bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pretreated advanced biliary tract cancer: Efficacy and safety analysis (BOLD-100-001).
Authors: O'Kane Grainne M. , Oh Do-Youn , Spratlin Jennifer , Rha Sun Young , Elimova Elena , Kavan Petr , Goodwin Rachel Anne , Cha Yongjun , Kim Seung Tae , McAllister E. Russell , Jones Michelle , Snow Malcolm , Lemmerick Yasmin , Spera Gonzalo , Pankovich Jim 
Published: June 2024

4115 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies. Methods: In this prospective Phase 2 study, patients with pretreated advanced biliary tract cancers (BTC) received BOLD-100 (625 mg/m2) in combination with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate the efficacy of BOLD-100 in three clinical endpoints (PFS, OS, and ORR). Disease Control Rate (DCR) was also determined. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 22 pts with advanced metastatic BTC (5 gall bladder, 5 intrahepatic, 8 distal, 1 perihilar, and 3 unk) were enrolled and treated in the study. At enrollment, pts had a median age of 61 years [range 33, 81] and had a median of 10.9 months from diagnosis of metastatic disease. All patients were ECOG ≤ 1. Patients had a median of 2 prior systemic therapies [range 1, 5] with 13 receiving 2 or more prior regimens. 21/22 BTC patients received prior GEM/CIS, 8 pts had prior 5-FU treatment and 6 prior IO. On study, pts received a median of 4 cycles BOLD-100 + FOLFOX [range 1, 41]. Median PFS was 6.0 [95% credible interval (CI) 3.8, 10] months, median OS 7.3 [CI 4.5, 13] months, ORR 6% [1,23] and DCR 83% [62, 95] in the 18 evaluable patients. Six patients had reductions in their target lesions with 1 partial response. Study treatment was well tolerated. For the 22 treated patients, 21 reported 1 or more treatment-related adverse events (AEs), most commonly neutrophil count decreased (n=10, 46%), nausea (n=8, 36%), fatigue (n=7, 32%), peripheral sensory neuropathy (n=6, 27%), and pyrexia (n=6, 27%). Nine patients (41%) reported G3/4 neutrophil count decreased. Conclusions: BOLD-100 combined with FOLFOX is an active and well-tolerated treatment regimen in Stage IV BTC. There were no new safety signals detected. The mPFS, mOS, ORR and DCR data in this advanced BTC cancer population indicate a treatment combination worthy of further study for this difficult to treat cancer. Clinical trial information: NCT04421820 .
PD-1 inhibitor (sintilimab) and lenvatinib plus TACE-HAIC as conversion therapy for initially unresectable HCC: A single-arm, phase 2 clinical trial (PLATIC).
Authors: Yuan Yunfei , Qiu Jiliang , Huang Zhenkun , He Wei , Yuan Yichuan , Wang Chenwei , Li Binkui 
Published: June 2024

4123 Background: The current standard treatment for initially unresectable hepatocellular carcinoma (uHCC) is transarterial chemoembolization (TACE) or systemic treatments, but these approaches led to poor conversion resection rate. We aimed to investigate the clinical activity and safety of downstage conversion therapy with Sintilimab, a PD-1 inhibitor, Lenvatinib and TACE- HAIC (hepatic arterial infusion chemotherapy) in uHCC patients (PLATIC trial). Methods: This single-arm, Simon two-stage, phase 2 study was done at Sun Yat-sen University Cancer Center, Guangzhou, China. Patients received TACE-HAIC, followed by 200mg Sintilimab, Lenvatinib (8mg for BW < 60kg, 12mg for BW ≥ 60kg). The primary endpoint was the conversion to resection rate. Safety was analyzed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04814043). Results: Between May 19, 2021, and August 20, 2023, 57 patients were enrolled, and all were included in the efficacy and safety analysis set. The conversion to resection rate was 77.2% (44/57, 95% CI, 64.2 to 87.3) after a median 3 cycles of conversion therapy. Overall response rate was 77.2% per mRECIST and 42.1% per RECIST 1.1 criteria. The median duration of response (mDoR) was 11.5 months (95% CI, 9.8 to NA), and the median progression-free survival (mPFS) was 14.3 months (95% CI, 11.7 to 21.9). Treatment-related adverse events (TRAEs) of grade 3/4 were reported in 37 (64.9%) patients, with the most frequent being increased gamma-glutamyl transferase (36.8%), followed by abdominal pain (19.3%). Among 44 successful conversion patients, 29.5% (13/44) patients obtained a pathological complete response, with a mPFS of 15.3 months (95% CI, 11.9 to NA) and 12-month PFS rate of 59.4% (95% CI, 45.4 to 77.9). Conclusions: Sintilimab plus Lenvatinib and TACE-HAIC provided promising rate of conversion to resection in patients with initially unresectable HCC, with an acceptable TRAEs. Clinical trial information: NCT04814043 . [Table: see text]
Differences in genomic and transcriptomic landscapes of human papillomavirus (HPV)–positive neuroendocrine neoplasms and HPV-positive carcinoma.
