bluuebunny/crossref_metadata_2025_split huggingface dataset:
ARC-8: Phase 1/1b randomized study of quemliclustat + gemcitabine/nab-paclitaxel ± zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma.
Authors: Wainberg Zev A. , Manji Gulam Abbas , Bahary Nathan , Ulahannan Susanna Varkey , Pant Shubham , Uboha Nataliya Volodymyrivna , Oberstein Paul Eliezer , Lu Lawrence H , Scott Jennifer R. , Wu Wilson , Rhee Joon , Nuyten Dimitry S. A. , O'Reilly Eileen Mary 
Published: January 2024

665 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) remains a challenging cancer to treat, with median survival of <1 year. In PDAC, extracellular adenosine (eADO) produced from ATP is released from tumor cells and suppresses antitumor immune responses. Quemliclustat (Q) is a potent and selective small-molecule inhibitor of soluble and cell-bound CD73, a key enzyme involved in the production of eADO within the tumor microenvironment. Elevated CD73 expression is found in 40-60% of PDAC and correlates with poor clinical outcome. ARC-8 evaluated Q ± anti-PD-1 antibody zimberelimab (Z) in combination with gemcitabine/nab-paclitaxel (G/nP). Methods: ARC-8 (NCT04104672) is a phase 1b dose escalation and expansion study in patients (pts) with treatment-naive mPDAC. Q 100mg was previously determined as the recommended dose for expansion (Manji et al., 2021). Q 100 mg is administered with standard doses of G/nP with Z (240 mg IV Q2W) in the dose expansion (Cohort A; QZ+G/nP) and in randomized (2:1) cohorts either with Z (Cohort A1; QZ+G/nP) or without Z (Cohort A2; Q+G/nP). Adverse events (AEs) are recorded and graded per NCI CTCAE 5.0. Clinical activity is assessed every 8 weeks per RECIST v1.1. Endpoints include measures of safety and median overall survival (OS). Results: As of June 19, 2023, 122 patients with untreated mPDAC were treated with Q 100mg, including 93 pts treated with QZ+G/nP (dose escalation, n=6; cohort A, n=26; and randomized cohort A1, n=61) and 29 pts treated with Q+G/nP (Cohort A2). Median age was 66 years, 66% ECOG of 1, and 65% had liver metastasis at baseline. Median survival follow-up was 21 months (mos). Efficacy is summarized in Table 1. All patients reported AE, 85% Grade 3+ AE, and 23% discontinued study treatment due to AE. Most common Grade 3+ AE was neutrophil count decreased (31%) and anemia (25%). Conclusions: Results from ARC-8 demonstrate the addition of Q 100 mg ± Z to G/nP was safe and tolerable, with no significant added toxicity to GnP. Modulation of eADO with Q may confer benefit beyond radiographic measures of disease. The OS is promising and supports further development of Q in mPDAC. Clinical trial information: NCT04104672 . [Table: see text]
Biweekly gemcitabine plus nab-paclitaxel as first-line therapy for older adult patients with unresectable pancreatic cancer: A prospective study.
