bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early experience with nivolumab, gemcitabine, and lenvatinib for fibrolamellar hepatocellular carcinoma.
Authors: Kent Paul , Tasse Jordan C , Schadde Erik , Kato Tom , Humar Abhinav , Fisher Oliver M , Dixon Matthew , Stockwell Tom , Cornelius Albert , Kim Thomas , Ellison Jessica 
Published: June 2023

4076 Background: Fibrolamellar Carcinoma (FLC) is a rare deadly form of liver cancer affecting adolescents and young adults (AYA), presenting at an advanced stage, with up to 80% relapse, and no proven systemic therapies. Effective systemic therapies could convert patients to resectable or prolong progression free survival (PFS) and overall survival. Because of reported successes with nivolumab + lenvatinib (LEN) and of Gemcitabine (GEM) + LEN, and the potential synergy of GEM with NIV through elimination of myeloid suppressor cells in the tumor microenvironment, we offered NIV+LEN+GEN (NLG) to relapsed/refractory FLC patients ineligible for clinical trials. Our objective is to describe our initial experience using NLG in high risk AYA FLC patients. Methods: We reviewed the records of all FLC patients discussed at the FibroFighters National Tumor Board who received NLG. Results: Twenty-five patients (10F,15M), median age 20 (7-56), all stage IV, received a total of 322 cycles of NLG (median 11 cycles/patient,19 neoadjuvant, 1 adjuvant, 4 both). The median number of relapses, prior systemic therapies, and surgeries were 2(0-6), 3(0-6), and 2(0-7) respectively. Most patients had failed NIV+LEN (n = 8) or GEM+LEN (n = 7) prior to starting NGL. The 17 patients with at least one evaluation had a mean follow up of 10 months (3-23) and 18 cycles (6-38) of NGL with the best response by RECIST 1.1 of CR(1), PR(6), SD(10), and PD(0), for an objective response rate (PR+CR) of 41% and disease control rate (CR+PR+SD) of 100%, and estimated best volume response median of -20% (-89%,+10%). There have not yet been any progressions. Three of the 7 who were too soon for imaging, have had resolution of ascites. The PFS and Overall Survival at 6, 9, and 12 months are: 1.0/1.0, 0.82/0.82, 0.67/0.67. Two of 17 with carcinomatosis have no evidence of disease on PET and MRI after 10 cycles. Twenty-two of 24 are continuing NGL. Nine of 16 unresectable patients became surgical candidates, of these 4 showed > 50% necrosis histologically at surgery. 13 of 17 showed necrosis on imaging. Eleven of 16 are currently in their longest PFS since diagnosis. Sixteen patients had serial tumor-informed circulating DNA (Signatera) during therapy: Five became negative (0.0 mean tumor molecules/ml plasma), and overall mean drop was -27% (-93%, +111%). No patients have stopped therapy. The most common toxicities were hypertension and fatigue in 25% and 20% respectively, grade 1 or 2. There have been no grade 3 or 4 toxicities to date. Conclusions: Our retrospective experience with NGL for FLC offers another potential systemic option for patients who are not surgical candidates or with multiple relapses. NGL was well tolerated and provided excellent disease control to patients with few options. Prospective trials are needed.
Liquid-biopsy detection of FGFR2 and other actionable rearrangements in GI malignancies.
