bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 107-gene Nanostring assay effectively characterizes complex multiomic gastric cancer molecular classification in a translational patient-derived organoid model.
Authors: Skubleny Daniel , Purich Kieran , Williams Thomas , Wickware Jim , Ghosh Sunita , Spratlin Jennifer L. , Schiller Dan E. , Rayat Gina 
Published: June 2022

4049 Background: Multi-omics profiling of gastric cancer (GC) has produced numerous molecular classification systems. However, widespread clinical implementation and testing of molecular subtypes are currently limited. Here, we develop, validate and implement a custom Nanostring assay capable of allocating GC molecular subtypes to clinical specimens in a translational patient-derived organoid model. Methods: Using publicly available whole-transcriptome data, machine learning models were developed to predict GC molecular subtypes from 376 Cancer Genome Atlas (TCGA) and 1797 Tumour Microenvironment Score (TME) patients. Models were generated using feature selection with 10-fold nested cross-validation. GC biopsies from 10 local patients were preserved in paraffin (tumour) and established as an organoid culture (organoid). Gene expression was measured using Nanostring. The allocation of molecular subtypes was internally and externally validated using gold-standard reference features in public databases comprising 2202 GC patients and 10 tumour-organoid pairs, respectively. We evaluated the concordance of tumour-organoid molecular subtypes and explored the correlation between subtype scores and in-vitro chemotherapy response. Results: Classification models for TCGA (57 genes) and TME (50 genes) predicted subtypes with an accuracy ± standard deviation of 89.46% ± 0.04 and 89.33% ± 0.02, respectively. Subtype assignment of microsatellite instability (MSI) in reference to capillary electrophoresis was found to have 99.3% [95% CI 97.4-99.9, n = 277] internal and 100% [95% CI 83.2-100, n = 20] external accuracy. In reference to Epstein-Barr Virus (EBV) in-situ hybridization, EBV type internal and external accuracy was 98.7% [95% CI 97.4-99.5, n = 552] and 100% [95% CI 83.2-100, n = 20], respectively. TCGA Genomically Stable (GS) scores followed a previously characterized enrichment of diffuse-type histology compared to intestinal-type in internal and external cohorts (Dunn’s Test, p < 0.0001 and p < 0.05, n = 1471 and n = 15, respectively). Statistically similar subtype scores (Paired Wilcoxon, p > 0.05) were found for tumour-organoid pairs. Discordance occurred in three tumour-organoid pairs. In-vitro Drug Sensitivity Score was not statistically efficacious in any molecular subtype, but Pearson correlation identified increasing efficacy with increasing EBV and MSI scores. Conclusions: Patient-derived organoids generally recapitulate the molecular subtype of parent tumours; however, in specific cases, subtype discordance occurs. Although additional external validation is required, our 107 gene assay effectively captures multi-omics classification systems in GC and allows future inquiry into the prognostic and therapeutic implications of these molecular subtypes.
A phase I study of TST001, a high affinity humanized anti-CLDN18.2 monoclonal antibody, in combination with capecitabine and oxaliplatin (CAPOX) as a first-line treatment of advanced G/GEJ cancer.
Authors: Gong Jifang , Li Ning , Guo Weijian , Zhang Jian , Li Hongli , Zhao Fuyou , Li Wei , Sun Meili , Xia Zhenzhong , Shen Yu , Wang Jianming , Lu Lingmin , Qi Chuan , Qian Xueming , Shi Michael , Shen Lin 
Published: June 2022