Authors: Ikezawa Kenji , Imai Toshihiro , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Ohkawa Kazuyoshi 
Published: January 2024

672 Background: Although the number of older adult patients (aged ≥ 75 years) with pancreatic cancer (PC) is increasing, there are still limited data regarding chemotherapy for these patients, who experience adverse events more frequently than younger patients with PC. In this study, we evaluated the efficacy and safety of biweekly gemcitabine plus nab-paclitaxel (GnP) as first-line therapy for older adult patients with unresectable PC. Methods: We conducted a single-center prospective study. Patients aged ≥ 75 years with pathologically proven unresectable pancreatic adenocarcinoma were enrolled after obtaining written informed consent. Patients were treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle. The primary endpoint was the overall response rate. Secondary endpoints included disease control rate, overall survival, progression-free survival, 1-year survival rate, 2-year survival rate, and adverse events. Results: From August 2018 to March 2021, 17 patients were enrolled (locally advanced 4; metastatic 13). Five patients (29.4%) were men, and the median age was 77 years (range: 75-81). The median Geriatric 8 score was 13 points (range 6-17). Biliary drainage was performed in three patients. The overall response rate was 47.1% (8/17). Disease control rate was 82.4% (14/17). Median overall survival was 16.8 months (95% confidence interval (CI) 5.9-24.6) and median progression-free survival was 8.3 months (95% CI: 4.9-10.1), respectively. The 1-year survival rate and 2-year survival rates were 58.8% and 29.4%, respectively. Grade 3 or 4 hematologic adverse events and non-hematologic adverse events were observed in 17.6% (3/17) and 29.4% (5/17), respectively. No deaths was observed in association with biweekly GnP regimen. Conclusions: Biweekly GnP as first-line therapy can provide favorable treatment outcomes with tolerable toxicity in older adult patients with unresectable PC. Clinical trial information: jRCTs051190038 .
Maintenance therapy with olaparib or selumetinib plus durvalumab (S+D) according to genetic profile of metastatic pancreatic adenocarcinoma (m-PDAC) controlled with modified FOLFIRINOX (mFFX): A phase II randomized MAZEPPA GERCOR D19-02 PRODIGE-72 study.
Authors: Hammel Pascal , Ben Abdelghani Meher , Roth Gael , Ulusakarya Ayhan , Ghiringhelli François , Toullec Clemence , Borg Christophe , Hentic Dhome Olivia , Trouilloud Isabelle , Dahan Laetitia , Hiret Sandrine , Bouche Olivier , Rinaldi Yves , Blanc Jean-Frédéric , De La Fouchardiere Christelle , Neuzillet Cindy , Kamal Maud , Falcoz Antoine , Turpin Anthony , Guimbaud Rosine 
Published: January 2024

673 Background: Maintenance treatments in m-PDAC patients (pts) after FFX induction is discussed. We assessed the efficacy of genetic-driven maintenance in pts with controlled disease. Methods: In this multicenter, open-label, phase II study, PS 0-1 pts with histologically confirmed m-PDAC controlled after 4 months (mo) of mFFX received a genetically-driven maintenance therapy (centralized analysis): BRCAness - olaparib 300 mgx2/d (Arm A); no BRCAness, but KRAS mutation - randomization (2:1) to S+D (1500 mg IV q4w + 75 mg PO BID; Arm B) or FOLFIRI q2w (Arm C), until confirmed progression or toxicity. Statistical hypotheses: Arm A, PFS4mo rate after inclusion - H0: PFS4mo ≤40%, H1: PFS4mo ≥70%; Arm B and C, H0: PFSc=PFSb, H1: PFSc<PFSb (one-sided 2.5% α-type I-error and 10% β-type 2). A prespecified single interim analysis for futility using a-spending function with O’Brien-Fleming boundaries was planned after 33.1% of events (~93 pts). The Kaplan-Meier method and a swimmer plot were applied. Results: 124 pts were included in the study; Arm A: 16 pts (male: 9, median age: 67 years, PS 0: 9 pts) received olaparib; PFS 4mo: 50%; median PFS: 3.7 mo (1.7-9.4), ORR: 13%, median OS: 18 mo (5.5-21.5). Arm B/Arm C: at interim analysis (12/5/2022): 104 pts were randomized (Arm B/Arm C: 70/34); median PFS in Arms B and C: 3.5 mo (95% CI 2.1-3.9) vs 5.7 mo (95% CI 2.2-10.7), respectively. Due to futility, inclusions were stopped. At final analysis (data cutoff: 06/15/2023) with median follow up of 11.2 mo (95% Cl 9.4-13.1): 108 pts (male: 53%, age: 63.5 years, PS 0: 44%) were treated (Arm B/Arm C: 72/36). 123/124 pts (ITT population) had ≥1 cycle treatment (median: 4.0 [IQR, 2.0-6.0]). Primary endpoint was not met: median PFS 3.7 mo (95% Cl 2.1-5.0) in Arm B vs 6.6 mo in Arm C (95% Cl 2.6-8.7); HR=1.6 (0.99-2.58), P=0.0523. Median OS (entire population): 12.7 mo (95% CI 8.7-18.2); 10.1 mo (95% CI 8.3-20.6) in Arm B and 17.3 mo (95% CI 8.4-20.9) in Arm C. The toxicity profile: ≥1 grade 3-4 treatment-related arms (A/B/C) was as expected: 18.8%, 23.6%, 28.6% of pts. Conclusions: MAZEPPA study did not meet its primary endpoint of improving PFS4mo in m-PDAC pts treated with S+D maintenance vs those receiving FOLFIRI. Data on genomic alterations analyses will be presented at the congress. Clinical trial information: NCT04348045 .