Authors: Kasi Pashtoon Murtaza , Lee Jessica Kim , Tukachinsky Hanna , Pasquina Lincoln W , Vanden Borre Pierre , Decker Brennan James , Pavlick Dean C. , Allen Justin , Parachoniak Christine , Schrock Alexa Betzig , Lovly Christine M. , Oxnard Geoffrey R. , Subbiah Vivek 
Published: June 2023

4085 Background: Actionable rearrangements (RE) represent an emerging therapeutic target for GI malignancies. However, there remains uncertainty whether liquid biopsy (LBx) assays testing circulating tumor DNA (ctDNA) can detect RE with the same fidelity as tissue biopsy. Here we report the performance of ctDNA-based comprehensive genomic profiling (CGP) for the detection of RE leveraging an FDA-approved >300-gene platform, with a focus on data from patients with GI malignancies. Methods: An institutional research database of clinical CGP results for tissue biopsy (TBx, FoundationOneCDx) and LBx (FoundationOneLiquid CDx) from patients with cancers of the GI tract was reviewed. Sensitivity for FGFR2 RE was studied in patients with cholangiocarcinoma (CCA) or carcinoma of unknown primary (CUP) and both TBx and LBx CGP available. Results: Across 7870 GI LBx, 1094 predicted pathogenic RE were detected in 826 cases (10%) including 283 oncogenic kinase RE, 686 inactivating RE, and 125 other gain-of-function RE. FGFR2 was the most frequently rearranged gene, enriched in CCA (4.4%, 37/833) and stomach (3.0%, 11/368). EGFR RE (38) occurred across 6 cancer types and included 8 fusions, 15 c-terminal truncations, 4 intragenic deletions/inversions, and 3 kinase domain duplications. BRAF RE (31) were detected among in colorectal (22) and pancreas (9) cases. LBx detected 44 exon 3 skipping (protein stabilizing) RE in CTNNB1 (beta-catenin) across all samples. Other frequent activating RE were detected in MYC (36), FGFR3, RET, ROS1 (21 each), and ALK (13). Potentially targetable inactivating RE were detected in BRCA1 (28), ARID1A (24), STK11 (22), PTEN (17), TSC2 (14), and BRCA2 (8). Focusing on CCA, FGFR2 RE were more prevalent in cases with elevated (≥1%) ctDNA tumor fraction (TF, 26/342, 7.6%), matching the prevalence in TBx (7.8%, 505/6,492) with a similar spectrum of fusion partners seen for both TBx and LBx (30% BICC1, 70% rare for both). In 13 CCA/CUP patients positive for FGFR2 RE by TBx, LBx detected 12 (92%) including 8 different fusion partners; the false negative case had TF <1%. In 11 CCA LBx samples with FGFR2 resistance mutations detected, LBx CGP successfully detected a driver FGFR2 RE in 10 and driver C382R mutation in 1. Conclusions: Rearrangements are represented across GI malignancies, including many that result in known oncogenic drivers that may be targetable with available therapies. We observe reliable detection of FGFR2 fusions in ctDNA, in contrast to some prior publications. ctDNA represents a pragmatic analyte for detection of rearrangements and other actionable alterations, offering timely result return when tissue is inadequate or unavailable. [Table: see text]
Real-world multicentre analysis of patients with hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (A+B): Efficacy, esophagogastroduodenoscopy (EGD) uptake and bleeding complications.
Authors: LEE Cha Len , Freeman Mark , O'Donnell Conor , Moffat Gordon Taylor , Kosyachkova Ekaterina , Lyubetska Hanna , Meyers Brandon M. , Gordon Vallerie Lynn , Ding Philip Q. , Kay Aileigh , Bucur Roxana , Cheung Winson Y. , Knox Jennifer J. , Tam Vincent C. 
Published: June 2023

4105 Background: The IMbrave150 trial established A+B as a standard of care for HCC and an EGD within 6 months (mos) of starting treatment to detect esophagogastric varices and prevent bleeding complications was advised. However, the value of performing EGD in all patients (pts) is unknown. Methods: We conducted a retrospective analysis of all HCC pts treated with A+B between July 2020 to August 2022 at 5 cancer centres from the Canadian provinces of Ontario, Alberta and Manitoba (members of the HCC-CHORD Consortium). Pts characteristics and treatment history including efficacy, EGD details and bleeding events were collected. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated. A comparative analysis was conducted to compare the correlation between the EGD uptake and bleeding events. Results: A total of 112 pts were identified (median age 66 years, 87% male, 24% East Asian, 67% liver cirrhosis, 33% HCV, 25% HBV, 15% NASH, 23% BCLC B, 71% BCLC C, 91% Child-Pugh A, 29% main portal vein invasion, 45% ALBI grade 1 and 54% ALBI grade 2). Prior to systemic, 61% had locoregional therapies. 