bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resource utilization and total cost of care among Medicare advantage patients with metastatic pancreatic cancer receiving NCCN category 1 preferred regimens.
Authors: Dieguez Gabriela , Tomicki Samantha , DeStephano David , Hsu Benjamin , Cockrum Paul 
Published: January 2022

531 Background: Medicare Advantage accounts for almost 40% of Medicare beneficiaries in 2021. There is limited research evaluating utilization and cost for Medicare Advantage patients with metastatic pancreatic cancer (m-PANC) receiving various NCCN Category 1 preferred regimens. Methods: We used ICD-10 diagnosis codes to identify patients with m-PANC without end-stage renal disease in the 2016-2019 Milliman Consolidated Health Cost Guidelines Sources Database (CHSD) claims files. Study patients had 2+ claims with a pancreatic cancer diagnosis and Medicare Advantage coverage for 3 months pre- and 1 month post-metastasis diagnosis. Patients with stand-alone Part D plan coverage or aged<65 years were excluded. Total cost of care (TCOC) was the sum of the average paid by the insurer and patient. Study patients were treated with NCCN Category 1 preferred regimens: 1L gemcitabine/nab-paclitaxel (gem/nab), 1L gemcitabine monotherapy (gem mono), 1L FOLFIRINOX (FFX), and 2L+ liposomal irinotecan (5FU was not included in this analysis; see Limitations for further details). Results: Of the approximately 2.5 million patients covered by Medicare Advantage in CHSD, there were 946 patients that received an NCCN Category 1 chemotherapy regimen between 2016 and 2019. Among NCCN Category 1 preferred regimens, patients receiving 2L+ liposomal irinotecan had the lowest mean admissions per beneficiary and mean readmission rate (0.5 and 8%) compared to patients receiving gem/nab (0.8 and 12%), gem mono (0.6 and 8%), or FFX (0.6 and 9%). Patients receiving 2L+ liposomal irinotecan also had the shortest length of stay per inpatient admission in days (2.9) compared to patients receiving gem/nab (5.1), gem mono (3.6), or FFX (4.3). Mean claims per beneficiary for emergency department observations was lowest among patients receiving 2L+ liposomal irinotecan (0.7), compared to patients receiving gem/nab (0.9), gem mono (1.0), or FFX (0.89). Patients receiving 2L+ liposomal irinotecan had lower median TCOC ($31,885) than patients receiving gem/nab ($39,479) or FFX ($32,632). Conclusions: Patients with Medicare Advantage receiving 2L+ liposomal irinotecan-based regimens to treat m-PANC had lower healthcare resource utilization in key categories and lower median total costs than patients receiving other NCCN Category 1 preferred regimens. Limitations: Analysis of different populations or time periods may yield different results. Our study used claims data and not electronic health records (EHRs), so we could not control for clinical covariates. Patient characteristics and regimen performance might influence which regimens patients receive. We did not adjust TCOC or utilization for LOT durations. We did not study whether liposomal irinotecan-based therapy patients received concomitant 5FU or prior gemcitabine-based therapy.
Pancreatic cancer detection using 5-hydroxymethylation signatures in plasma-derived cell free DNA in high-risk patients with new onset diabetes.