Stereotactic body radiotherapy compared to conventionally fractionated radiotherapy for locally advanced or oligometastatic pancreatic cancer.
Authors: Mizrahi Ofri , Falick Michaeli Tal , Hubert Ayala , Wygoda Marc R. , Blumenfeld Philip 
Published: January 2024

677 Background: Pancreatic cancer, particularly in its locally advanced and oligometastatic forms, poses a formidable therapeutic challenge. Radiotherapy remains an important treatment in an attempt to gain local control, however there is no consensus on whether stereotactic body radiotherapy (SBRT) is appropriate as compared to conventionally fractionated radiotherapy (CFRT). Herein, we report our experience. Methods: We conducted a retrospective analysis of patients with locally advanced and oligometastatic pancreatic cancer who received definitive radiotherapy at our institution between January 2010 and March 2023 with SBRT 30-50 Gy in 3-5 fractions or CFRT 50-60 Gy in 25-30 fractions. We excluded all patients with resectable disease who underwent surgery. Clinicopathological data, treatment regimens, and radiation parameters were collected and analyzed. Results: A total of 51 patients (17 females, 34 males; median age: 67.9 years). 24 patients (47.1%) were treated with CFRT, and 27 patients (52.9%) were treated with SBRT. Median time of follow-up for the entire cohort was 14.4 months. A total of 13 patients (25%) experienced a Local failure (LF) at a median time of 18.5 months, with no difference observed between CFRT and SBRT groups. Cancer-specific mortality (CSM) was statistically significant with a lower mortality rate in SBRT (37%) vs CFRT group (63%) (p<0.004). Several treatment characteristics and dosimetric factors such as sex, age, receipt of chemotherapy, type of chemotherapy, use of elective nodal irradiation, GTV size, biologically equivalent dose (BED) corrected prescribed dose, minimum dose to GTV, or max dose to GTV did not predict local failure. There was no difference in QOL and toxicity between the two groups. Conclusions: In our cohort, local failure rates remain high and were similar between patients treated with SBRT compared to those treated with conventionally fractionated radiotherapy. We were unable to identify any specific predictors for local recurrence in this patient population. Our observation of a lower CSM rate among patients who received SBRT needs further study. The findings underscore the need to further improve radiotherapeutic approaches in an attempt to improve local control in locally advanced disease.
Exocrine pancreatic insufficiency as a possible predictor of pancreatic cancer development.
Authors: Gore James , Romo Karina G. , Peeples James , Noor Abdullah A. , Uwaifo Gabriel I. 
