bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of minimal residual disease profiling in resectable hepatocellular carcinoma.
Authors: Hu Jie , Zhou Jian , Tang Haoran , Jia Cancan , Xie Feng , Zhang Yue , Jia Shidong 
Published: January 2024

530 Background: Detecting post-surgical residual disease is a critical clinical requirement in resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions have indicated that ctDNA holds promise as a tool for prognostic assessment. Nevertheless, these methods exhibited limited sensitivity and failed to meet the minimal residual disease (MRD) threshold. Here we report the prognostic value of MRD profiling in HCC patients who have undergone hepatectomy. Methods: This retrospective study involved 88 HCC patients who underwent surgical resections in China, from January to May in 2016. During surgery, tumor and normal tissue specimens were collected. Plasma samples were obtained 7 days post-surgery. PredicineBEACON, a baseline tissue- or blood-informed MRD assay, was used for MRD profiling. This entailed identifying tumor-specific mutations through whole exon sequencing of tissue samples. Subsequently, a personalized MRD panel, selecting up to 50 mutations via bioinformatics pipelines merged with a fixed panel featuring 500 tumor actionable hotspots, was created for each patient. To detect MRD in post-surgery plasma samples, we employed ultra-deep sequencing at a coverage of 100,000X, utilizing the designed panel. Results: In the cohort of 88 patients, the distribution based on Barcelona Clinic Liver Cancer (BCLC) staging was as follows: 79.5% stage A (N=70), 12.5% stage B (N=11), and 8.0% stage C (N=7,). The MRD assay identified 36 patients as MRD+ and 52 patients as MRD-. We observed significant correlations between MRD status and both relapse-free survival (RFS) and overall survival (OS). For MRD+ patients, the median RFS was 17.1 months, while it was not reached for MRD- patients (p=0.0013). Likewise, the median OS for MRD+ patients was 40.1 months, in contrast to it not being reached for MRD- patients (p=0.0012). The MRD positivity rate stood at 100% in stage C patients, a significantly higher percentage compared to the rates observed in stage B (36.4%, p=0.0256) and stage A (36.2%, p=0.0042). Significantly, MRD status emerged as a pivotal prognostic differentiator among clinically low-risk patients in stage A: among MRD+ patients, the median RFS was 23.3 months, whereas it was not reached for MRD- patients (p=0.05). Additionally, the median OS of both MRD+ and MRD- was not reached but their survival curves showed significant differences (p=0.038). Conclusions: This study demonstrated the clinical utility of ctDNA MRD assay in patients with resectable HCC, as notably evident in the robust detection of MRD using plasma samples collected 7 days after surgery. Furthermore, the assessment of post-surgical MRD status provided valuable prognostic insights into both patient survival and the risk of disease relapse. ctDNA MRD status played a pivotal role as a prognostic differentiator, particularly among clinically low-risk patients.
Molecular differences with therapeutic implications in early-onset compared to average-onset cholangiocarcinoma.
Authors: Jayakrishnan Thejus , Baca Yasmine , Xiu Joanne , Patel Mehrie , Weinberg Benjamin Adam , Lou Emil , Datta Jashodeep , Khushman Moh'd M. , Gulhati Pat , Goel Sanjay , Biachi de Castria Tiago , Florou Vaia , Nair Kanika G. , Kamath Suneel Deepak , Khorana Alok A. 
