bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of germline variants in patients with pancreatic neuroendocrine tumors.
Authors: Mohindroo Chirayu , Baydogan Seyda , Agarwal Parul , Laheru Dan , Wright Robin , Prakash Laura , Mork Maureen E , Klein Alison , Maxwell Jess , Katz Matthew H. G. , Dasari Arvind , Kim Michael Paul , He Jin , McAllister Florencia , De Jesus-Acosta Ana 
Published: June 2023

4135 Background: About 10% of pancreatic neuroendocrine tumors (pNETs) are thought to be related to inherited syndromes, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). Here, we report the prevalence of pathological/likely pathological germline variants (PV/LPV) in 2 cohorts: 1) High-risk and 2) Unselected. Methods: We retrospectively collected clinical data of patients with biopsy proven pNETs seen at MD Anderson Cancer Center (MDACC) and Johns Hopkins Hospital (JHH). Cohort 1 (high risk cohort) included 132 patients seen at MDACC, who underwent germline testing based on high-risk criteria such as early onset, personal or family history of cancer and syndromic features between 2013 -2019. Cohort 2 (unselected cohort) included 106 patients seen at JHH, who underwent germline testing following their diagnosis of pNETs between 2020 to 2022. Results: In the high-risk cohort (n = 132), 33% (n = 44) had PV/LPV, and 17 % (n = 22) had a variant of unknown significance (VUS). Amongst the 132 patients, 35% underwent multigene panel testing, 53% had targeted germline testing and 12% had a physician documented outside test diagnosis. The demographics consisted of 52%(n = 69) females, 67% (n = 88) white, 54%(n = 71) had metastatic disease, 58%(n = 76) underwent surgical resection. WHO grading (n = 77) is as follows G1 (39%), G2 (59%), G3 (2%). In the unselected cohort (n = 106), 21% (n = 22) had PV/LPV, 28 % (n = 30) had a VUS. Of these, 93% of the patients underwent multigene panel testing. The demographics consisted of 42% (n = 44) females, 67% (n = 88) white, 48% (n = 51) had metastatic disease, 60% (n = 64) underwent surgical resection, WHO grading (n = 93) is as follows G1 (37%), G2 (49%), G3 (14%). Conclusions: PV/LPV are prevalent in patients with sporadic pNET irrespective of high-risk features or family history. While in the high-risk patients there is a higher prevalence, we also identified a 21% prevalence of PV/LPV with universal germline testing in the unselected cohort. In both cohorts, we identified a high number of mutations in the DNA repair pathway not previously described, which could affect subsequent therapies and surveillance for patients and their family members. The findings support upfront universal germline testing in all patients with diagnosis of pNETs. [Table: see text]
Phase 2 trial of pembrolizumab and olaparib (POLAR) maintenance for patients (pts) with metastatic pancreatic cancer (mPDAC): Two cohorts B non-core homologous recombination deficiency (HRD) and C exceptional response to platinum-therapy.
Authors: Park Wungki , O'Connor Catherine , Chou Joanne F. , Schwartz Carly , Varghese Anna M. , Larsen Mary , Balogun Fiyinfolu , Brenner Robin , Yu Kenneth H. , Diguglielmo Erin , Umeda Shigeaki , Karnoub Elias , Keane Fergus , Zhang Haochen , Joshi Smita Suhas , Riaz Nadeem , Kelsen David Paul , Capanu Marinela , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary 
Published: June 2023

4140 Background: Maintenance olaparib improves PFS in g BRCA1/2m (core HRD) in mPDAC (Golan, NEJM 2019). Whether other HRD indicators, such as gene mutations other than g BRCA1/2m (non-Core HRD, Cohort B) and exceptional platinum responders (Cohort C, response > 6 months) may benefit from PARPi in mPDAC remains unanswered. We hypothesized that pembrolizumab and olaparib (POLAR) combination may improve outcome by immunogenic cell death. Methods: We conducted an open-label, non-randomized, phase 2 trial of POLAR as maintenance therapy for pts with mPDAC whose disease had not progressed for 4 months (m) in Cohort B or 6 m in C. Herein, we report on Cohorts B & C. Eligibility: ECOG 0-1, mPDAC meeting eligibility of B or C. POLAR (Pembrolizumab 200mg IV Q3W+ OLApaRib 300mg BID) until disease progression or limiting toxicity. Objective response rate (ORR), median