Published: January 2024

679 Background: Chronic and acute pancreatitis are established risk factors for pancreatic cancer. Chronic pancreatitis and pancreatic cancer are also common causes of exocrine pancreatic insufficiency (EPI), which is characterized by inadequate pancreatic secretion of exocrine digestive enzymes. Although the association between EPI and pancreatic cancer has been thought to be linked by preceding chronic pancreatitis, it is unclear if EPI, regardless of etiology, is a risk factor or early marker for pancreatic cancer or cancer in general. Methods: This is a retrospective observational study utilizing the electronic health records of Ochsner Health System, Louisiana, over a 3-year period from January 2017 to January 2020 to identify patients with a diagnosis of EPI by ICD-10 codes. Two cohorts were reviewed: patients with EPI (n=677) and patients with pancreatitis (n=1852). Both history of acute and/or chronic pancreatitis were included in the pancreatitis cohort. The cohorts were compared based on cancer prevalence at the start and end of the 3 year observation period. Results: In the EPI cohort, the cancer prevalence was 15.95% (108) at start, and 43.9% (297) at end, (p<0.05); and pancreatic cancer prevalence at start was 6.65% (123) and 29.8% (552) at end (p<0.05). In the pancreatitis cohort, the cancer prevalence was 5.4% (100) at start and 15.9% (294) at end (p<0.05); and pancreatic cancer 0.8% at start and 5% at end (p<0.05). Conclusions: Over a 3 year period, the rise in prevalence of general cancer and pancreatic cancer was higher in the EPI cohort compared to the pancreatitis cohort. Additionally, there was a statistically significant 2.8-fold increase in prevalence of cancer diagnosis and 4.5-fold increase in prevalence of pancreatic cancer diagnosis in the EPI cohort over the 3 year observation period. Though this is an observational study, it suggests the possibility that EPI, regardless of etiology, may be an independent predictor/risk factor for the development of future cancer in general and pancreatic cancer in particular. In addition it appears that this risk potential is substantively greater than that from a history of pancreatitis alone.
Enhanced blood-based colorectal cancer screening with improved performance in detection of early stage disease.
Authors: Duenwald Sven , Young Greenwald William , He Yupeng , Xiong Liyang , Forouzmand Elmira , Gaile Daniel , Valouev Anton , Raymond Victoria M. , Talasaz AmirAli , Chudova Darya 
Published: January 2024

68 Background: Blood based colorectal cancer (CRC) screening has been validated for use in average risk populations (ECLIPSE NCT#04136002; Guardant Health, USA). Here we present the performance of an enhanced version of a blood-based screening test developed to optimize detection of low shedding tumors by leveraging epigenomic features of cell-free DNA (cfDNA). Test performance was assessed across screen-relevant individuals from the intended use population, including a collection of screen-detected CRC and enriched cohort of individuals with endoscopy finding of CRC. Methods: We trained a regression model to classify whether aberrant cfDNA originated from individuals with CRC or non-ACN individuals and compared performance to an original model in a fixed set of screen-relevant samples sequenced to a median of 11M reads per sample across a panel approximately 1Mb in size. Model optimization focused on identifying training settings and samples to maximize detection of low shedding screen-relevant tumors and introduced noise reduction techniques to minimize technical variation. The final enhanced model was trained in over 4500 samples; the calling cut-off was set targeting 90% specificity in the average-risk population following US-Census age distribution. Analytical Limit of Detection (LoD) was estimated using ~5,000 in silico dilution samples generated from blood samples from 25 CRCs and ~1,650 non-ACNs. Results: This training approach yielded a 2X improvement in the analytical LoD95 (0.004% vs 0.008%) compared to the original model validated in the ECLIPSE trial. The model also yielded an increase in overall CRC clinical sensitivity from 84% to 91%, N=45, with notable sensitivity improvement from 76% to 88% in detecting early localized stage I/II CRC, N = 25, while maintaining specificity at 91%. Conclusions: This enhanced cfDNA-based CRC screening blood test shows improved performance in early stage CRC detection demonstrating the potential of continuous improvement in the performance of cfDNA-based screening tests powered by data and clinical insights.
Kinetics of CA19-9 decline in a randomized phase III study of irinotecan liposome injection, oxaliplatin, 5-fluorouracial/leucovorin (NALIRIFOX) or nab-paclitaxel plus gemcitabine (GEM+NABP) in patients who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas (NAPOLI 3).