Authors: Lou Emil , Krause Harris Benjamin , Elliott Andrew , Wahidi Marya , Rader Janet S. , Teoh Deanna Gek Koon , Park Soo J , Wallbillich John , Benjamin David Joseph , Rezazadeh Arash , Duerksen-Hughes Penelope , Morris Robert , Gogoi Radhika , Zaiem Fadi , Herzog Thomas J , Thaker Premal H. , Oberley Matthew James , Soares Heloisa P. , Ali-Fehmi Rouba 
Published: June 2024

4127 Background: HPV is an infectious cause of several malignancies. Neuroendocrine neoplasms (NEN) are highly heterogeneous, ranging from low-grade indolent tumors to high-grade clinically aggressive carcinomas. Aside from cervical NENs, most have not traditionally been associated with HPV, but our initial studies uncovered a subset of NENs that are HPV 16/18 positive. To identify actionable differences between HPV+ NEN and non-NENs, genomic and transcriptomic landscapes were investigated. Methods: 101343 solid tumors were sequenced at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (whole or hybrid exome) and RNA (whole or hybrid transcriptome) and assayed for HPV16/18 positivity (HPV+) via DNA sequencing. Mutation prevalence for pathogenic SNVs/indels (-Mt) and copy number amplification (CNA) were calculated. Expression of Ki-67 mRNA ( MKI67) was used to infer high grade vs low grade NEN. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy, interferon 𝛾">γ score (IFN). Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Fisher’s exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p < .05). Results: Among all solid tumor types, rates of HPV+ were highest in cervical carcinomas (70%, 1200/1716), followed by vulvar squamous cell carcinoma (31%, 126/410) and head and neck (HN) carcinomas (28%, 668/2413), with HPV+ tumors also found in NENs (6%, 96/1620). Within NENs, the highest HPV+ rates were observed for those with a tumor origin of cervical (76%, 55/58), anorectal (AR, 27%, 29/106), female genitourinary tract (23%, 12/52) and HN (19%, 7/36). Amongst HPV+ NEN, 93% were high grade compared to 54% of HPV- NEN (p < .001). Focusing on AR, cervical and HN primary sites, significant differences in the genomic landscape were observed between non-NEN v NEN tumors (Table 1). Non-NEN tumors had a significantly higher IFN compared to NEN across sites (Cervical: -0.20 v -0.61, AR: -0.33 v -0.58, HN: -0.16 v -0.54 arbitrary units, p < .001 all). Non-NEN tumors at AR, cervical and HN sites were significantly enriched for several genes sets related to immune response (Interferon α/γ, TNFα/NF-κβ, IL6/JAK/STAT3 and inflammatory response). Conclusions: Our data suggest that non-NEN HPV+ tumors are enriched for gene sets related to immunotherapy response, and that HPV+ NENs have alterations that vary by anatomic site. We uncover a category of HPV+ NENs with distinct genomic and transcriptomic landscapes compared to non-NEN tumors. [Table: see text]
GATA6 expression in advanced pancreatic ductal adenocarcinoma (PDAC) as a prognostic and predictive biomarker in the Canadian COMPASS trial and the Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS.
Authors: Mc Laughlin Ronan Andrew , Salvatore Lisa , Barone Diletta , Deng Yangqing , Notta Faiyaz , Jang Gun Ho , Alfieri Sergio , Quero Giuseppe , Piro Geny , Carbone Carmine , Chiaravalli Marta , Bensi Maria , Bagalà Cinzia , Hutchinson Shawn , Dodd Anna , Fischer Sandra , Gallinger Steven , Knox Jennifer J. , Tortora Giampaolo , O'Kane Grainne M. 
