bluuebunny/crossref_metadata_2025_split huggingface dataset:
The potential use of blood-based tumor fibrosis markers as diagnostic and prognostic biomarkers in patients with biliary tract cancer.
Authors: Christensen Troels Dreier , Jensen Christina , Willumsen Nicholas , Larsen Ole , Leerhøy Bonna , Hansen Carsten Palnaes , Madsen Kasper , Nielsen Dorte , Johansen Julia S. 
Published: June 2022

4082 Background: Patients with biliary tract cancer (BTC) have a very poor prognosis. A better understanding of the disease and potential novel biomarkers are needed. BTC is characterized by a collagen-rich desmoplastic extracellular matrix (ECM), and tumor fibrosis is linked to cancer progression and treatment resistance. We tested the diagnostic and prognostic use of seven circulating biomarkers associated with ECM remodeling. We evaluated both pro-peptides (pro-peptide of collagen type III (Pro-C3), VI (PRO-C6), XI (PRO-C11)) and degradation fragments (matrix metalloproteinase (MMP) degraded collagen type III (C3M) and IV (C4M), granzyme B degraded collagen type IV (C4G), citrullinated and MMP degraded vimentin fragment (VICM)). Methods: The study included 269 patients with all stages of BTC (intrahepatic cholangiocarcinoma (CC) (n=124), extrahepatic CC (n=89), and gall bladder cancer (n=56)), and 49 patients with benign biliary tract disease. Serum samples were collected from the patients with BTC before surgery (n=36), 1st line (n=199), and 2nd line (n=56) treatment. A total of 22 patients had samples collected at two timepoints. The seven ECM markers and carbohydrate antigen 19-9 (CA19-9) were analyzed using enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay. Results: The levels of C3M, C4M, PRO-C3, PRO-C6, PRO-C11, and VICM were significantly elevated in patients with BTC compared to patients with benign disease (Wilcoxon test, adjusted p-value < 0.05). Area under receiver operating characteristics curve (AUC) identified PRO-C3 (AUC=0.87) as the ECM marker that best discriminated between patients with BTC and controls. A model combining PRO-C3 and CA19-9 further improved the diagnostic accuracy (AUC=0.97). Elevated levels of four markers (C3M, C4M, PRO-C3 and PRO-C6) before 1st line treatment for BTC were associated with short overall survival (OS) in separate multivariate cox regression analyses adjusting for CA19-9, performance status, and stage. Similarly, elevated levels of PRO-C3 and PRO-C6 before 2nd line treatment were associated with short OS (Table). Conclusions: We identified specific blood-based collagen fragments as potential novel biomarkers for BTC. Our results indicate that patients with BTC have an elevated collagen remodeling, and that increased collagen turnover is associated with a poor prognosis for these patients. [Table: see text]
Efficacy and safety of low-dose apatinib in advanced hepatocellular carcinoma.