PFS (mPFS), median overall survival (mOS), disease control rate (DCR), CA 19-9, cfDNA and baseline HRD mutational signature were analyzed. Results: Cohorts B and C enrolled N=15 each. N=25 pts evaluable by RECIST 1.1. Median follow-up 9.9 (1.3-22.8) and 11.3 (5.8-23) m, respectively. Efficacy details are shown. G3-5 AEs related to treatment: 5/14 (36%): 1 diarrhea (7%), 1 hyperglycemia (7%), 2 anemia (14%), 1 lipase increased (7%). Cohort B: 9/15 (60%) ATM, 3 CHEK2, 2 MUTYH, 1 BLM, 1 FANCC. Canonical gene mutations for mPDAC were less common for pts in Cohort B, especially in ATM PA group (n=9) vs C. Median genomic instability score (GIS) was computed and higher 28 (0-38) vs 9 (0-24) in Cohort B vs C, p=0.052. Median tumor mutation burden (TMB) was not different between B and C (3.3 and 4.1). Conclusions: Clinical activity of POLAR maintenance observed in select pts in B and C. Although PFS was modest (mPFS of 4m [2.1-5.4] in B + C), an intriguing survival signal (mOS at 14m [10-NR] from first POLAR dose) was seen in select patients without chemotherapy. Extensive correlative analyses underway to evaluate response and resistance (SPORE: 1P50CA257881-01A1). Cohort A (core HRD) actively accruing. Clinical trial information: NCT04666740 . [Table: see text]
Randomized phase 2 study of nab-paclitaxel and gemcitabine with or without tocilizumab as first-line treatment in patients with advanced pancreatic cancer (PACTO).
Authors: Chen Inna Markovna , Johansen Julia S. , Theile Susann , Madsen Kasper , Dajani Olav , Lorentzen Torben , Zimmers Teresa , Nielsen Dorte 
Published: June 2023

4147 Background: Pancreatic cancer (PC) presents one of the most aggressive malignancies for which currently available treatments are modestly effective. We report the findings of a randomized phase 2 trial (NCT02767557) to test the efficacy of gemcitabine/nab-paclitaxel (gem/nab) with or without tocilizumab (toc), as first-line treatment in patients with locally advanced or metastatic PC. Methods: Prior to randomization, a safety cohort of 6 participants received gem 1000 mg/m2, nab 125 mg/m2 (days 1, 8, and 15 of each 28-day cycle) and toc 8 mg/kg (day 1 of each cycle). Participants were then randomized 1:1 to receive gem/nab or gem/nab/toc. Patients had modified Glasgow Prognostic Score of 1 or 2 and were stratified by performance status (PS) and stage. The primary endpoint was the overall survival (OS) rate at 6 months (OS6). Secondary end points included median progression-free survival (PFS), median OS, overall response rate (ORR), and safety. Results: A total of 147 patients were treated; 141 were randomized to receive gem/nab/toc (n = 70), or gem/nab (n = 71). As of January 9, 2023, the median follow-up was 8.1 months (IQR 4.2–13.9). OS6 was 68.6 % (95% CI, 56.3-78.1) in gem/nab/toc group and 62.0% (95% CI, 49.6-72.1) in gem/nab group (p = 0.41). No significant differences in the median OS or PFS were observed between the gem/nab/toc group and the gem/nab group (OS, 8.4 versus 8.0 months; HR, 0.75; 95% CI, 0.54-1.05; p = 0.10), and (PFS, 5.6 versus 5.5 months; HR, 0.85; 95% CI, 0.61-1.20; p = 0.36). The 12, 18 and 24-month OS rates were 37.1% (95% CI, 26.0%-48.3%), 27.1% (17.4%-37.8%), 10% (4.4%-18.3%) for gem/nab/toc and 28.2% (18.3%-38.9%), 7.0% (2.6%-14.5%), 2.8% (0.5%-8.8%) for gem/nab, respectively. The ORR was 37.1% (95% CI, 25.9%-49.5%) in gem/nab/toc group and 35.2% (24.2%-47.5%) in gem/nab group. The incidence of grade 3 or higher treatment related adverse events was 88.2% in gem/nab/toc and 63.4% in gem/nab group (p < 0.001). Of those, neutropenia (55.3% versus 16.9%), and thrombocytopenia (40.8% versus 11.3%) were most common. Two and one treatment-related deaths, respectively, in gem/nab/toc and gem/nab group, occurred during the study. Conclusions: In patients with advanced PC, the addition of tocilizumab to gem/nab did not result in improved OS rate at 6 months. Although more patients were alive at 18 months in the gem/nab/toc, long-term survival rates exceeding 24 months were not different between groups. The biomarkers for selection of patients who might benefit from gem/nab combined with tocilizumab are to be identified. Clinical trial information: NCT02767557 .