Published: June 2024

4150 Background: Modified FOLFIRINOX (mFFX) and gemcitabine + nab-paclitaxel (GnP) are current 1st line options in advanced PDAC. GATA6 expression, a transcription factor identifies the classical phenotype and is associated with superior overall survival (OS), low GATA6 predicts a basal-like phenotype, associated with a poorer prognosis. We have previously established high concordance between GATA6 expression by RNAseq and in situ hybridization (ISH). Recent studies suggest a survival difference between primary tumor anatomical locations, it is unknown if GATA6 expression influences this. This multicentre study evaluates GATA6 as a prognostic and predictive biomarker and determines its impact on primary tumor location. Methods: Patients were included from COMPASS and a retrospective IRCCS cohort. COMPASS participants had GATA6 by RNAseq and IRCCS cohort by ISH, all treated in 1st line metastatic setting with mFFX or GnP. The primary endpoint was OS by GATA6 expression and by 1st line treatment. We investigate if there are OS differences between primary tumor anatomical locations. The Kaplan Meier method was used to assess OS. The log-rank test was used to examine whether there is a significant difference between the OS in different groups. GATA6 as a predictive biomarker to response to therapy was assessed by the interaction term for GATA6 and treatment group in a Cox proportional hazards model. Results: The combined analysis included 465 pts (253 COMPASS and 212 IRCCS). Baseline characteristics were similar. The combined median age was 64 yrs (28, 84); 402 (86%) had metastatic PDAC and 63 (14%) locally advanced. 56 (12%) had prior surgery, 40 (9%) had prior adjuvant therapy. In total, 296 (64%) and 169 (36%) were GATA6 high and low respectively. OS in months (m) analyses by GATA6 expression are summarized (Table). We demonstrate no difference between OS based on primary tumor location (p=0.09), however, regardless of location, GATA6 high tumors show statistically significant better OS. We confirm, by interaction term, GATA6 as a predictive biomarker, with GATA6 high predictive of response to mFFX while low expression demonstrates less benefit with mFFX (p=0.003). Conclusions: GATA6 is a highly prognostic biomarker. We did not find an association with tumor location, which also was not prognostic in this study. Importantly GATA6 was predictive of survival in patients receiving mFFX, suggesting GATA6 low tumors should receive 1st line GnP based regimens. Clinical trial information: NCT02750657 . [Table: see text]
Serial circulating tumor DNA monitoring for predicting treatment response and prognosis in patients with pancreatic cancer.
Authors: Lee Jongchan , Ahn Jinwoo , Jung Kwangrok , Lee Jong-chan , Youn Yuna , Hwang Jin-Hyeok 
Published: June 2024

4154 Background: Circulating tumor DNA (ctDNA) is considered an effective indicator for real-time monitoring of therapeutic efficacy and prognosis prediction in various malignant tumors. We conducted a study to investigate whether serial ctDNA monitoring can predict recurrence, disease progression, and prognosis in pancreatic cancer. Methods: A total of 231 with pancreatic cancer were prospectively enrolled. Among them, 167 patients (52 in the resection group, 115 in the palliative treatment group) were assessable for serial ctDNA at scheduled intervals (total ctDNA evaluations: 614). CtDNAs were analyzed using individualized droplet digital PCR to measure the mutant allele fraction of KRAS G12/13 screening multiplex Kit, with the results reported as variant allele fraction (VAF). The percent changes of ctDNA (Δ ctDNA) were correlated with radiologic response at each evaluation. Associations between ctDNA and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: CtDNAs were detected in 143 of 167 eligible patients (85.6%). The detection rate increased with the advancing stage ( P= 0.016) and varied based on the metastatic site (liver: 98.0% vs. peritoneum, 88.9%; P= 0.011). In the resection group, there was no significant difference in Δ ctDNA regarding recurrence, nor were there statistically significant difference in terms of RFS and OS based on postoperative ctDNA detection. Conversely, in the palliative treatment group, patients with progressive disease (PD) exhibited significantly higher Δ ctDNA compared to those with stable disease (SD) or partial response (PR) ( P< 0.001). Patients whose Δ ctDNA increased before radiologically PD had their Δ ctDNA levels increased an average of 2.53 months earlier. Notably, higher ctDNA were linked to shorter PFS (HR 1.84; 95% CI 1.07 to 3.18, P = 0.03) and OS (HR 2.15; 95% CI 1.20 to 3.86, P = 0.01) in metastatic patients. Patients who achieved ctDNA clearance at 8 weeks demonstrated more favorable outcomes in terms of PFS (HR 0.53; 95% CI 0.30 to 0.92, P = 0.02) and OS (HR 0.50; 95% CI 0.28 to 0.90, P = 0.02). Similar benefits were observed for those who experienced at least one ctDNA clearance (PFS, HR 0.27; 95% CI 0.16 to 0.44, P < 0.001; OS, HR 0.31; 95% CI 0.19 to 0.50, P < 0.001). Conclusions: Our findings suggest that serial ctDNA monitoring holds promise in predicting treatment response and prognosis for unresectable pancreatic cancer patients.