Authors: Meng Lingbin , Zheng Zhuangzhuang , Ji Rui , Xu Xiaochun , Xin Ying , Jiang Xin 
Published: June 2022

4104 Background: Apatinib, a tyrosine kinase inhibitor, has shown promising effects on advanced hepatocellular carcinoma (HCC) recently. However, studies on its efficacy and safety are limited with controversial findings. Therefore, this study aimed to reveal the efficacy and safety of low-dose apatinib for the treatment of advanced HCC in the real world. Methods: Between January 2017 and August 2020, 178 patients with advanced HCC treated with apatinib at three different institutions were included for the present study. 174 patients received oral apatinib 250 mg daily and 4 received 500 mg daily until disease progression. 25 and 103 patients were also treated with immunotherapy and transcatheter arterial chemoembolization (TACE) at least once, respectively. Tumor response and adverse reactions were evaluated according to RECIST 1.1 and CTCAE 5.0 respectively. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of variables in a univariate and multivariate setting. Results: During the 24-month follow-up period, 0 (0%), 28 (15.73%), 103 (57.87%) and 47 (26.40%) patients achieved a compete response (CR), partial response (PR), stable disease (SD), and progressive disease (PR), respectively. The overall response rate (ORR) and disease control rate (DCR) were 15.73% and 73.60% respectively. Interestingly, among the 28 patients with PR, 27 received apatinib as the first or second line treatment and 21 received immunotherapy or TACE as a combined treatment, indicating early application of apatinib and combination treatment could provide better efficacy. Kaplan-Meier analysis revealed the median overall survival (OS) and progressive-free survival (PFS) were 16.0 and 7.0 months respectively, which are significantly higher than previously reported survival of sorafenib in advanced HCC. Univariate Cox analysis indicated medication lines, distant metastasis, aplpha fetoprotein (AFP) level, portal vein tumor thrombus (PVTT) and combination therapy significantly affected OS and PFS. Multivariate Cox analysis confirmed third-line treatment (HR = 3.21; 95%CI = 1.54–6.68; p= 0.002), and PVTT (HR = 1.75; 95%CI = 1.13–2.70; p= 0.011) were independently associated with worse PFS. In contrast, apatinib combined with immunotherapy (HR = 0.52; 95%CI = 0.32–0.83; p= 0.008) or TACE (HR = 0.27; 95%CI = 0.18–0.40; p< 0.001) were independently associated with better PFS. Similar findings were also present on OS. The most common treatment-related adverse events were hypertension (29.21%), fatigue (16.85%), hand and foot syndrome (16.29%), vomiting (14.04%), liver dysfunction (6.18%), and proteinuria (6.74%). No severe (grade ≥3) adverse events were observed. Conclusions: Low-dose apatinib is able to provide effective and safe treatment for advanced HCC. Early application of apatinib and combination treatment could provide even better efficacy.
Clinical and genomic characterization of ERBB2-altered gallbladder cancer.
Authors: Mondaca Sebastian , Schultz Nikolaus , Roa Juan Carlos , Walch Henry S. , Sepulveda Santiago , Harding James J. , Yaqubie Amin , Garcia Patricia , Aguayo Gloria , Nervi Bruno , Li Bob T. , Abou-Alfa Ghassan K. 
Published: June 2022

4114 Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.
Analysis of molecular characterization: Pancreatic ductal adenocarcinoma with hepatic metastases.
Authors: He Yonggang , Huang Xiaobing , Li Jing , Tang Yichen , Du Pengyao , Zhang Yaxuan , Liu Chuang , Li Ling 
Published: June 2022

4129 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Distant metastasis is the leading cause of cancer death. Approximately 50% of PDAC patients are discovered to have distant metastases, mainly in the liver. Chemotherapy is the main recommended treatment for metastatic PDACs, with a median survival time of only 4-6 months and the 5-year survival of 1%. Therefore, deciphering the molecular mechanisms of metastatic PDAC is urgently for exploring effective therapeutic targets. Methods: 93 normal-paired samples from patients with PDAC were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: A total 93 patients with PDAC were analyzed, including hepatic metastases (15/93), lymph node metastases (1/93), colon metastases (1/93), pelvic metastases (1/93), and no distant metastasis (75/93). In PDAC patients without distant metastasis, the most frequent mutated gene was KRAS (72%), followed by TP53 (60%), CDKN2A (21%), SMAD4 (17%), ARID1A (11%), RNF43 (9%), and RBM10 (8%). In PDAC patients with hepatic metastases, we found that the most frequent one was KRAS (100%), followed by TP53 (87%), CDKN2A (40%), SMAD4 (40%), RNF43 (13%), and RBM10 (6%). Furthermore, four PDAC patients occurred KRAS copy number amplification, including 2 cases of hepatic metastases. And a hepatic metastases PDAC patient had ERBB2 and MET copy number amplification. We also found that seven no-metastasis patients carried pathogenic or likely pathogenic germline variants, including BRIP1, PALB2, RECQL, ATM, RAD50, FANCM and BRCA1. Conclusions: High frequency mutation genes in PDAC patients with hepatic metastases were highly consistent with those of no-metastasis patients. KRAS and TP53 gene co-mutations were extensively mutated in hepatic metastases patients. Our results revealed the molecular mechanisms driving PDAC hepatic metastases should be considered in further study.