Published: January 2024

536 Background: Early-onset cholangiocarcinoma (eoCCA) is among early-onset cancers with the fastest rising rates, yet little is known about its biology. We sought to compare the molecular characteristics of eoCCA with average-onset CCA (aoCCA) with an age cut-off of 50 years, utilizing a real-world multi-omics dataset. Methods: The study comprised patients whose tumors underwent molecular analysis at Caris Life Sciences (Phoenix, AZ) using whole exome and whole transcriptome analyses. Patients were categorized by age as eoCCA defined as <50 years and aoCCA >50 years. Gene expression profiles were analyzed for transcriptional signatures predictive of immunotherapy response including the T-cell inflamed score (TIS) and interferon-gamma (IFG) score. P values (adjusted for multiple testing) were considered significant at False Discovery Rate (FDR) P<0.05 for molecular comparisons and FDR P<0.25 for Gene Set Enrichment Analysis (GSEA). Insurance claims data was used for survival comparison using Kaplan-Meier estimates. Results: The study included 5587 patients - 453 patients with eoCCA and 5134 with aoCCA (Table). Of targetable mutations ( FGFR2, IDH1, IDH2, ERBB2, BRCA, BRAF), FGFR2 fusion was significantly more prevalent in eoCCA (15.7% vs 5.9% in aoCCA, FDR P<0.001). Rates trended higher in eoCCAfor MSI-H tumors (4.1% vs 2.4%), and high tumor mutational burden (6.1% vs 5.1%) but not significantly different (FDR P=1). The IFG score (Fold Change FC: 1.1, FDR P=0.01) and TIS (FC:17.3, FDR P=0.03) were significantly higher in aoCCA vs eoCCA. On GSEA, angiogenesis was enriched in eoCCA (normalized enrichment score NES=1.51, FDR P=0.16) while IFG (NES= -1.58, FDR P =0.06) and inflammatory response (NES= -1.46, FDR P=0.18) were enriched in aoCCA. Median OS was longer in eoCCA (16.5 vs 13.3 months, Hazard Ratio (HR) 0.86, 95%CI 0.78-0.95, P=0.004). Among patients treated with immunotherapy, median OS was longer in patients with eoCCA (19.2 months, n=19) vs aoCCA (7.6 months, n=150) - HR 0.52, 95%CI 0.28-0.94, p=0.03. No survival difference was identified in patients on chemotherapy (HR 0.91, 95%CI 0.76-1.08, P=0.28). Conclusions: In the largest age-stratified analysis of molecular characteristics of CCA, we identified crucial differences, including higher prevalence of FGFR2 fusions and significant differences in immunotherapy-related markers, angiogenesis enrichment, and inflammatory response. Patients with eoCCA experienced better outcomes with immunotherapy even though immune-oncology-relevant markers favored aoCCA. Our findings, especially higher FGFR2 fusion prevalence in eoCCA, underscore the need for NGS testing and the potential for age-tailored therapeutic strategies. [Table: see text]
Comprehensive clinico-molecular profile and efficacy of anti-HER2 therapy for HER2-amplified biliary tract cancer.
Authors: Inoue Kanae , Nakamura Yoshiaki , Caughey Bennett , Zheng-Lin Binbin , Ueno Makoto , Furukawa Masayuki , Kawamoto Yasuyuki , Itoh Shinji , Umemoto Kumiko , Sudo Kentaro , Satoh Taroh , Mizuno Nobumasa , Kajiwara Takeshi , Fujisawa Takao , Bando Hideaki , Yoshino Takayuki , Strickler John H , Bekaii-Saab Tanios S. , Morizane Chigusa , Ikeda Masafumi 
Published: January 2024

544 Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The prevalence of HER2 amplification in BTC has been reported to be 5-20%, and clinical trials suggested the clinical benefit of HER2-targeted treatment in this disease subpopulation. In a global collaboration, we investigated the comprehensive clinico-molecular characterization as well as the efficacy of anti-HER2 therapy in HER2-amplified BTC. Methods: Patients with advanced BTC who received systemic therapy were included from the GOZILA and MONSTAR studies in Japan and from the COLOMATE trial in the US. Genomic alterations were detected by tissue next-generation sequencing (NGS), including FoundationOne CDx and TempuslxT, and plasma circulating tumor DNA NGS including Guardant360 and FoundationOne Liquid CDx. The clinico-molecular characteristics were evaluated in an exploratory cohort comprised of patients from Japan, whereas the efficacy of anti-HER2 therapy was assessed in a biomarker selected cohort with patients from both Japan and the US. Results: Of 439 patients included in the exploratory cohort, 43 (10%) had HER2 amplification. BTC with primary tumor location in the gallbladder accounted for 58% of primary sites of patients with HER2 amplification. TP53 mutation (84% vs 61%, p=0.003) and BRAF amplification (9% vs 2%, p=0.030) were significantly more frequent in patients with HER2 amplification compared to those without, and no KRAS mutation co-occurred with HER2 amplification. There was no significant difference in overall survival (OS) between patients with and without HER2 amplification (17.7 months [M] vs 16.9 M, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65-1.40, p=0.799). Of 58 patients with HER2-amplified BTC included in the biomarker selected cohort (43 Japan, 15 US), 27 (47%) received anti-HER2 therapy. The median OS of patients treated with anti-HER2 therapy was significantly longer than that of patients who did not receive anti-HER2 therapy (24.3 M vs. 12.1 M, HR 0.43, 95% CI 0.23-0.82, p=0.011). Multivariate analysis also identified anti-HER2 therapy as an independent prognostic factor for OS (HR 0.42, 95% CI 0.20-0.85, p=0.015). Conclusions: HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.