4062 Background: TST001 is a recombinant humanized IgG1 antibody specifically against human Claudin 18.2 (CLDN18.2) with high affinity and enhanced FcR engaging of NK cells, which can induce strong antibody-dependent cellular cytotoxicity (ADCC) activities. TST001 monotherapy dose-escalation study has been completed (IGCC2022-ABS-1152) and promising anti-tumor activities were observed in advanced gastric cancer patients with CLDN18.2 overexpression who had failed multiple lines of prior therapies. The current study is an open-label, multi-center, multiple cohorts, phase I clinical trial of TST001 monotherapy or in combination with standard treatments in Chinese patients with advanced or metastatic solid tumors (NCT04495296). Methods: This cohort is aimed to determine the recommended phase II dose, evaluate safety, tolerability and preliminary efficacy of TST001 in combination with CAPOX as a 1st line treatment of advanced G/GEJ cancer. A 3+3 design was utilized in the dose escalation phase with treatment naïve advanced G/GEJ cancer patients regardless of Claudin18.2 expression. Claudin 18.2 positive G/GEJ cancer patients were planned to be enrolled in the dose expansion phase in selected dose cohorts. Results: The TST001/CAPOX combination cohort was initiated in August 2021 and is ongoing in multiple sites in China with a data cutoff date of January 27, 2022. 12 subjects were dosed with TST001 with a dose range from 1 to 8mg/kg Q3W in combination with the standard dose of CAPOX in the dose escalation phase and one subject with central lab tested Claudin 18.2 overexpression was dosed in the expansion phase of TST001 at 6mg/kg Q3W with CAPOX. There was no subject experienced dose-limiting toxicity. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (76.9%), anemia (69.2%), vomiting, AST increased (63.8% respectively), hypoalbuminemia, ALT increased (46.2%, respectively). Treatment related grade 3 AEs were hypertension （15.4%）, anemia, hypoproteinemia, WBC count decreased, hypocalcemia aggravated (7.7%, respectively). Among the eight patients from the dose escalation part (with no CLDN18.2 expression selection yet with measurable disease ) with at least one post-treatment tumor assessment, four had achieved partial response, three had achieved stable disease and one had progressive disease as the best tumor response per RECIST1.1. Conclusions: Conclusion: TST001 in combination with CAPOX in first line gastric cancer patients is safe and encouraging anti-tumor activities have been observed. Additional data from the 6 mg/kg dose expansion cohort will be updated at the meeting. Clinical trial information: NCT04495296.
Patient-reported outcomes for the phase 3 TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.
Authors: Burris III Howard A. , Okusaka Takuji , Vogel Arndt , Lee Myung Ah , Takahashi Hidenori , Breder Valeriy Vladimirovich , Blanc Jean-Frédéric , Li Junhe , Watras Magdalena , Xiong Julia , Abraham Jayne , Patel Nikunj , Wang Julie , Rokutanda Nana , Cohen Gordon , Oh Do-Youn 
Published: June 2022

4070 Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of durvalumab (D) in combination with (+) gemcitabine and cisplatin (GC) as first-line treatment for patients (pts) with advanced biliary tract cancer (BTC).1 D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC and represents a new treatment option. Methods: A pre-planned secondary objective of TOPAZ-1 was to assess pt-reported outcomes (PROs) for pts receiving D + GC versus PBO + GC. Pts with BTC were randomized 1:1 to D (1500 mg) or PBO, + G (1000 mg/m2) and C (25 mg/m2), for up to 8 cycles, followed by D or PBO monotherapy until disease progression, unacceptable toxicity, or other discontinuation criteria were met. PROs were assessed with the European Organisation for Research and Treatment of Cancer 30-item Quality of Life (QoL) Questionnaire, EORTC QLQ-C30 (C30), and the BTC 21-item module, EORTC QLQ-BIL21 (BIL21). Time to deterioration (TTD) was the primary assessment of PROs; defined as the time from randomization to the date of the first pre-specified, clinically meaningful deterioration (e.g. disease progression). The PRO analysis set included all pts from the full analysis set who completed a questionnaire. Results: Compliance rates for PROs were high at baseline (>81%) and remained high (majority >70% over 28 cycles) for both treatment groups. Baseline scores were comparable between treatment groups. Addition of D was well tolerated, with no significant difference in TTD in D + GC versus PBO + GC for pt-reported symptoms or functioning using either C30 or BIL21 (Table), or Global Health Status/QoL (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.69–1.12; p=0.279). Conclusions: Addition of D to GC improved OS (Oh D-Y, et al. J Clin Oncol 2022;40(suppl 4). Abs 378) and was well tolerated with no difference in TTD of QoL for pts, supporting D + GC as a new treatment option for pts with BTC. Clinical trial information: NCT03875235. [Table: see text]
Antibiotic therapy and association with oncological outcomes from targeted and immune-based therapy in hepatocellular carcinoma (HCC).
Authors: Pinato David J. James , Li Xiaoxue , Mishra-Kalyani Pallavi Shruti , D'Alessio Antonio , Fulgenzi Claudia A.M. , Wei Guo , Schneider Julie A. , Rivera Donna , Pazdur Richard , Theoret Marc Robert , Casak Sandra J. , Lemery Steven , Fashoyin Ibilola , Cortellini Alessio , Pelosof Lorraine Cheryl 
Published: June 2022

