu, Wolfgang Michael Korn, Heinz-Josef Lenz, Gino Kim In, Evanthia T. Roussos Torres, Janice M. Lu, Darcy V. Spicer, Bing Xia, Dave S. B. Hoon, Elisa Krill-Jackson, Arielle Lutterman Heeke, Sarah Sammons, Claudine Isaacs, Foluso Olabisi Ademuyiwa, Cynthia X. Ma, Antoinette R. Tan, Irene Kang
Journal: Journal of Clinical Oncology (2021)

1034 Background: The Ras-MAPK pathway is a known driver of tumorigenesis and therapeutic target in a variety of cancers. Alterations in this pathway have been linked to decreased tumor immunogenicity. However, molecular alterations in the Ras-MAPK are rare in breast cancer (BC) and their clinical implications remain unclear. As mutational status does not accurately correlate with transcriptional activity, a MAPK pathway activity score (MPAS, Wagle et al., 2018, npj Precision Medicine) is indicative of MAPK activation and correlates with response to MEK (MEKi) or BRAF inhibition (BRAFi). Our goal was to determine the frequency of molecular alterations in the Ras-MAPK and correlate to MAPK pathway activation in MBC. Methods: A total of 6464 BC samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS and immune cell fraction (ICF, Quantiseq) were assessed by mRNA analysis. Wilcoxon, Fisher’s exact, or Dunnett’s test was used. All results shown were statistically significant (p &lt; 0.05). Results: The predominant alteration of RAS genes was mutation followed by amplification, no fusions were detected (Table). Only 0.17% of all tumors harbor KRAS G12c mutations. The highest MPAS scores were found in KRAS mutants (mut), HRAS mut (Q61, G1213), BRAF V600 (class 1) mut and NRAS Q61 mut (Table) and therefore used to define Genomic MAPK Activated Tumors (GMAT). GMAT compared to wild type (WT) had significantly higher PD-L1 expression, TMB and MSI/dMMR. GMAT had less B cells (3.4% vs 4.4%), more M1 Macrophages (4.4% vs 3.4%) and neutrophils (5.5% vs 2.7%) regardless of HR status but less NK cells (2.3% s 3.0%), MSDCs (0.9% vs 3.0%) only in HR- tumors with respect to WT. GMAT tumors showed more frequent mutation rate (mr) of PIK3CA (HR+: 57.3% vs 40%; HR-: 41.9% vs 17.9%). HR+ tumors had a higher mr of MSH3 (11.8% vs 0.6%) while HR- tumors had higher mr of PIK3R1 (9.6% vs 3.8%), RhoA (5.3% vs 0.5%), DNA repair genes (TERT, 18.2% vs 1.0%; ARID1A, 18.2% vs 5.9%; PRKDC, 3.9% vs 0) and lower TP53 mr (54.5% vs 85.8%) compared to WT. Conclusions: Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi. GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.[Table: see text]
Baseline and short-term financial burden (FB) in colorectal cancer (CRC) treated with curative intent: Early results of ECOG-ACRIN EAQ162CD.
Authors: Sheetal Mehta Kircher, Fenghai Duan, Ilana F. Gareen, Ellen Underwood, Jorean Sicks, Jennifer Marie Marie Suga, Heather Kehn, Paul Tracy Mehan, Jared David Acoba, Michael A Taylor, Lynne I. Wagner, Ruth Carlos
Journal: Journal of Clinical Oncology (2021)