Validation of the PDACai signature in predicting relative benefit from frontline FOLFIRINOX (FFX) and gemcitabine/nab-paclitaxel (GA) for patients (pts) with metastatic pancreatic cancer (mPDAC).
Authors: Pishvaian Michael J. , Blais Edik Matthew , Thach Dzung , Brody Jonathan Robert , Matrisian Lynn McCormick , Halverson David Charles , DeArbeloa Patricia , Rocha Flavio G , Hendifar Andrew Eugene , Petricoin Emanuel 
Published: June 2023

4149 Background: Nearly 50% of pts with mPDAC never receive a 2nd line of therapy for metastatic disease following frontline FFX or GA. Genomic alterations in the DDR pathway (e.g. BRCA1/2) are associated with increased progression-free survival (PFS) on platinum-containing regimens (e.g. FFX), but other biomarker-treatment associations that predict benefit from GA and/or FFX in mPDAC remain unexplored. In this retrospective real-world evidence (RWE) study, we use a data-driven machine learning approach to gain new insights from the mutational landscape in mPDAC and validate the PDACai signature in predicting personalized benefit from both FFX and GA. Methods: We analyzed real-world outcomes from 711 pts with mPDAC who underwent genomic profiling via the Know Your Tumor program or were referred to Perthera by treating oncologists. Chart-abstracted PFS data on either 1st line FFX or GA were split (60:40) into independent training and validation cohorts for each regimen. All models integrate a shared set of clinical (age < 63, sex) and lab-agnostic molecular features derived from clinical NGS testing reports (DDR pathway alterations, specific KRAS variants, frequently mutated genes). Relative benefit scores predicted by FFX or GA models were evenly binned into three PDACai signature categories representing lower, middle, and upper tertiles for each independent cohort. Statistical differences in median PFS were evaluated using ordinal Cox regression. Results: Median PFS followed predicted trends as generated by PDACai for each therapy in training and validation cohorts. The predictive utility of PDACai was confirmed in the independent validation cohorts when comparing PFS on FFX (p = 0.03744; HR = 0.75 [95% CI: 0.58-0.98]) and GA (p = 0.00006861; HR = 0.65 [95% CI: 0.53-0.8]) across tertiles. Conclusions: Response to chemotherapy is heterogeneous and difficult to predict in pts with mPDAC. Using RWE, the PDACai signature successfully predicted relative differences in PFS on both FFX and GA in mPDAC. With prospective validation, personalized insights generated by PDACai from pts with similar biomarker profiles could be used to tailor treatment sequencing in pts with NGS testing results, particularly those without actionable genomic findings. [Table: see text]
Tandem duplicator phenotype: A novel targetable subgroup in pancreatic cancer?