Authors: Chandana Sreenivasa R , Wainberg Zev A. , Melisi Davide , Macarulla Teresa , Pazo Cid Roberto A. , De La Fouchardiere Christelle , Dean Andrew Peter , Kiss Igor , Lee Woo Jin , Goetze Thorsten , Van Cutsem Eric , Paulson Andrew Scott , Bekaii-Saab Tanios S. , Pant Shubham , Hubner Richard , Xiao Zhimin , Li Jia , Benzaghou Fawzi , O'Reilly Eileen Mary 
Published: January 2024

687 Background: The NAPOLI 3 study (NCT04083235, N = 770) reported that NALIRIFOX improved overall survival (OS) vs Gem+NabP with manageable toxicity in 1L treatment of metastatic pancreatic adenocarcinoma. We explored changes in CA19-9 levels and their potential associations with efficacy as an important tumor marker in pancreatic adenocarcinoma. Methods: In NAPOLI 3, CA19-9 was evaluated at baseline and every 8 weeks until patients discontinued study treatment. The detection limit of CA19-9 was 8000 kU/L in this study. The Cox proportional hazards regression and logistic regression were employed to investigate the relationship between CA19-9 decrease and OS, progression-free survival (PFS), and overall response rate (ORR). Results: Patients with evaluable CA19-9 (levels =< 8000) at baseline and additional measurements at weeks 8 and 16 were included in the analysis (NALIRIFOX, n = 179; Gem+NabP, n = 194). The median baseline CA19-9 level was 378.0 and 409.7 kU/L for the NALIRIFOX and Gem+NabP arms, respectively. Overall, patients with (vs without) any CA 19-9 decrease by week 16 had a higher ORR (59.9% vs 35.2%; p = 0.002), a longer median PFS (9.2 vs 6.2 months; p < 0.001) and a longer median OS (14.2 vs 8.7 months; p = 0.005), respectively in a pooled analysis of the treatments. In the NALIRIFOX arm, patients with any CA19-9 decrease by week 16 had a higher confirmed ORR of 65.1% compared with those without at 42.4% ( p < 0.001), a median PFS of 9.5 vs 7.1 months ( p < 0.001) and a median OS of 15.4 versus 8.4 months ( p = 0.004), respectively. In the Gem+NabP arm, patients with CA19-9 decrease by week 16 had a higher ORR of 55.5% compared with those without at 23.8% ( p = 0.012), a median PFS of 7.6 versus 5.8 months ( p < 0.001) and a median OS of 13.7 versus 11.9 months ( p = 0.235), respectively. Conclusions: CA19-9 decrease by week 16 has the potential to be an early prognostic factor for OS, PFS and ORR. The results should be interpreted with caution as a considerable percentage of patients were excluded due to non-evaluable CA19-9 that exceeded the lab detection limit of 8000 kU/L. Clinical trial information: NCT04083235 .
Clinical outcomes and molecular characteristics of patients with pancreatic acinar cell carcinoma.