Authors: Haan David , Guler Gulfem , Bergamaschi Anna , Volkmuth Wayne , Levy Samuel 
Published: January 2022

539 Background: Pancreatic cancer (PaCa) is the third leading cause of cancer death in the United States despite a low incidence rate. It is often diagnosed when cancer has already metastasized to distant organs. Late diagnosis deprives patients of potentially curative treatments such as surgery and impacts survival rates. People with new onset diabetes (NOD) are at 6-8 fold increased risk for PaCa compared to the general population. Indeed, 0.85% of patients with NOD will be diagnosed with PaCa within 3 years. This population of PaCa patients with NOD constitute 25% of all new pancreatic cancer diagnoses. Surveillance of the NOD population for PaCa presents an opportunity to shift PaCa diagnosis to earlier stage. Methods: Whole blood was obtained from a cohort of 167 PaCa patients and 490 patients with cancers other than PaCa as well as 836 non-cancer controls with and without NOD. Plasma was processed to isolate cfDNA and 5hmC libraries were generated and sequenced. 5hmC data is used to generate models for PaCa detection using Bluestar Genomics’s technology platform. Results: To investigate whether PaCa can be detected in plasma, we interrogated plasma-derived cfDNA hydroxymethylation in PaCa patients and non-cancer controls. Models trained using 5hmC-based biomarkers from cfDNA consistently performed with a mean test sensitivity of 61.1% [95% confidence interval (CI): 35.7% to 82.7%] and a test specificity of 97.6% (CI: 93% to 99.5%) measured across 50 cross validation iterations within the training data set, which was composed of 48.3% early stage (Stages I & II) disease. The final model was trained using all of the training data, yielding 58.4% (CI: 47.5% to 68.8%) sensitivity at 98% (CI: 96.5% to 99.0%) specificity. This model was then tested on an independent test set with 22 PaCa patients (51.7% early stage, 15 of which was NOD) and 123 non-cancer control patients (53 of which were NOD) and yielded a classification performance of 59.1% (CI: 36.4% to 79.3%) sensitivity at 95.9% (CI: 90.8% to 98.7%) specificity. The model performance in the subset of patient cohort with NOD was 53.3% (CI: 26.6% to 78.7%) sensitivity at 94.3% (CI: 84.3% to 98.8%) specificity. Lastly, sensitivity observed on an independent validation set, composed of 56 PaCa and 117 ITTP samples, was 46.4% (CI: 33.0% to 60.2%) with 100% (CI: 96.8 to 100%) specificity. Conclusions: Our results demonstrate PaCa detection in plasma-derived cfDNA using 5hmC profiles. Overall, the model performed consistently between the training and independent validation datasets. A larger clinical study is under development to clinically validate the model described in this study with the goal of identifying occult PaCa within the NOD population in order to enable earlier detection and thus improve patient outcomes.
Efficacy of SBP-101, a polyamine metabolic inhibitor, administered in combination with gemcitabine and nab-paclitaxel, as a first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Singhal Nimit , Sigal Darren , Tebbutt Niall C. , Hezel Aram F , Nagrial Adnan , Lumba Sumit , George Thomas J. , Smith Sheri Lynn , Gagnon Suzanne , Cullen Michael T. , Walker Michael 
Published: January 2022

575 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A 4th cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for Phase 1b expansion. Results: Fifty patients were enrolled (N=25, Phase 1a and N=25, Phase 1b) and received up to 13 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=14), LFT/transaminase abnormalities (N=15), vision abnormalities (N=10), injection site pain (N=13), dehydration (N=7), nausea (N=7). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N=6) and retinal toxicity (N=8) both occurring after prolonged treatment and requiring dose reduction or discontinuation. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 1/29 (3%) achieving a complete remission 13/29 achieving partial responses (45%) and 10/29 achieving stable disease at 8 weeks (35%). PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Sixteen subjects are in survival follow-up. Median OS is 10.1 months and is not final. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. A vision screening program will be used in future studies to mitigate retinal toxicity. Clinical trial information: NCT03412799.
Understanding extended duration of therapy (DOT) among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens.