Authors: Farooq Abdul Rehman , Zhang Amy , O'Kane Grainne M. , Denroche Robert Edward , Jang Gun Ho , Fischer Sandra , Dodd Anna , Holter Spring , Wilson Julie , Grant Robert C. , Aung Kyaw Lwin , Zogopoulos George , Elimova Elena , Prince Rebecca M. , Jang Raymond Woo-Jun , Biagi James Joseph , Notta Faiyaz , Gallinger Steven , Knox Jennifer J. , Tsang Erica S 
Published: June 2023

4161 Background: Validated biomarkers are urgently needed to provide a more precise approach in pancreatic cancer (PDAC). Homologous recombination deficiency (HRD) is a heterogenous cohort in PDAC and predicts platinum and PARP inhibitor sensitivity. The BRCA-1 genotype associates with distinct tandem duplications (TDs), however non-BRCA 1 TD phenotypes (TDP) have been observed across tumour types and may be associated with perturbations in CDK12, FBXW17, and CCNE1. Here, we characterize the prevalence and outcomes of TDP in a large series of prospectively sequenced PDAC. Methods: Whole-genome sequencing was performed in 191 early stage resected and 275 advanced PDAC cases in the PanCuRx initiative and the COMPASS trial at the Ontario Institute for Cancer Research and Princess Margaret Cancer Centre. Tumors underwent laser capture enrichment prior to sequencing. TD scores were calculated as previously described by Menghi et al, and HRDetect scores assigned. Samples were classified as classical or basal-like by Moffitt. Outcomes of patients with TDP tumors were evaluated. Tumors that are nonHRD and nonTDP are referred to as typicals. Results: Of 466 cases, 46 were identified as TDP (9.9%; 17 resected, 29 advanced). Subgroups of TDP by etiology included BRCA1 (n=8; 6 germline, 2 somatic), somatic CCNE1 (n=1), and unknown (n=37; no identified alterations in TDP-related genes). Pathogenic germline variants were not found in unique genes other than BRCA1. HRD TDP was associated with a significantly smaller TD size compared to nonHRD TDP (median 12 kb vs. 125 kb, p<0.0001) and median TD load of 114. NonHRD TDP genomes exhibited elevated TD load (median 70 vs. 13, p<0.0001) and HRDetect scores (p<0.0001) compared with typicals. NonHRD TDP was not prognostic in resected PDAC disease (p=0.6361) compared with typicals. We observed a trend towards improved response to 1st-line platinum therapy in nonHRD TDP vs. typicals (p=0.066) for patients with advanced disease. When stratified for only ‘classical’ RNA subtype cases as per Moffitt classification (HRD TDP:2 basal-like, 8 classical, 1 unknown; nonHRD TDP: 9 basal-like, 25 classical, 1 unknown), platinum therapy was correlated with better response in non-HRD TDP vs. typicals (n= 10, 70% ORR, p=0.0108) highlighting the chemoresistance of the basal-like subgroup. Superior survival was not observed in this small cohort. Conclusions: In PDAC, the etiology of nonHRD TDP is unclear but may represent a potential marker for platinum and DNA damage response agents. Further investigation is warranted with a larger sample size.
Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): An international randomised trial.
Authors: Abu Hilal Mohammed , Korrel Maarten , Jones Leia , van Hilst Jony , Björnsson Bergthor , Boggi Ugo , Bratlie Svein Olav , Butturini Giovanni , Casadei Riccardo , Edwin Bjørn E. , Esposito Alessandro , Falconi Massimo , Groot Koerkamp Bas , Keck Tobias , de Kleine Ruben , Kokkola Arto , Lips Daan , Luyer Misha , Zerbi Alessandro , Besselink Marc G. 
Published: June 2023

4163 Background: In the absence of randomised trials, the oncological safety of minimally invasive distal pancreatectomy (MIDP) in patients with pancreatic cancer continues to be a matter of debate. Methods: An international randomised non-inferiority trial including patients with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, <1mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients who did not undergo a resection. The pre-defined non-inferiority margin was set at -7%. Results: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). The modified intention-to-treat population included 117 patients in the MIDP group and 114 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 4%, 90% CI -6 to 14%; p=0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p=0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p=0.45). Other postoperative outcomes were comparable. Conclusions: In this trial, the rate of radical resection following MIDP was non-inferior compared to ODP. This confirms the oncological validity of the minimally invasive approach in patients with resectable pancreatic cancer. Clinical trial information: ISRCTN44897265 .
Incidence, epidemiological characteristics, and cause-specific survival analysis of ampullary carcinoma using the SEER database.