Authors: Eslinger Cody , Yee Claire , Seddighzadeh Bobak , Elsabbagh Zaid , Pai Rish , Hartley Christopher P. , Bekaii-Saab Tanios S. , Starr Jason S. , Halfdanarson Thorvardur Ragnar , Sonbol Bassam Bassam 
Published: January 2024

688 Background: PACC is a rare malignancy originating from the exocrine pancreas, accounting for less than 1% of all pancreatic cancers. Due to the rarity of the disease entity, there is a paucity of data to guide treatment decisions. This retrospective study aims to provide additional clinical characteristics and outcomes to aid in future treatment decisions. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) patients (pts) denoting acinar or mixed-acinar cell carcinoma were searched between 2002 to 2023 and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) were collected. Results: A total of 62 pts (74% male, n = 46) were identified with median age 64 years old. Histologic subtypes were 67% pure acinar cell carcinoma (42/62), 24% mixed acinar-neuroendocrine (15/62), and 8% mixed acinar-adenocarcinoma (5/62). AJCC stages at diagnosis were 34% stage I/II (21/62), 16% stage III (10/62), and 50% stage IV (31/62). Early-stage disease was treated with upfront surgical resection (81%, 17/21). Locally advanced disease received neoadjuvant therapy (NAT) followed by surgical resection (80%, 8/10). FOLFIRINOX was most often chosen as NAT (65%, 11/17), while others received gemcitabine-based NAT. The R0 resection rate was 86%. The 3 and 5-year survival estimates for stage III were 90.9% (95% CI: 75.4 – 100%) and 67.3% (95% CI: 42.3 – 100%), respectively. The 3 and 5-year survival estimates for stage IV were 36.6% (95% CI: 18.6 – 71.9%) and 29.3% (95% CI: 13.1 – 65.5%), respectively. Median survival time for stage IV was 3 years. Somatic NGS testing was done in 24 pts with alterations found in: homologous recombination (HR) in 42% (10/24); RAF alterations in 25% (6/24); mismatch repair (MMR) in 13% (3/24; none of them with MMR germline mutations), 1 ETV6-NTRK3 fusion, and 1 FGFR mutation. Germline NGS testing was done in 21 pts and alterations in HR were seen in 33% (7/21) of pts. This led to additional therapeutic options in 46% (11/24) of pts. Conclusions: Unlike PDAC, PACC is a genomically diverse disease, with potentially targetable alterations in RAF, HRD, and MMR genes, offering additional therapeutic options for significant number of pts. In addition, more than one-third of the pts harbored germline mutations in HR genes. Therefore, somatic and germline testing should be considered for any pt diagnosed with PACC.
The prognostic value of mutational signatures in pancreatic cancer.
Authors: Light Nicholas , Zhang Amy , Hamza Oumaima , Jang Gun Ho , Dodd Anna , Wilson Julie , O'Kane Grainne M. , Tsang Erica S , Notta Faiyaz , Knox Jennifer J. , Gallinger Steven , Grant Robert C 
Published: January 2024

689 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall survival (OS), however there are significant outliers. Understanding the biological factors driving PDAC cancer may reveal new biomarkers and treatment strategies. Mutational signatures, imprinted in the cancer genome, encode the life history of the cancer and may be used to stratify tumors into clinically-relevant subgroups. Methods: In this study we performed mutational signature analysis (MutationalPatterns, COSMIC v3.3) on whole genomes from 434 PDAC patients, comprising 167 patients with resected primary tumors, and 267 advanced PDACs from patients enrolled in the COMPASS trial. We evaluated whether the mutational signatures detected associate with OS using the log-rank test in the overall cohort and stratified by disease stage, adjusting for multiple hypotheses with 5% false discovery rate (FDR). We further characterized these associations in exploratory analyses. Results: Among the 55 COSMIC signatures detected in the overall cohort, the presence of three signatures significantly associated with OS after FDR correction. SBS85, a signature associated with indirect effects of activation-induced cytidine deaminase, was present in 18/434 (4.1%) samples, and was significantly associated with improved OS in the overall study population (log-rank p=6.5e-4, FDR-adjusted-p=0.026). SBS93, a signature of unknown etiology previously seen in other gastrointestinal cancers, was present in 4/434 (0.9%) samples, and was significantly associated with worse OS in the overall study population (log-rank, p=7e-6; FDR-adjusted-p=1.1e-3). SBS33, also of unknown etiology and previously seen in other gastrointestinal cancers, was present in 73/434 (16.8%) samples. It was seen more frequently in advanced disease (Fisher’s-exact p=1.9e-4), but was significantly associated with worse OS only in the resected cohort (log-rank, p=2.3e-4, FDR-adjusted-p=0.012). Conclusions: We identified three mutational signatures—SBS85, SBS93, and SBS33—that have not previously been described in PDAC and associate with OS. Further characterization of these novel signatures in PDAC and their underlying biology may uncover new treatment avenues.