Authors: Mokrzecky Cheryl , Cockrum Paul , Surinach Andy , Becerra Carlos Roberto 
Published: January 2022

579 Background: Few analyses have identified characteristics associated with extended DOT (eDOT) among a large group of patients (pts) treated with liposomal irinotecan. This study examines the characteristics associated with eDOT among pts with mPDAC treated with liposomal irinotecan in a real-world setting. Methods: This retrospective observational study utilized the Flatiron Health EHR database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan-based regimens between January 2016 and October 2020. eDOT was defined as a DOT > 2 standard deviations (SD) above the mean. Demographic and clinical characteristics evaluated included age, sex, stage at diagnosis, ECOG performance score (PS), and the number of prior lines of therapy at the time of treatment initiation. Dose delays and dose reductions during treatment were assessed. Additionally, changes in lymphocyte counts during treatment were described. Chi-squared test and Fisher’s exact test were used to test for significance for categorical variables and the t-test was used for continuous variables. Results: 675 pts with mPDAC treated with a liposomal irinotecan-based regimen were included. The overall mean DOT was 14.6 weeks (SD: 22.1). There were 30 pts (4.4%) that met the definition for eDOT. Patient sex and median age at treatment initiation were similar between those with eDOT and non-eDOT: male, 46.7% vs. 51.9% (p = 0.582); age, median 70 years vs 69 years (p = 0.923), respectively. A higher proportion of pts with eDOT had ECOG PS of 0-1 compared to those with non-eDOT, 73.3% vs 57.7%, respectively (p = 0.397). At treatment initiation 80.0% of pts who had eDOT had a serum albumin level of ≥ 35g/L versus 55.2% of pts with non-eDOT (p = 0.013). On average, those with eDOT experienced a 55.1% reduction in lymphocyte count (baseline to nadir) during treatment compared to a 34.7% reduction among pts with non-eDOT (p < 0.0001). Pts who experienced eDOT were more likely to be treated in earlier lines of therapy than those with non-eDOT: 33.3% vs 14.1% received 0 prior lines and 46.7% vs 47.3% received 1 prior line, respectively (p = 0.008). 53.3% of pts with eDOT experienced a dose reduction (of at least 7mg/m2) compared to 24.7% pts with non-eDOT (p = 0.0005). All pts with eDOT experienced a dose delay of > 16 days during treatment versus 45.3% of pts with non-eDOT (p < 0.0001). Conclusions: This real-world study identified pts treated earlier in their disease course with a liposomal irinotecan-based regimen and normal baseline serum albumin were more likely experience extended DOT. Treatment modifications and delays appear to have enabled longer treatment duration with liposomal irinotecan-based regimens. Further prospective studies should be considered to characterize factors that may predict extended DOT.
Detection of circulating DNA methylated BCAT1 and IKZF1 in pancreatic adenocarcinoma.
Authors: Winter Jean M. , Sheehan-Hennessy Lorraine , Pedersen Susanne Kartin , Young Graeme P. , Symonds Erin L. 
Published: January 2022

597 Background: Pancreatic adenocarcinoma patients have poor survival outcomes and there are no non-invasive tests to aid diagnosis or therapy. Detection of circulating tumour DNA (ctDNA) methylated for BCAT1 and/or IKZF1 is over 60% sensitive for colorectal adenocarcinoma. Both pancreatic and colorectal adenocarcinomas are of endodermal origin, therefore, these methylated biomarkers might also have utility in detecting pancreatic cancer. The aim of this study was to investigate whether individuals with pancreatic adenocarcinoma have detectable methylated BCAT1 and IKZF1 DNA in circulation. Methods: In this pilot study, pre-treatment blood and clinicopathological findings were collected from 21 patients diagnosed with pancreatic adenocarcinoma. DNA isolated from plasma was bisulfite-converted and assayed for methylated BCAT1, IKZF1 and a non-methylated region in ACTB (for yield estimates). Samples with methylation in either gene was deemed positive. Chi -squared test was used to compare positivity between Stage I/II and Stage III/IV cases. The sum of percent (%) methylation ([average BCAT1]+[average IKZF1])/average ACTB) ± standard error was compared between stages using Kruskal-Wallis rank test. Results: 10/21 (47.6%) patients were positive for methylated BCAT1 and/or IKZF1. There was a trend of increasing positivity with advancing stage (Stage I/II 2/8 (25.0%) vs Stage III/IV 8/13 (61.5%, p=0.104)), and for higher % methylation with more advanced disease (Stage II 0.01%±0.004 vs Stage IV 5.0%±3.7, p=0.06). No other comorbidities or demographics were associated with positivity. Conclusions: Assay for methylated BCAT1 and IKZF1 ctDNA detects approximately two-thirds of late-stage pancreatic adenocarcinoma. Future studies are warranted to assess the clinical utility of these biomarkers for detection and monitoring of pancreatic cancer. Clinical trial information: 12616001138471.