Authors: Gor Rajvi , Gwalani Pranav , Gor Dhairya , Gwalani Twinkle , Narvel Hiba , Vegivinti Charan Thej Reddy , Desai Sudhamsh , Vikash Fnu , Vikash Sindhu , Yusuf Hasiya , Kumar Abhishek 
Published: June 2023

4168 Background: Ampullary carcinomas (AC) are rare and comprise only 0.2% of gastrointestinal malignancies, and there is a paucity of studies analyzing them. We studied the incidence, demographics, tumor characteristics, and survival variables of patients with AC using the Survival, Epidemiology, and End Results [SEER] November 2021 database. Methods: We identified 3650 patients aged >18 with microscopically confirmed adenocarcinoma of the ampulla using ICD-O-3 site code C241 and histology codes (8140-8147, 8480, 8490, 8500). The epidemiological characteristics and the survival variables included were age, gender, ethnicity, and American Joint Committee on Cancer [AJCC] Staging. The overall 5-year survival (OS), cause-specific 5-year survival (CSS), and CSS plots across different strata were plotted using the Kaplan-Meier Method. The analysis was done using the Cox proportional hazard regression model (p<0.05). Results: The overall age-adjusted incidence of AC was 0.3 per 100,000 cases. The median age at diagnosis was 69 (Interquartile range - 59, 78). It was more common in males (56.03%) and Non-Hispanic White (58.96 %), with the most common stages at a presentation being stage 2B IIB (22.08%) and stage III (22.11%). The observed overall 5-year survival was 31%, and the cause-specific 5-year survival was 37.5%. The CSS was not significantly associated with gender (p=0.06). The estimated hazards of death attributed to AC increase by 13% (p < 0.0001) for every 10-year increase in age at diagnosis above 67 years. The CSS was also associated with race, with African Americans and Hispanics being associated with higher hazards of death attributed to AC when compared to Non-Hispanic Whites with HR of 1.5 (p<0.0001) and 1.12 (p=0.01), respectively. Conclusions: Ampullary carcinoma is more commonly seen in males and non-Hispanic Whites with a median age of 69 years. Patients are typically diagnosed in stages IIB and III. Lower CSS rates were associated with advancing age, African American, and Hispanic populations. We need further studies to determine whether these disparities between different races are due to socioeconomic, genetic, or biological factors. Additional studies investigating how different treatment options affect AC survival, especially in this population subset, can be explored. [Table: see text]
Multi-institutional study evaluating the role of circulating tumor DNA (ctDNA) in management of appendiceal cancers (AC).
Authors: Belmont Erika , Bansal Varun Vivek , Zeineddine Mohammad A. A. , White Michael , Polite Blase N. , Liao Chih-Yi , Eng Oliver S. , Turaga Kiran , Shen John Paul Y.C. , Shergill Ardaman 
Published: June 2023

4170 Background: AC frequently present with peritoneal metastases (PM) which are difficult to accurately measure with imaging techniques or serum tumor markers. ctDNA is a novel, promising biomarker to assess minimal residual disease (MRD) and therapy response. Its utility in AC with PM is poorly studied due to the rarity of this disease condition. This is a report on the role of ctDNA in AC management. Methods: Patients with AC managed at two high volume centers between 01/01/2019 to 12/15/2022were included in this study. CtDNA measurements were prospectively collected using Signatera tumor informed ctDNA assay during clinical care and these data were abstracted retrospectively. Cox-proportional hazards were utilized for survival analysis. Results: 97 patients with AC were included with a median age of 57 (IQR 53-66) years, majority being non-Hispanic white (85%) and female (63%). 68 (70%) patients had ctDNA assay drawn at the time of confirmed clinical disease (radiographic or laparoscopic). The sensitivity of ctDNA was 56% (CI 44% - 67%)) for all grades, and 66% (CI 49% - 80%) for grade 3 tumors. 65 (67%) patients underwent cytoreductive surgery (CRS), of which 16 (24.6%) had preoperative ctDNA assays. Sensitivity in this cohort of surgical patients was 25% and positive ctDNA showed poor correlation with PCI score at time of surgery (n=4, r = 0.38, p = 0.14). Any positive value for post-operative ctDNA was associated with lower disease free survival (DFS) (9 months (CI 5-13) in low grade AC and 10 months (CI 7-14) in high grade AC, compared to not reached for those persistently negative (p<0.001) over a median follow-up duration of 17 months. This difference persisted despite adjusting for adjuvant chemotherapy for high-grade disease (aHR = 11.2 (1.4-88.6), p = 0.023). Conclusions: This is the largest study reported to date of tumor informed ctDNA testing in patients with AC. These data show that ctDNA has low sensitivity in both the metastatic unresectable and in pre-operative settings. However, ctDNA positivity after CRS in AC has prognostic value and could be used to guide systemic therapy decisions.