1518 Background: Cancer therapy costs continue to rise, resulting in FB. FB in CRC treated with curative intent remains unexplored, particularly in the community oncology setting. We assess baseline FB and 3-month change, including predictors. Methods: Patients with newly diagnosed CRC treated with curative intent were enrolled through NCI Community Oncology Research Program (NCORP) Community Sites in a longitudinal study and completed the validated FACIT Comprehensive Score for Financial Toxicity (COST) instrument at baseline and 3 months. Higher COST score (range 0-44) indicates greater financial well-being. Pearson correlation compared baseline and 3-month measurements. Effects of patient demographics, clinical, self-efficacy variables (Table) and practice safety net affiliation were assessed using linear regression for baseline COST and COST difference at 3 months. F-tests identified covariates significantly predicting FB. Results: 450 and 296 participants completed the baseline and 3-month survey with a mean COST score 23.5 ± 11.9 and 24.6 ± 12.4, respectively (r=0.80, p&lt;0.001), considered grade 1 or mild. Financial resource indicators such as income, insurance type, high-deductible insurance and savings, along with self-efficacy strongly predicted baseline FB (Table). No assessed covariates predicted COST difference. Safety-net affiliation (54/450, 12%) did not predict COST outcomes. Conclusions: Among those with CRC treated with curative intent in community settings, FB at treatment initiation and 3-month follow-up are highly correlated. Financial resources predict FB at treatment initiation. Self-efficacy to manage finances predicted FB, suggesting interventions such as financial counseling and navigation delivered early in the treatment course may minimize downstream FB. Clinical trial information: NCT03516942. [Table: see text]
Abstract DP-015: BIOTINYLATED ESTROGENS A NOVEL TOOL FOR EARLY DETECTION OF ADDUCT IN OVARIAN CANCER
Authors: Kaushlendra Tripathi, Chinnadurai Mani, David W. Clark, Komaraiah Palle
Journal: Clinical Cancer Research (2019)

Abstract Elevated estrogens exert their carcinogenic effects by at least three different mechanisms; they promote cell proliferation by transcriptional regulation of estrogen responsive genes, cause generation of reactive oxygen species and other free radicals, and directly react with DNA and form potentially mutagenic adducts. However, unbalanced estrogen metabolism has been linked to development of several malignant diseases including breast, endometrial and ovarian cancer and has been identified as a risk factor for these cancers. The metabolic breakdown of estogens is regulated by a series of reactions mediated by hepatic and peripheral enzymes that balances the induction and reduction of cellular stress. An imbalance in this enzymes and processes can lead to highly reactive catechol estrogen metabolites that can react with DNA, form carcinogenic DAN-adducts and lesions. Although several studies established a connection between estrogen-induced DNA damage and carcinogenesis, the underlying molecular mechanisms have been difficult to study because of the technical challenges in detecting and analyzing the variety of different DNA lesions that are formed by estrogen compounds. Moreover, detection and analysis of these adducts are important to directly monitor estrogen metabolites induced cellular responses in the cells. Towards this, we developed a novel method using biotinylated-estrogens that allows immunodetection of estrogen-induced DNA adducts by Slot-blot and single-cell molecular combing and proximity ligation assays. Using these modified estrogens we first time quantitatively detected these adducts on DNA by immune Slot-blot techniques and on DNA fibers. Furthermore, similar to other environmental carcinogens estrogens activates replication associated DNA damage responses and induces chromosomal instability. Hence, first time our studies demonstrate that biotin-labeled estrogens could be a powerful tool to detect estrogen adducts and to probe associated DNA damage responses and cellular responses. Citation Format: Kaushlendra Tripathi, Chinnadurai Mani, David W. Clark, Komaraiah Palle. BIOTINYLATED ESTROGENS A NOVEL TOOL FOR EARLY DETECTION OF ADDUCT IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-015.
Identification of patients at high risk for preventable emergency department visits and inpatient admissions after starting chemotherapy: Machine learning applied to comprehensive electronic health record data.
Authors: Dylan J. Peterson, Nicolai P. Ostberg, Douglas W. Blayney, James D. Brooks, Tina Hernandez-Boussard
Journal: Journal of Clinical Oncology (2021)