Real-world use of PARP inhibitors in BRCA1/2-mutated pancreatic cancer: A retrospective analysis.
Authors: Amin Suvina , Li Weiyan , Joo Seongjung , Adeboyeje Gboyega , DeArbeloa Patricia , Petricoin Emanuel , Blais Edik Matthew , Pishvaian Michael J. 
Published: January 2022

599 Background: BRCA1 or BRCA2 mutations can be found in approximately 6 to 8 percent of patients patients with metastatic pancreatic adenocarcinoma (mPaC). Olaparib is the only PARP inhibitor (PARPi) approved in the EU and the US as maintenance treatment for biomarker-selected patients with mPaC in the 1st line platinum-sensitive setting. However, treatment sequencing can be heterogeneous, and there is a lack of real-world data on patterns of PARPi use in relation to platinum use in BRCA1/2-mutated mPaC. Methods: Longitudinal records collected between 1/2012-12/2020 were analyzed for a cohort of 55 mPaC patients with BRCA1 or BRCA2 mutations identified by commercial NGS testing who enrolled in Perthera’s US real-world observational registry study. Treatment patterns including PARPi utilization and platinum-sensitivity (16 weeks without progression at any point within known history) were abstracted via physician notes across all lines of therapy. Results: PARPi use was documented in 60% (N=33) of 55 patients with BRCA1/2-mutated mPaC in any treatment setting. Within this cohort, 21 patients received a single agent PARPi outside of clinical trials. Among these patients, only 38% (8 of 21) transitioned to a PARPi in a platinum-sensitive context, and only 14% (3 of 21) of these transitions occurred before 2nd line. Notably, 6 patients received a PARPi in the platinum-resistant setting. Within the broader cohort, platinum-sensitive criteria was fully met for 73% (40 of 55); however, only 49% (27 of 55) reached this milestone of platinum-sensitivity prior to initiating a 2nd line therapy. Conclusions: The majority of these BRCA1/2-mutated patients received a PARPi-based therapy in a variety of contexts with respect to line of therapy and prior platinum history. These findings highlight the value of upfront genetic and molecular testing and the need for further exploration to identify factors associated with treatment response as well as optimized treatment sequencing.
Genomic classification of clinically advanced pancreatic ductal adenocarcinoma (PDAC) based on methylthioadenosine phosphorylase (MTAP) genomic loss (MTAP loss).
Authors: Ngoi Natalie , Scholefield Emma L. , Parini Vamsi , Huang Richard S.P. , Janovitz Tyler , Danziger Natalie , Levy Mia Alyce , Pant Shubham , Javle Milind M. , Ross Jeffrey S. , Rodon Ahnert Jordi 
Published: January 2022

604 Background: MTAP loss is represented across a wide variety of cancer types including PDAC and is an emerging target for synthetic lethality-based cancer therapies. Preclinically, MTAP loss leads to the accumulation of 2-methylthioadenosine, reduced protein arginine N-methyltransferase 5 (PRMT5) methylation activity and increased vulnerability to targeting of the methionine adenosyltransferase IIα (MAT2A)/ PRMT5 axis. In addition, 9p21 loss, homozygous co-deletion of MTAP/CDKN2A or homozygous deletion of either gene have been associated with an immunologically “cold” tumor microenvironment, primary resistance to anti PD(L)1 immunotherapy (IO) and poor prognosis phenotype (Han G, Nat Commun 2021). We investigated concurrent mutations and immune biomarkers in clinical PDAC samples with MTAP-loss versus -intact status. Methods: From a series of 177705 consecutive cases, we performed comprehensive genomic profiling on 9423 cases of PDAC using an FDA-approved assay (F1CDx) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by immunohistochemistry (Dako 22C3). Furthermore, we correlated pertinent findings within a database of 16558 cases of clinically advanced cancer with MTAP loss. Results: 2003 (21.3%) of 9423 PDAC demonstrated MTAP-loss. Similar gender, age and number of GA per tumor were observed