Artificial intelligence (AI)-powered tumor microenvironment (TME) analysis to identify potential biomarkers for ICIs with or without bevacizumab in hepatocellular carcinoma (HCC).
Authors: Chon Hong Jae , Kim Gwangil , Kang Beodeul , Hong Jung Yong , Kang Haeyoun , Hwang Sohyun , Lee Sung Hwan , Jung Sanghoon , An Chansik , Lee Won Suk , Kim Seulki , Lim Yoojoo , Ali Siraj Mahamed , Ock Chan-Young , Lim Ho Yeong , Kim Chan 
Published: January 2024

549 Background: While immunotherapies have been approved for use in HCC patients, there is a need for validated predictive biomarkers that correlate with treatment outcomes. We investigated whether AI-powered spatial analysis of non-cancerous cells within the TME can be potential biomarkers for ICIs with or without bevacizumab in advanced HCC. Methods: Analysis of images of H&E-stained slides was conducted by an AI model, Lunit SCOPE IO in pre-treatment tumor samples of 163 HCC patients treated with atezolizumab plus bevacizumab as first-line ( n=82), or monotherapies of nivolumab or pembrolizumab as ≥ second-line ( n=81) at CHA Bundang Medical Center or Samsung Medical Center. We analyzed the correlation between clinical outcomes after the treatment and AI-powered TME-related variables, including TILs and endothelial cells, within intratumoral or stromal areas. Inflamed immune phenotype (IIP) was defined as cases exhibiting enrichment of intratumoral TILs. Results: Baseline characteristics, including Child-Pugh liver classification, Barcelona Clinic Liver Cancer stage, and hepatitis B virus, were well-balanced between treatment regimens. IIP was predictive of longer progression-free survival (PFS) of nivolumab or pembrolizumab monotherapy (median PFS 4.7 months for IIP vs. 2.2 months for non-IIP; hazard ratio [HR] 0.50; 95% confidence interval [CI] 0.25-0.99; p=0.042), but not PFS of atezolizumab plus bevacizumab (median PFS 6.8 months vs. 6.2 months; HR 0.92; 95% CI 0.50-1.69; p=0.762). PFS of atezolizumab plus bevacizumab was significantly longer in cases harboring intratumoral endothelial cell density in the highest quartile (median PFS 6.7 months for upper 25% vs. 3.9 months for lower 75%; HR 0.51; 95% CI 0.27-0.97; p=0.037), while there was no significant difference in PFS of pembrolizumab or nivolumab monotherapy (median PFS 2.3 months vs. 2.8 months; HR 1.02; 95% CI 0.59-1.77; p=0.935). Conclusions: AI-powered TME analysis shows IIP is predictive of longer PFS with ICI monotherapies, whereas intratumoral endothelial cell density is specifically associated with PFS of atezolizumab plus bevacizumab in advanced HCC. The latter finding may suggest efficacy of combined VEGFRi and ICI activity is dependent on the amount of baseline tumor vasculature.
Real-world analysis of patients with advanced gastrointestinal (GI) cancers harboring inactivating TSC1 and TSC2 alterations using the Foundation Medicine genomic database.
Authors: Deming Dustin A. , Alonzo Palma Norma , Navarro Willis H. , Iyer Gopa , Kwiatkowski David J. 