90% received A+B as first-line therapy, while 9% received it as second-line and 1% as third-line. Outcomes of pts treated with A+B are shown. Before starting A+B, 78 pts (70%) had completed an EGD within 6 mos. Of these, 32 pts (41%) had evidence of varices on EGD, and 15 (20%) required treatment with either banding or beta-blockers. All bleeding events in this population was 15% (n=17). Bleeding rates in the EGD and non-EGD groups were 18% (n=14) and 9% (n=3), respectively. Bleeding adverse events were 5%(n=6) gastrointestinal vs 10%(n=11) non-gastrointestinal (6 epistaxis, 1 ecchymosis, 1 periodontal and 3 unspecified). The GI bleeding rates in the EGD and non-EGD groups were 6% (n=5) and 3% (n=1). Conclusions: Outcomes of HCC pts treated with A+B in Canada are comparable to those observed in the IMbrave150 trial. Our study detected and treated varices at twice the rate of the IMbrave150 trial among the EGD group, reflecting real-world treatment of a high-risk population. Yet, pts who had no EGD before starting A+B, presumably due to a low risk of portal hypertension based on physicians’ judgement, did not experience more bleeding/GI bleeding than those who had an EGD. This supports the approach of selective EGD prior to A+B, and more guidelines are needed in this area. Outcomes and response rate of patients(pts) treated with Atezolizumab with Bevacizumab in this study. [Table: see text]
FDA analysis of treatment efficacy based on etiology of hepatocellular carcinoma.
Authors: Saung May Tun , Fan Jiaxin , Cheng Joyce , Shen Yuan-Li , Casak Sandra J. , Lemery Steven , Fashoyin-Aje Lola A. 
Published: June 2023

4117 Background: Retrospective analyses of trial-level data report that etiology of hepatocellular carcinoma (HCC) (e.g., viral versus [vs.] non-viral) may influence efficacy of systemic therapies used in advanced HCC. FDA conducted an analysis of 9 randomized controlled trials (RCTs; n=5,417) to assess treatment effects based on drug class, treatment line, and HCC etiology. Methods: FDA conducted a retrospective, exploratory analysis of 3 RCTs comparing first line (1L) treatment with anti-programmed cell death (ligand)-1-containing regimens (αPD-[L]1) to single-agent anti-vascular endothelial growth factor therapy (αVEGF), and 6 RCTs comparing second line (2L) treatment consisting of αPD-(L)1 or αVEGF to placebo. For each line of treatment (1L or 2L), meta-analyses of overall survival (OS) were performed for the overall treatment effect and by disease etiology, viral (hepatitis B [HBV], or hepatitis C [HCV]) vs. non-viral. Subgroup analyses were performed to investigate the confounding effect of subsequent therapy (yes vs. no) and region (Asian vs. non-Asian) on etiology. Trial-level hazard ratios (HRs) and 95% confidence intervals (CI) were mostly calculated using patient-level data submitted to FDA. Pooled HRs and CIs were calculated using a random-effects model. Results: While 1L αPD-(L)1 improved OS compared to 1L αVEGF in the overall population (HR [95% CI]: 0.8 [0.73, 0.88]), treatment effects were comparable for viral (HR [95% CI]: 0.75 [0.6, 0.92]; n=1,435) and non-viral (HR [95% CI]: 0.83 [0.72, 0.95]; n=979) subgroup analyses, and not influenced by subsequent therapy or region. Analyses based on specific viral infection (i.e., HBV or HCV), showed that improvement in OS for αPD-(L)1 vs. αVEGF appeared larger for HBV (HR [95% CI]: 0.7 [0.59, 0.82]; n=833) compared to HCV (HR [95% CI]: 0.83 [0.6, 1.16]; n=602). Treatment effects were also comparable in 2L for different etiologies for both αPD-(L)1 (HR [95% CI] for viral: 0.76 [0.62, 0.93]; n=529 and non-viral: 0.85 [0.65, 1.11]; n=337) and αVEGF (HR [95% CI] for viral: 0.79 [0.69, 0.9]; n=1,288 and non-viral: 0.74 [0.63, 0.88]; n=849), and not influenced by subsequent therapy. Nonetheless, compared to placebo, αPD-(L)1 had a larger treatment effect with HBV (HR [95% CI]: 0.69 [0.5, 0.94]; n=459) compared to non-viral etiologies. Conclusions: The results did not demonstrate that etiology of HCC was predictive of OS for both treatment classes based on retrospective, exploratory meta-analyses of 9 RCTs; however, the treatment effects may be more pronounced in patients with HBV who received αPD-(L)1 as 1L or 2L. Uncertainty remains regarding subgroup treatment effects given limited number of trials in the analyses (mostly leading to approvals), overlapping CIs, number of patients in some subgroups, retrospective nature, and exclusion of trials with inadequate data regarding etiology of HCC.