Post-progression therapies and outcomes for patients with advanced, BRCA-related pancreatic cancer after receipt of PARP inhibitors: A national retrospective cohort study.
Authors: Jafry Baqir , Kazmi Syed Mohammad Ali , Al Mutar Salwan , Reiss Kim Anna , Brown Timothy J 
Published: June 2024

4156 Background: Maintenance therapy with poly-ADP ribose polymerase (PARP) inhibitors (PARPi) can delay progression of advanced platinum-sensitive pancreatic cancer in patients with mutations in BRCA1, BRCA2or PALB2. However, there are limited data to guide treatment decisions and outcomes following progression with PARPi. Thus, we sought to compare outcomes of post-progression platinum and non-platinum therapies for patients with pancreatic cancer after receipt of PARPi using a nationwide cohort. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified longitudinal patient-level data originated from approximately 280 cancer clinics. Patients were eligible for inclusion if they received maintenance olaparib for advanced pancreatic cancer and subsequently received post-progression chemotherapy. Post-progression chemotherapy was characterized as platinum (P) or non-platinum (NP). Demographics, tumor stage, and lab values were compared using the Chi-squared test or Mann Whitney U test. Overall survival (OS) and time to treatment discontinuation (TTD) were evaluated using the Kaplan Meier method with an index date of initiation of post-progression therapy. Given the limited anticipated sample size, no formal comparisons were made between treatment groups. Cox proportional hazards models were constructed to identify associations between baseline clinical factors and outcomes. Results: Of 11,179 patients were included in the database, 26 met inclusion criteria for this analysis after progressing on olaparib and subsequently receiving post-progression chemotherapy. Most patients were white (81%) and non-Hispanic (77%). Twelve (46%) received post-progression P, while 14 (54%) received post progression NP. No significant differences were noted in baseline characteristics between groups. Among patients on P, the most common regimens were gemcitabine and cisplatin (50% n=6), FOLFIRINOX (17%, n=2), and FOLFOX (17%, n=2). Of those on NP, the most common regimens were gemcitabine and nab-paclitaxel (50%, n=7) and FOLFIRI (29%, n=4). The median OS for post progression therapies was 4.8 months for P and 4.1 months for NP group. The median TTD for these post progression therapies was 0.9 months for P and 1.5 months for NP. No baseline clinical factors were associated with time-to-event in Cox regression analyses. Conclusions: In this analysis, patients who progressed on olaparib rapidly progressed on post-progression P and NP and had limited survival. Further work will be needed to identify mechanisms of resistance to PARPi and to optimize post-progression treatments. This work adds to a growing body of literature supporting an individualized approach to post-progression therapy decisions for these patients.
Molecular landscape and site of metastasis in PDAC.
Authors: Rahman Shafia , Baca Yasmine , Singh Harshabad , Xiu Joanne , Mallick Atrayee B , Rubinstein Mark P. , Aguirre Andrew , George W. Jr.  , Pishvaian Michael J. 