Published: January 2024

558 Background: Genomic profiling of GI tumors can identify potentially actionable genetic alterations, ultimately leading to better outcomes in patients who currently have few treatment options. In exploratory biomarker analyses of patients with perivascular epithelioid cell tumors treated with the mTOR inhibitor nab-sirolimus (AMPECT, NCT02494570), those with inactivating alterations in the tumor suppressor genes TSC1 or TSC2 (critical negative regulators of mTOR activity) had confirmed responses (8/9 patients with inactivating TSC2 alterations and 1/5 patients with inactivating TSC1 alterations). PRECISION 1, a currently enrolling tumor-agnostic study, will evaluate nab-sirolimus in patients with TSC1 or TSC2 alterations. To enumerate the frequency of these alterations in GI cancers, we analyzed data from a real-world genomic database. Methods: Next-generation sequencing (NGS) data from Foundation Medicine’s genomic database of patients with advanced cancer were analyzed using the FoundationInsights web-based platform to identify patients with GI cancers who had inactivating TSC1 or TSC2 alterations (short variants [base substitutions, insertions and deletions], rearrangements, and copy number deletions). Tumor mutational burden (TMB), microsatellite instability status and other mutations were also characterized in this group of patients. Results: As of 29 March 2022, tumor tissue NGS data were available for 5816 patients with GI cancers bearing alterations in TSC1 or TSC2. Of these, 1642 patients had at least one inactivating alteration. The GI tumor types that most frequently expressed inactivating alterations in TSC1 or TSC2 were hepatocellular carcinoma (alterations in 6.5%); colorectal adenocarcinoma (1.7%); gastrointestinal stromal tumors (1.7%); and cholangiocarcinoma (1.6%). Of all 1642 patients, 688 were female, and most (74%) were 51–80 years of age when the sample was obtained. Of patients with inactivating TSC1 and TSC2 alterations, 37.6% were in TSC1 and 62.9% were in TSC2 and included short variants (31.3% and 48.4%), rearrangements (2.7% and 6.6%), and copy number deletions (3.5% and 7.4%), respectively. TMB was low (<6 mutations/megabase) in 58% of patients, and most patients had microsatellite stable (MSS; 71.3%) tumors. Other commonly mutated genes in this cohort were TP53 (62.7%), APC (38.5%) and KRAS (30.4%). Conclusions: TSC1 and/or TSC2 alterations were commonly observed in GI cancers. These cancers were frequently microsatellite stable and of low TMB suggesting that these are actionable alterations that may be candidates for targeted therapy. This hypothesis is being tested in the PRECISION 1 (NCT05103358) trial which is open for enrollment or just-in-time clinical trial sites and available to patients with GI cancers harboring TSC1 or TSC2 alterations.
APC as a high-utility mutational biomarker that may identify subpopulations of patients with mutant RAS/BRAF and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).
Authors: Thota Ramya , Yeatman Timothy , Gandhi Nishant , Yang Mingli , Schell Michael , Pflieger Lance , Loboda Andrey , Nebozhyn Michael , Elliott Andrew , Xiu Joanne , Sledge George W. , Khushman Moh'd M. , Lou Emil , Goel Sanjay , Pledger Warren Jack 
Published: January 2024

56 Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRASWT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APCMUT) and TP53( TP53MUT) might predict cetuximab sensitivity, particularly in RASWT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53MUT/ APCMUT were associated with improved E-OS compared to TP53MUT alone (hazard ratio [HR]=0.565, p<0.00001), APCMUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APCWT, APCMUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APCMUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p<0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]
Patient factors and survival outcomes of pancreatic signet cell carcinoma: A comprehensive review and analysis.
Authors: Lee Aron , Bine Christopher , Czaplicki Alec , Nielsen Eric , Silberstein Peter T. 