Characteristics and outcomes of patients with young-onset versus average-onset cholangiocarcinoma in the United States.
Authors: Grewal Udhayvir Singh , Dhaduk Rikeenkumar , Patel Sagar , Singh Achintya D , Chau Justin James , Chakrabarti Sakti 
Published: June 2023

4118 Background: Cholangiocarcinoma (CCA) is a lethal malignancy originating from the epithelium lining the biliary tree, with a rising incidence in the Western world. CCA is commonly diagnosed after the age of 50 years, referred to as average-onset CCA (AOCCA), which has known risk factors and predictors of overall outcomes. However, robust data regarding the characteristics and outcomes of patients with young-onset (diagnosed <50 years of age) CCA (YOCCA) are lacking. Methods: Data on patient characteristics, tumor characteristics, incidence, and mortality were retrieved from the SEER database spanning a period from the year 2000 to 2017 (representing 48% of the US population).Intrahepatic CCA (iCCA) was identified with a topography code of C22.0 (liver) and a histology code of 8140, 8160, 8161, 8480, 8481, or 8500 or with a topography code of C22.1 (intrahepatic bile ducts) and a histology code of 8000, 8010, 8020, 8140, 8160, 8161, 8260, 8480, 8481, 8490, or 8500. Extrahepatic CCA (eCCA) was identified with a topography code of C24.1 (extrahepatic biliary ducts) and a histology code of 8000, 8010, 8020, 8140, 8160, 8161, 8260, 8480, 8481, 8490, or 8500, or for any case with a topography code of C22.0, C22.1, or C24.0 and a histology code of 8162 (Klatskin tumor). A comparison was made between the patients with YOCCA and AOCCA. Trends in incidence were analyzed using the Joinpoint regression model. Overall survival distributions were estimated using the Kaplan-Meier method. Results: A total of 28,367 patients were included in the analysis, which included 2,082 (7.34%) patients with YOCCA. We noted an increase in the incidence of YOCCA over the study period (annual percentage change=+2.53, p=0.003). The majority of the patients in the YOCCA group were males (54.66%), White (50%), and had iCCA (71.9%). When compared to AOCCA, these patients were more likely to be males (54.7% vs 52.4%, p=0.048), non-White (39.8% vs 35.5%, p=0.007), and have a diagnosis of iCCA (71.9% vs 65.7%, p<0.0001). Patients in the YOCCA group were more likely to present with regional spread (31.6% vs 28.4%, p<0.0001) and metastatic disease (31.9% vs 25.6%, p<0.0001). YOCCA patients were also more likely to receive surgery (33.3% vs 22.7%, p<0.0001) and chemotherapy (62.6% vs 37.3%, p<0.0001) compared to patients in the AOCCA group. Patients with YOCCA had a significantly better median overall survival (13 months vs. 7 months, p<0.001) than patients with AOCCA. Conclusions: The current analysis showed a significant increase in the incidence of YOCCA over the 17 years of the study period. Patients with YOCCA were more likely to be non-White, males and present with iCCA. Despite presentation with advanced-stage disease (with regional spread or metastatic disease), patients with YOCCA were more likely to receive cancer-directed therapy and had better overall survival than patients with AOCCA.
Genomic characterization of somatic mutations by race and ethnicity in pancreatic cancer defined through AACR project GENIE.