The impact of HRD in patients with pancreatic adenocarcinoma undergoing surgical resection: An updated analysis.
Authors: Jonsdottir Gudbjorg , Masson Asgeir Thor , Jacobus Laura S. , Churchman Michelle L. , Edge Stephen B. , Noonan Anne M. , Cavnar Michael J. , Ulahannan Susanna Varkey , Sahin Ibrahim Halil , Chan Carlos Hou Fai 
Published: June 2022

4132 Background: Limited data is available regarding which mutations in the homologous recombination repair (HRR) pathway beyond BRCA can be targeted with platinum-based chemotherapy in the perioperative setting in patients with pancreatic ductal adenocarcinoma (PDAC). In this updated analysis, we assess the outcome of patients with homologous recombination deficiency (HRD) in response to platinum vs. non-platinum based perioperative chemotherapy in resected PDAC and have included additional variants linked to HRD. Methods: Patients with resectable PDAC, diagnosed between 1999-2020 from the participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Patient’s germline and somatic whole exome sequencing (WES) data were analyzed for known pathogenic and likely pathogenic variants according to ClinVar for the following HRR pathway genes: BRCA1, BRCA2, PALB2, BRIP1, BRAD1, BLM, BAP1, ATM, RAD51C, RAD51, RAD50, RAD54B, CHECK2, NBN, FANCA/B/C/D2/E/F/G, ARID1A, MRE11 and XRCC2. The Kaplan Meier method was used to compare median overall survival (mOS) between patients with and without HRR pathway mutations in response to perioperative platinum vs non-platinum-based chemotherapy. Multivariate cox proportional hazard model was used to calculate HR and 95% CIs adjusting for age, sex and pathologic stage. Results: The ORIEN cohort included 311 patients with resectable PDAC and available WES data. A total of 22 patients (7%) had an HRR pathway mutation. Of these, 8 (36%) received perioperative platinum-based chemotherapy and 9 (41%) a non-platinum based regimen, 4 patients (23%) received no perioperative systemic treatment. Frequency of HRR variants detected: BRCA2 n=8 (2.6%), BRCA1 n=3 (1%), ATM n=2 (0.6%), ARID1A n=1 (0.3%), BRIP1 n=1 (0.3%), CHECK2 n=1 (0.3%), FANCG n=1 (0.3%), PALPB2 n=1 (0.3%), RAD50 n=4 (1.3%), RAD51C n=1 (0.3%). The mOS for patients with HRR mutations exposed to perioperative platinum-based chemotherapy was 3.5 years (95% CI 3.4-NA), patients with HRR mutation but no platinum exposure had a mOS of 1.2 years (CI 0.9-NA). In patients with no HRR mutation exposed to platinum-based chemotherapy mOS was 2.7 years (CI 2.3-3.9) and in those without exposure mOS was 2.9 years, p=0.43. Comparison of risk of death between the 4 groups is demonstrated in the table. Conclusions: There was a trend towards improved survival in patients with PDAC who harbored a HRR pathway mutation and were treated with perioperative platinum-based chemotherapy compared to those with no platinum exposure. Our results highlight the importance of identifying patients with HRD beyond BRCA and the need for large prospective studies in the perioperative setting to further assess their predictive role. [Table: see text]
Evaluation of stage IV pancreatic adenocarcinomas based on mutational profiling of tumors.