Published: June 2024

4159 Background: More than 50% of patients with Pancreatic ductal adenocarcinoma (PDAC) have metastatic disease at the time of diagnosis and liver is the most common site of metastatic spread. Liver metastasis (LM) is associated with poor prognosis. Herein we examine the difference in molecular landscape of PDACs with LM versus other metastatic sites (OM). Methods: Total of 7,979 PDAC tumors underwent next-generation sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). Tumors were then evaluated and divided into LM (N=4988) site vs OM (N=3073) sites based on tissue specimen sites. RNA expression data was used to analyze transcriptional signatures as well as tumor immune microenvironment (TME) using Quantiseq. Real-world overall survival (rwOS) information was obtained from insurance claims data and calculated from time of collection or first treatment to last contact. Hazard ratio (HR) was calculated using Cox proportional hazards model, and P values were calculated using log-rank test.Significance for molecular comparisons was calculated using either chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q<0.05). Results: Mutations in TP53 (81% vs 67%), KRAS (88% vs 83%), ARID1A (13% vs 11%), KDM6A (4% vs 3%), and BRCA1 (1.3% vs 0.7%) were all significantly higher in LM vs OM (all <0.05). Conversely, TMB-H (3% vs 4%), MSI-H (0.7% vs 1.3%), GNAS (1% vs 3%), STK11 (1% vs 3%), ATM (3% vs 5%), PTPRD (2% vs 9%) and RNF43 (5% vs 6%) mutations were significantly lower in LM vs OM (all q<0.05). In the TME, B cells, Tregs, M1, M2 macrophages, and NK cell infiltration was lower in LM vs OM (FC: 0.62-0.91, q<0.05). However, LM had higher neutrophil infiltration vs OM (FC: 1.1, q<0.05). Both interferon-gamma score (IFG) and T cell inflamed score (TIS) were significantly higher in OM vs LM (q<0.05). OM had better OS than LM (11.4 m vs 6.8 m, HR=0.65 95% CI: 0.62-0.68, p<0.001). This association held for tumors treated with Immune Checkpoint Inhibitors (ICI) (9.6 m vs 4.6 m, HR=0.71 95% CI: 0.52-0.97, p=0.031), Gemcitabine/Nab-paclitaxel treated (15.3 m vs 8.1 m, HR=0.57 95% CI: 0.52-0.61, p<0.001) as well as mFOLFIRINOX treated tumors (20.3 m vs 12.0 m, HR=0.57 95% CI: 0.52-0.63, p<0.001). Conclusions: When comparing pancreatic LM to OM sites, our data reinforces the observation that OS is better in OM vs LM and response to ICI was better in OM vs. LM. Significant differences were observed in molecular landscape, TME and signatures that are predictive of immunotherapy response (TIS and IFG scores). [Table: see text]
Perioperative fuzuloparib plus mFOLFIRINOX for resectable pancreatic adenocarcinoma: A phase 1 study.
Authors: Zhan Qian , Wen Chenlei , Zou Siyi , Li Fanlu , Chen Dongjie , Sheng Zhen , Yu Zhixin , Gao Denghui , Shen Baiyong 
Published: June 2024

4163 Background: Surgical resection followed by adjuvant mFOLFIRINOX is currently the standard of care for resectable pancreatic adenocarcinoma. Neoadjuvant therapy has the potential to induce tumor downsizing and improve R0 resection rate. In this study, we aimed to explore the feasibility of the PARP inhibitor fuzuloparib in combination with mFOLFIRINOX as the neoadjuvant and adjuvant therapy in patients (pts) with resectable pancreatic adenocarcinoma. Methods: This was a dose escalation and expansion phase 1 study in pts with histologically or cytologically confirmed, high-risk resectable or borderline resectable pancreatic adenocarcinoma. Eligible pts received perioperative treatment with fuzuloparib plus mFOLFIRINOX (up to 12 cycles of 14 days each, with 4 to 6 cycles administered preoperatively; fuzuloparib at escalating doses starting at 30 mg BID), followed by maintenance fuzuloparib at 150 mg BID. Dose-limiting toxicities (DLTs) were observed during the first 2 treatment cycles. The primary objectives were safety and tolerability. Results: As of Oct 31, 2023, 15 pts were enrolled, including 3 pts in the fuzuloparib 30 mg cohort and 12 pts in the 60 mg cohort. Twelve (80.0%) pts completed neoadjuvant therapy as planned. Eight (53.3%) pts underwent surgical resection, and all pts achieved R0 resections (100.0%; 95% CI, 63.1–100.0). Four of the 8 (50.0%) pts proceeded to adjuvant therapy (30 mg cohort: 0/2 [0%]; 60 mg cohort: 4/6 [66.7%]). There were no DLTs identified. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12 (80.0%) pts, with the most common being decreased neutrophil count, decreased white blood cell count, hypokalemia, and anemia. No unexpected TRAEs were reported. No patients discontinued study treatment due to TRAEs. Conclusions: Perioperative fuzuloparib plus mFOLFIRINOX was generally tolerated and had acceptable safety profile in pts withresectable pancreatic adenocarcinoma. Neoadjuvant fuzuloparib plus mFOLFIRINOX prior to surgery achieved a R0 resection rate of 100%. Clinical trial information: NCT04425876 .