Authors: Maldonado J. Alberto , Tai Chin-Hsien , Alewine Christine 
Published: June 2023

4138 Background: KRAS, TP53, SMAD4, and CDKN2A are widely recognized as the most common somatic mutations amongst patients with pancreatic ductal adenocarcinoma (PDAC); however, previous genomic studies have disproportionately included non-Hispanic White (NHW) patients with little to no inclusion of racial and ethnic minorities, particularly non-Hispanic Black (NHB) and Hispanic patients. Additionally, little is known about the distribution of KRAS point mutations in PDAC in specific racial and ethnic groups. Here, we describe somatic mutation differences in a larger and more racially and ethnically representative PDAC cohort than previously characterized. Methods: PDAC mutational data was downloaded from AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) v13.0, an international data registry of sequenced tumor samples from nearly 150,000 patients, on cBioPortal. PDAC cancer type was identified using OncoTree code. NHW, NHB, Hispanic (of any race), and Asian patients were then selected. Mutational frequency was calculated for all mutations. The primary objective was to compare the mutation frequencies between NHW and other races with respect to the most common mutations. To maximize power, we included any mutation with a frequency ≥5.0% where testing for mutation of that gene had been performed in at least 150 patients. Specific point mutations in KRAS were also extracted with stratification for racial and ethnic group. Fisher’s Exact Test was used to calculate the statistical significance of the differences in mutation frequency between NHW and minority groups. Results: Patients in the PDAC cohort included 5,292 individuals (NHW N = 4296, 80.7%; NHB N = 264, 5.0%; Hispanic N = 460, 8.7%; Asian N = 299, 5.7%). As compared to the NHW group, NHB patients had higher rates of TP53 (78.7% vs 69.0%, P = 0.0006) and PTPRT (5.3% vs 1.8%, P = 0.0095) mutations but fewer GNAS (0.4% vs 2.8%, P = 0.0097) mutations while Asian patients had higher frequency of ARID1A mutations (13.0% vs 8.8%, P = 0.024). KRAS G12D mutation was more prevalent in Hispanic patients (47.0% Hispanic vs 41.1% NHW, P = 0.0238), although rate of KRAS mutation overall was the same. Prevalence of KRAS G12C mutation was equivalent amongst all groups with an overall 1.6% frequency. Conclusions: Understanding the genomic landscape of PDAC is critical as we move towards increased use of targeted therapies to treat this disease. In this study, TP53, PTPRT, GNAS, and ARID1A mutations were shown to occur at different frequencies in specific racial and ethnic groups. G12D mutation of KRAS was disproportionately increased in Hispanics. These differences in molecular landscape amongst racial and ethnic groups could contribute to precision medicine strategies used to address this deadly disease.
Clinical utility of next generation sequencing (NGS) on circulating tumor DNA (ctDNA) in patients (pts) with pancreatic cancer (PC).
Authors: Keane Fergus , Saadat Lily , O'Connor Catherine , Chou Joanne F. , Brannon Angela Rose , Cowzer Darren , Crowley Fionnuala , Debnath Neha , Bowman Anita , Xu Fei , Park Wungki , Zervoudakis Alice , Balogun Fiyinfolu , Varghese Anna M. , Yu Kenneth H. , Kelsen David Paul , Capanu Marinela , Berger Michael F. , Wei Alice Chia-chi , O'Reilly Eileen Mary 
Published: June 2023

4154 Background: ctDNA provides opportunities for identifying targeted therapies, a source to conduct NGS when tissue acquisition is infeasible, detection of minimal residual disease (MRD), and identification of resistance mutations. There are limited large data sets to inform clinical utility and limited correlation of NGS of ctDNA and tumor in PC. Herein, we evaluate the ctDNA detection rate in multiple cohorts of PC and report the ctDNA-tissue genotype concordance in PC at Memorial Sloan Kettering (MSK). Methods: Pts with PC at MSK who had ctDNA prospectively collected using the MSK-ACCESS 129 gene ctDNA NGS assay, were identified. ctDNA detection was defined as the identification of a mutation, copy number (no.) alteration or structural variant. Tissue-based NGS using MSK-IMPACT gene assay was performed for pts with adequate tissue, and matched with ctDNA by date. Clinical, pathologic and outcome data were abstracted. Data