Authors: Poruk Katherine E , Moran Amber , Doctor Vicki , Elvin Julia Andrea , Radhi Saba , Loaiza-Bonilla Arturo , Schink Julian C. , Markman Maurie 
Published: June 2022

4139 Background: Curative treatment of pancreatic adenocarcinoma (PDAC) remains a challenge, as most patients present with advanced disease that has spread to other organs. The main opportunity for cure for these individuals remains systemic therapy. An improved understanding of the tumor biology is needed to appropriately target therapies for individual patients. We present cohort of Stage IV PDAC patients who underwent prospective comprehensive genomic profiling (CGP) in a national cancer network to evaluate genomic mutations, treatment patterns and survival. Methods: Between 2013 and 2021, 458 patients with Stage IV PDAC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue for treatment decision-making. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Patient demographics and outcomes were retrospectively reviewed with IRB approval. Results: Median patient age at presentation was 59 years (range, 26-84) and a majority were male (55%). Median overall survival was 15 months. Most patients were treated with first line chemotherapy, predominantly gemcitabine or FOLFIRINOX. GA were identified in 98% (n = 447) of PDAC patients. The most common genomic alterations were in KRAS (85%), TP53 (75%), CDKN2A (52%), SMAD4 (21%), ARID1A (9%), BRCA2 (5%), RNF43 (4%), and BRCA1 (1%). A mutation in one of the four commonly mutated genes ( KRAS, TP53, CDKN2A, or SMAD4) was identified in 94% (n = 426). Median overall survival was significantly worse for patients with mutations in KRAS or TP53 (both, P < 0.05). 185 patients (40%) had an actionable mutation based on the Know Your Tumor registry trial, including mutations in BRCA1, BRCA2, BRAF, CHEK2, ATM, ATK and STK11. MSI status was noted for 226 patients; only one patient was MSI-high. Tumor Mutational Burden (TMB) was known for 228 patients and was split as follows: 199 TMB-low (87%), 27 TMB-intermediate (12%), and 2 TMB-high (1%). TMB status was not associated with OS (P = 0.21). PD-L1 status was obtained in 20 patients, with 9 PD-L1 positive (45%); this was not associated with OS (P = 0.66). Of the 38 patients with a BRCA1 or BRCA2 mutation, 31 (82%) were treated with Olaparib. Other commonly utilized therapies included Niraparib (n = 56), Regorafenib (n = 8), Everolimus (n = 34), Erlotinib (n = 8), and Cetuximab (n = 6). Conclusions: In a large series of Stage IV PDAC patients assayed with CGP, GA were identified in 98% of tumors but only 40% had an actionable mutation. Most patients continue to be treated with conventional chemotherapy despite a sizeable group with targetable mutations. Further work is needed to identify targeted therapies for the more common mutations in PDAC given their impact on overall survival.
A randomized, non-comparative, phase II study of maintenance OSE2101 vaccine alone or in combination with nivolumab (nivo) or FOLFIRI after induction with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): First interim results of the TEDOPAM GERCOR D17-01 PRODIGE 63 STUDY.