1511 Background: Acute care use is one of the largest drivers of cancer care costs. OP-35: Admissions and Emergency Department Visits for Patients Receiving Outpatient Chemotherapy is a CMS quality measure that will affect reimbursement based on unplanned inpatient admissions (IP) and emergency department (ED) visits. Targeted measures can reduce preventable acute care use but identifying which patients might benefit remains challenging. Prior predictive models have made use of a limited subset of the data available in the Electronic Health Record (EHR). We hypothesized dense, structured EHR data could be used to train machine learning algorithms to predict risk of preventable ED and IP visits. Methods: Patients treated at Stanford Health Care and affiliated community care sites between 2013 and 2015 who met inclusion criteria for OP-35 were selected from our EHR. Preventable ED or IP visits were identified using OP-35 criteria. Demographic, diagnosis, procedure, medication, laboratory, vital sign, and healthcare utilization data generated prior to chemotherapy treatment were obtained. A random split of 80% of the cohort was used to train a logistic regression with least absolute shrinkage and selection operator regularization (LASSO) model to predict risk for acute care events within the first 180 days of chemotherapy. The remaining 20% were used to measure model performance by the Area Under the Receiver Operator Curve (AUROC). Results: 8,439 patients were included, of whom 35% had one or more preventable event within 180 days of starting chemotherapy. Our LASSO model classified patients at risk for preventable ED or IP visits with an AUROC of 0.783 (95% CI: 0.761-0.806). Model performance was better for identifying risk for IP visits than ED visits. LASSO selected 125 of 760 possible features to use when classifying patients. These included prior acute care visits, cancer stage, race, laboratory values, and a diagnosis of depression. Key features for the model are shown in the table. Conclusions: Machine learning models trained on a large number of routinely collected clinical variables can identify patients at risk for acute care events with promising accuracy. These models have the potential to improve cancer care outcomes, patient experience, and costs by allowing for targeted preventative interventions. Future work will include prospective and external validation in other healthcare systems.[Table: see text]
Prevalence of inferred clonal hematopoiesis (CH) detected on comprehensive genomic profiling (CGP) of solid tumor tissue or circulating tumor DNA (ctDNA).
Authors: Emmanuel S. Antonarakis, Zheng Kuang, Hanna Tukachinsky, Christine Parachoniak, Andrew David Kelly, Ole Gjoerup, Aparna Aiyer, Eric Allan Severson, Dean C. Pavlick, Garrett M. Frampton, Jeffrey Michael Venstrom, Geoffrey R. Oxnard
Journal: Journal of Clinical Oncology (2021)

3009 Background: The increased use of ctDNA CGP has paralleled increased detection and interest in CH, which can confound CGP results from ctDNA or tissue, and can be associated with hematologic and cardiovascular morbidity. However, paired-depth sequencing of white blood cells (WBC) for confirmation of CH is not widely available. We here study the prevalence of inferred CH (iCH), which refers to incidental detection on routine clinical CGP of variants attributable to CH due to their known CH association and their negligible prevalence in solid tumors. Methods: A database of clinical CGP results was reviewed, including two 324-gene NGS panels for tumor tissue (FoundationOne CDx) and plasma ctDNA (FoundationOne Liquid CDx). Analysis was limited to NSCLC, breast, prostate, colorectal, and pancreatic cancers. iCH was defined as any pathogenic mutation in ASXL1, DNMT3A, and TET2, and prespecified mutations in JAK2, SF3B1, U2AF1, MYD88, IDH2, MPL, CBL. Variant allelic frequency (VAF) &gt; 2% was considered clinically significant and VAF &gt; 10% was considered high risk. Results: 100,905 total cases were studied; median age was 65 for tissue CGP and 68 for ctDNA. iCH was more commonly detected in ctDNA (1468/2891, 51%) than in tissue (9416/97993, 10%). Among cases with any iCH detected, multiple iCH mutations were seen more commonly in ctDNA (640/2891, 22%) than in tissue (987/98014, 1%). Focusing on clinically significant iCH ( &gt; 2% VAF), prevalence remained higher in ctDNA (22%, 637) than in tissue (8%, 7878), while the higher sensitivity of ctDNA testing identified more low level iCH (&lt; 2% VAF, 40% in ctDNA, 2% in tissue). Across cancer types, iCH &gt; 2% was consistently more common in ctDNA (Table). As expected, prevalence of iCH &gt; 2% increased with age (continuous variable, p &lt; 0.001). High risk iCH ( &gt; 10% VAF) was seen in 4% of total cases (most commonly ASXL1, TET2, DNMT3A); 1% of all cases had multiple clinically significant iCH variants ( &gt; 2% VAF). Focusing on a subset of 439 cases with both tissue and ctDNA results (median 1.5 months between samples), 290 iCH mutations were detected in ctDNA (median VAF 1%) but only 38 in tissue (median VAF 9%). Conclusions: Inferred CH is common on somatic CGP of cancer patients, with a high prevalence in ctDNA likely due to the deeper sequencing depth and WBC contamination. For the minority of patients with high VAF iCH, further research is needed to understand whether this might be representative of an occult hematologic condition deserving of further evaluation.[Table: see text]