are summarized with descriptive statistics. Overall survival (OS) estimated by Kaplan-Meier method from date of ctDNA draw to death/last follow up. Results: From 08/2019 to 07/2022, N= 414 pts with PC and ≥ 1 ctDNA sample included. Median age 69 years (range 29-92), female N=206 (50%). Stage at ctDNA collection: Stage I-III N= 203 (49%); Stage IV N= 211 (51%). ctDNA detection rate by no. of involved organs; 0 organs (MRD), N=7/30 (23%); 1-2 organs, N=158/270 (58.5%); 3-4 organs, N=82/102 (80.4%); >5 organs, 12/12 (100%). CtDNA detection rate by site of metastasis; Liver only, 75/99 (76%); peritoneum only, 15/25 (60%); lung only, 10/22 (45%). In pts with detected ctDNA median CA 19-9 was 494 U/mL (range 0, 247674) vs 100 U/mL (range 1, 22360) in pts with undetected ctDNA. In pts with detected ctDNA median CEA was 7 ng/mL (range 1, 2020) vs 4 ng/mL (range 1, 99) in pts with undetected ctDNA. In stage IV untreated pts, median OS 13 months(m) (95% CI; 7.3, 16) and 10 m (95% CI; 5.6, -) for ctDNA detected vs undetected, respectively. ctDNA detection rates by stage, and concordance between ctDNA and tissue-based NGS for common driver mutations KRAS, TP53, CDKN2A and SMAD4 in N=131 matched pairs are summarized in the table. Conclusions: ctDNA detection rates are high (89%) in pts with untreated stage IV PC, with high concordance between ctDNA and tissue-based NGS (87% - 95%). In untreated stage I-III PC, detection and concordance rates are lower (<50%). Detection rates are associated with disease burden, site of metastasis, CA 19-9/CEA levels. ctDNA is a promising tool in detection of somatic alterations in PC, particularly in stage IV disease, and is a complementary adjunct to tumor-based NGS. [Table: see text]
Impact of novel pan-RAS inhibitors on efficacy and resistance to AMG-510 and MRTX-1133 in pancreatic cancer cell lines.
Authors: Arshad Tariq , Donninger Howard , von Baby Becca , Ferrill Rachel , Burlison Joe , Trent John , Clark Geoffrey J. 
Published: June 2023

4155 Background: Mutant-activated RAS genes are the most frequently mutated gene family associated with cancer (almost 30% of all cancers contain a mutant RAS gene). KRAS is the predominant isoform mutated in cancer and is the isoform exclusively mutated in pancreatic ductal carcinoma (PDAC). Since almost all PDAC cases harbor a mutant RAS, it is arguably the most RAS-addicted tumor type. There is now considerable evidence implicating mutant KRAS as a driver of PDAC. Recently, several mutant KRAS-targeted therapies (sotorasib and adagrasib) have been developed and show promise in PDAC patients. We have developed a direct inhibitor of RAS with a predicted unique interaction region capable of directly binding to wild-type H- and K-RAS, but which shows preferential binding for KRAS G12D and G12C mutants. This novel inhibitor disrupts the RAS effector domain and blocks the ability of RAS to signal through its effectors. Methods: We used in silico virtual library screening to identify an initial candidate inhibitor which was effective at inhibiting the 3D growth of PDAC cells without affecting their growth in 2D. Subsequent iterative rounds of medicinal chemistry was then performed to identify a series of derivatives with enhanced activity, as determined by 3D growth inhibition assays and effects on Ras signaling, as determined by Western blot analysis of phosphor-ERK, phosphor-Akt and activation of Ral A. Results: Our series of RAS inhibitors effectively block PDAC cell growth in 3D without impacting their 2D proliferation and suppress the interaction of KRAS with its effector cRAF. The inhibitors also effectively inhibit RAS signaling in mutant RAS containing PDAC cells. Since our novel compounds are predicted to bind to RAS at a different site to either AMG-510 (G12C specific inhibitor) and MRTX-1133 (G12D specific inhibitor), we tested the co-operativity of our compounds with these existing agents. Our compounds enhanced the anti-proliferative effects of both MRTX-113 and AMG-510 in mutant KRAS G12D and G12C PDAC cells, respectively. Conclusions: We have developed a series of novel RAS inhibitors that directly bind preferentially to mutant KRAS that may serve as new mutant KRAS-targeted therapeutics, and that may also have the potential to enhance the efficacy or suppress the resistance of AMG-510 and MRTX-1133.