Authors: Hilmi Marc , Mitry Emmanuel , Turpin Anthony , Bouché Olivier , Metges Jean-Philippe , Ghiringhelli François , Trouilloud Isabelle , Roth Gaël , Baumgaertner Isabelle , Borg Christophe , Ammarguellat Hanifa , Guillet Marielle , Rinaldi Yves , Lecomte Thierry , Louvet Christophe , Lambert Aurélien , Hautefeuille Vincent , Garcia-Larnicol Marie-Line , Henriques Julie , Neuzillet Cindy 
Published: June 2022

4148 Background: OSE2101 is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts. This study aimed to assess the efficacy and safety of OSE2101 ± anti-PD1 nivo as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction chemotherapy. Methods: TEDOPaM-PRODIGE 63 was initially a 3-arm, open-label, randomized, non-comparative phase II study. Pts with aPDAC, HLA-A2 positive (blood) and no progression after 8 cycles of (modified) FOLFIRINOX were randomized 1:1:1 to receive FOLFIRI (standard Arm A), OSE2101 (subcutaneous injection on D1 Q3W x 6 doses then Q8W until M12 then Q12W up to M24, experimental Arm B) or OSE2101 + nivo (360 mg IV on D1 Q3W x 6 then 480 mg Q4W up to M24, experimental Arm C). FOLFIRI was reintroduced at disease progression in Arms B and C. Primary endpoint was overall survival (OS) rate at 12 months (M12) (Fleming two-stage design, H0: 25%; H1: 50%, one-sided alpha: 2.5%, power: 90%). 156 Pts were planned. Results: Following the occurrence of 2 tumor flares in Arm C, an Independent Data Monitoring Committee (IDMC) recommended to continue FOLFIRI as backbone in experimental Arm B and stop Arm C. Interim analysis results refer to 29 randomized Pts: 9/10/10 in Arm A/B/C, respectively. Median age was 63 years, 52% were men, 55% had ECOG PS 0, and 83% were metastatic. Best response to induction FOLFIRINOX was partial response in 48% and stable disease in 52%. With a median follow-up of 23 months, M12-OS rate was 44%, 40%, and 30% in Arm A, B and C. Other efficacy results are summarized in Table below. No OSE2101-related toxicity of grade ≥ 3 (G≥3) were observed in Arm B; 1 G3 cytokine-release syndrome (OSE2101-related) and 2 tumor flares (nivo-related) leading to death were observed in Arm C. Conclusions: Maintenance OSE2101 monotherapy showed a favorable safety profile and encouraging time to strategy failure warranting further evaluation. OSE2101 + nivo was associated with poorer outcomes leading to close Arm C. Following IDMC recommendation, the study is ongoing with the new design (maintenance FOLFIRI vs. FOLFIRI + OSE2101). Clinical trial information: NCT03806309. [Table: see text]
Evaluation of somatic and germline variants in patients with small bowel adenocarcinoma reveals clinically actionable targets.
Authors: Wei Deng , Liu Si , Li Xiaomo , Ma Tonghui 
Published: June 2022

4159 Background: Small bowel adenocarcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis and limited treatment options. Because the treatments for colorectal cancer showed limited efficacy in SBA, the NCCN guide strongly encourages SBA patients to participate in clinical trials. In this study, we aimed to explore clinically actionable variants in a large cohort of patients with SBA to assist oncologists to select the matched trials for patients. Methods: To explore therapeutic targets in 84 Chinese SBA patients, a deep sequencing panel (OncoPanscan, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results: Recurrent somatic mutations included TP53 (57%), KRAS (56%), APC (31%), SMAD4 (21%), MDM2 (13%), CTNNB1 (12%), KMT2C (12%), SOX9 (12%), ARID2 (12%), FAT3 (11%), FBXW7 (10%), SPTA1(10%) and PIK3CA (10%). Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib. We also found four type 2 MAP2K1 activating mutations (K57E, K57N, and F53L) which can be targeted by trametinib. Furthermore, oncogenic ERBB2/HER2 mutations were seen in 4 patients including S310F (n = 1), V842I (n = 2) and V777L (n = 1). We also found one patient harbored ERBB2/HER2 high magnification amplification. These five patients were candidates for HER2-targeted therapy clinical trials. Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib. In addition, we observed targetable gene amplification of MDM2 (n = 2) and FGF3/4/19 (n = 2). There were two patients with MLH1 loss-of-function germline mutations that may benefit from immunotherapy. Among 78 patients with available MSI status, three were designated as microsatellite instability. The median TMB of microsatellite stable patients was 2.82 mutations/Mb. Lastly, we observed five deleterious germline mutations, three for SBDS, one each for APC and ERCC5. Taken together, at least 33 (39%) patients in our cohort harbored actionable genetic alterations. Conclusions: Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.