Published: January 2024

608 Background: Pancreatic signet cell carcinoma is an aggressive, rare subtype of pancreatic adenocarcinoma that constitutes less than 1% of all pancreatic cancers. This subtype can manifest as solitary cells or a cluster within the background of pancreatitis, often leading to an incorrect diagnosis during biopsies. The rarity and challenges associated with its diagnosis significantly impact its poor prognosis. With an average age of diagnosis of 67.3 years and a median life expectancy of 12.6 months, there exists a lack of information on the disparities that exist in these patients and how patient demographics contribute to differences in survival outcomes. Methods: We used the National Cancer Database to identify patients diagnosed with pancreatic signet ring cell carcinoma (ICD-O-3 histology code 8490) between 2004-2019 (N=1746). Survival was evaluated using Kaplan-Meier curves and log-rank tests. Significance was set at p<0.05. Results: When analyzing insurance status, patients with private insurance had a statistically improved survival outcome (14.3 months) compared to those with Medicare (11.3 months), Medicaid (9.2 months) and without insurance (11.8 months) (p<0.05). Patients with private insurance had fewer positive regional lymph nodes (73), lower grade/differentiation (5.80) and an average tumor size of 444.40 millimeters. Patients treated at academic research programs had a statistically better survival outcome (15.1 months) compared to patients treated at comprehensive community (10.4 months) and integrated network (9.1 months) programs (p<0.001). Surgical treatment had statistically improved survival outcomes compared to non-surgical treatment (p<0.001) with the majority of these procedures being a partial pancreatectomy and duodenectomy with a partial gastrectomy. More patients received surgical intervention at academic research programs (p<0.001), and patients with private insurance predominately attended academic research programs (p<0.001). Conclusions: Factors associated with increased survival outcomes include insurance status, positive regional lymph nodes, grade/differentiation, treatment facility type and surgical intervention. These findings make a valuable contribution to the ongoing research on disparities affecting survival in patients with pancreatic signet cell carcinoma.
Improving timeliness and equity in germline genetic testing for pancreatic ductal adenocarcinoma patients: A comparative analysis and future strategies.
Authors: Zou Xianghui , Sidiqi Baho , Nguyen Cathy , Chen Ellen , Kauff Noah D. , King Daniel 
Published: January 2024

611 Background: Germline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). Our previous study identified delays in germline testing for socioeconomically disadvantaged patients. We aimed to compare delays before and after implementing recommendations for same-day germline testing and identify reasons why germline testing was not performed. Methods: Using an IRB-approved protocol, PDAC patients were identified from Jan 2022 to Dec 2022 in our EMR system. Median income was estimated by zip code. Delays were calculated as the difference between diagnosis and germline test date. Social work needs were assessed through EMR review. An in-depth chart review was conducted to identify why tests were not performed. Results: An additional 100 patients were found with tests performed. Compared to our previous 135-patient study with a median delay of 27 days (d) in testing, our recent data showed a median delay of 15d (p=0.0215). In our previous study, 50 out of 135 patients (37%) received testing within two weeks of their PDAC diagnosis, whereas our recent data showed that 49 out of 100 patients (49%) received testing within two weeks (c2=3.372, p=0.0663), a 32% relative increase. The negative correlation between median income and delays in testing (r=-0.2578, p=0.0025) found in our previous study no longer existed in our recent analysis (r=0.0419, p=0.6802). Compared to our previous study in underserved minority (UM) patients (African American and Hispanic), our recent data showed a significant decrease in the delays for testing in UM patients (66d vs 19d, p=0.0041). We did not identify a difference in delays for testing between UM and not UM patients in the recent dataset (UM: 19d vs not UM: 15d, p=0.8075). In addition, compared to our previous study in patients with social work (SW) needs, our recent data showed a significant decrease in the delays for patients with SW needs (104d vs 13d, p=0.0004). We did not detect a significant difference between patients with SW needs and without SW needs in our recent data (SW: 13d vs no SW: 15d, p=0.8041). Finally, in our analysis of 87 patients without documented tests, 51 (59%) received care elsewhere, 25 (29%) were never offered tests, 5 (6%) refused tests, and 6 (7%) pursued a palliative approach. Conclusions: Our recent analysis showed a significant decrease in delays of testing, as more patients received prompt testing after PDAC diagnosis. Socioeconomically disadvantaged patients and those with social work needs no longer experienced significant delays in testing. To further mitigate delays, we plan to initiate germline testing during the first visit by providing introductory videos to increase understanding of consent. Furthermore, the substantial number of patients who were not offered tests will raise physician awareness regarding the necessity of offering germline tests.