between MTAP-loss and -intact groups. Frequencies of TP53, CDKN2A/B, SMAD4, PTEN and ARID1A were significantly higher in MTAP-loss PDAC. However, previously-described biomarkers of IO efficacy (MSI, TMB, CD274 amplification and PD-L1 expression) and resistance ( STK11, KEAP1 and MDM2) were infrequent and similar in both groups. The frequencies of other potentially targetable GA including BRCA1/2, ATM, KRAS G12C, ERBB2, BRAF, FGFR1, NF1 and PIK3CA were also infrequent and similar in both groups of PDAC patients. Amongst a database of 16558 cases of clinically advanced cancer with MTAP loss, 1538 (9.3%) featured co-alterations in MTAP and SMAD4. 52% of the MTAP/SMAD4 co-altered cases were PDAC. Conclusions: MTAP loss is associated with a distinctive concurrent genomic profile in PDAC and represents a potential new synthetic lethality-based opportunity for treatment with PRMT5 and MAT2A inhibitors. Furthermore, MTAP loss may represent an independent negative predictive biomarker for immune checkpoint inhibition in PDAC.[Table: see text]
A multi-modular phase I/II study of UCB6114, a first-in-class, fully human IgG4P anti-Gremlin-1 monoclonal antibody, as monotherapy and in combination with mFOLFOX6 or trifluridine/tipiracil, for patients with advanced gastrointestinal (GI) tumors.
Authors: Sarker Debashis , Banerji Udai , Blagden Sarah Patricia , Cook Natalie , Evans T.R. Jeffry , Plummer Elizabeth Ruth , Braun Marina , Cleverly Ann , Diaz Nieves , Jones Paul , Matthews Ivan , Glatt Sophie 
Published: January 2022

TPS221 Background: Despite recent advances, effective treatment for GI cancers remains a significant unmet medical need. Gremlin-1 is secreted by the peri-tumoral stroma and down-regulates bone morphogenetic proteins (BMP) -2, -4, and -7 (members of the transforming growth factor-β superfamily), thereby allowing malignant cell expansion, renewal, and a more treatment-resistant mesenchymal phenotype. Gremlin-1 mRNA is highly expressed in multiple solid tumors including >60% of colorectal, pancreatic and esophageal cancers. UCB6114 is a first-in-class, fully human IgG4P monoclonal antibody optimized for neutralizing the activity of human Gremlin-1 thereby restoring BMP signaling. Preclinical studies have demonstrated that UCB6114 binds to Gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in vivo mouse models (including several GI cancers). Methods: ONC001 (clinicaltrials.gov: NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study evaluating the safety, pharmacokinetics (PK) and antitumor activity of UCB6114 administered intravenously as monotherapy or in combination with selected standard of care (SOC) regimens. Eligible patients (pts) are: aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. In the Phase I monotherapy dose escalation and adaption part (part A and A1; modified rolling 6 design), up to 66 pts with advanced solid tumors associated with high levels of Gremlin-1 mRNA expression will be recruited. In parts B and C (modified toxicity probability interval design), up to 54 pts with locally advanced or metastatic colorectal, gastric or gastroesophageal junction adenocarcinomas will receive UCB6114 in escalating doses in combination with either mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) or trifluridine/tipiracil, given at SOC dosing and schedules. The overarching objective of the phase I parts of the study (Parts A‒C) is to identify the recommended phase II dose of UCB6114 either as monotherapy or in combination. The primary objective is to characterize the safety profile of UCB6114; secondary and exploratory objectives include PK, antitumor activity (RECIST v1.1), and pharmacodynamics (including circulating Gremlin-1). Enrollment in ONC001 began in July 2020; as of Sept 2021, four dose escalation levels in the monotherapy dose-escalation module (Part A) have been completed without DLT. Recruitment to parts B and C is due to commence in Q4 2021. Clinical trial information: NCT04393298.