4089 Background: Immune checkpoint inhibitors (ICI) alone or in combination with tyrosine kinase (TKI) or VEGF pathway inhibitors (VEGFi) are therapeutic options in unresectable HCC (uHCC). Whether exposure to antibiotics (ATB), a consolidated adverse prognostic factor in ICI recipients, affects outcome in HCC remains unclear. Methods: FDA analysed patient-level data of 4098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or combinations (n = 584), TKI (N = 1968), VEGFi (n = 480) or placebo (n = 808) as part of 9 international clinical trials submitted to the US Food and Drug Administration in support of marketing applications. Associations for ATB exposure within 30 days before or after initiation of anti-cancer treatment (ATB) with overall (OS) and progression-free survival (PFS) were examined across therapeutic modality. Estimates were weighted by propensity score (PSW) using clinically relevant covariates. Results: Out of 4098 patients with uHCC mostly secondary to Hepatitis B (39%) or C (21%) infection, the majority were males (83%) with a median age of 64 (range 18-88), ECOG performance status of 0 (60%) and Child-Pugh A class (98%). Most patients had metastases (68%) but did not have macrovascular invasion (71%). Overall, 620 patients (15%) were ATB+, with comparable rates across placebo (12%), TKI (16%), VEGFi (15%), and ICI (16%). In the overall population, ATB was associated with shorter PFS (2.8 vs 3.9 months [m], HR 1.29, 95%CI 1.22-1.36) and OS (6.4 vs. 8.8 m; HR 1.36, 95%CI 1.29-1.43). In PSW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52, 95%CI 1.34-1.73), TKI (HR 1.29, 95%CI 1.19-1.39) and placebo (HR 1.23, 95%CI 1.11-1.37). Similar results were observed in PSW analyses of OS in patients treated with ICI (HR 1.22, 95%CI 1.08-1.38), TKI HR 1.40, 95%CI 1.30-1.52), and placebo (HR 1.40, 95%CI 1.25-1.57). Consistent outcomes were observed for ATB+ patients within ICI treatment subgroups, including patients treated with anti-PD-1 monotherapy (PFS HR 1.49, 95%CI 1.22-1.80; OS HR 1.31 1.02-1.68) and ICI combinations (PFS HR 1.50, 95%CI 1.26-1.77; OS HR 1.14 0.99-1.32). Conclusions: Unlike other oncological indications where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with inferior outcomes across a broad range of anti-cancer therapies for HCC and placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut liver axis remains to be demonstrated in translational studies.
A phase 2, randomized, open-label, multicenter study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC.
Authors: Jingjing Li , Qi Xu , Wei Qing , Han Zhe , Cong Luo , Zhang Fabiao , Ying Jieer 
Published: June 2022

4100 Background: BTC has a higher incidence in China rather than worldwide, with extremely poor prognosis, and the efficacy of standard first-line therapy (GemCis) is rather limited. TOPAZ-1 study suggested immunotherapy + GemCis as first line in advanced BTC significantly improved OS and PFS vs placebo + GemCis with manageable safety, but the median OS was just 12.8 months. SAGC is the first randomized controlled phase 2 trial to evaluate first-line immunotherapy + antiangiogenic targeted drug + GemCis in advanced BTC. Methods: In this randomized controlled study, pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized 1:1 to receive sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) in combination with GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) or GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles until disease progression or unacceptable toxicity. The primary objective was to assess the 1-year overall survival (OS). Secondary endpoints included OS, progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff for this interim analysis (11 November, 2021), 48 pts were randomized to sintilimab + anlotinib + GemCis (n=26) or GemCis (n=22). The primary objective was not meet: the 1-year OS was 52.5% with sintilimab + anlotinib + GemCis and 36.3% with GemCis (p=0.437), but there was a trend of nominal OS benefit in patients treated with sintilimab + anlotinib + GemCis. PFS was significantly improved with sintilimab + anlotinib + GemCis vs GemCis (6.4m vs 5m; p=0.014). ORR was 37.5% with sintilimab + anlotinib + GemCis and 26.7% with GemCis. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 69.2% of pts receiving sintilimab + anlotinib + GemCis and38.7% of pts receiving GemCis. TRAEs led to discontinuation of any study medication in 7.7% of pts receiving sintilimab + anlotinib + GemCis and 9.1% of pts receiving GemCis. Conclusions: In pts with advanced BTC, sintilimab + anlotinib + GemCis could improve OS and PFS vs GemCis with manageable safety, indicating sintilimab + anlotinib + GemCis may be a new first-line standard of care regimen. Research Sponsor: Innoventbio Biologics, Inc, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT04300959.
Genomic profile of intrahepatic cholangiocarcinoma with MTAP loss.
Authors: Tang Tin-Yun , Ross Jeffrey S. , Rodon Ahnert Jordi , Javle Milind M. 
Published: June 2022

4102 Background: Recent data suggests a role for immune-checkpoint inhibition in the management of intrahepatic cholangiocarcinoma (iCCA). Chromosomal 9p21 loss with CDKN2A/MTAP co-deletion commonly occurs in iCCA and may correlate with poor response to immunotherapy. Methods: 2,508 cases of intrahepatic cholangiocarcinoma underwent comprehensive genomic profiling with the FoundationOne CDx assay. PD-L1 expression was measured with IHC using the Dako 22C3 antibody and measured with the tumor proportion score (TPS) method. Prevalence of different selected genomic alterations in tumors with MTAP loss was compared against MTAP intact tumors using Fischer’s exact test. Results: In 2,508 cases analyzed, 15.5% of tumors were found to have MTAP loss. Of these, 98.7% had concomitant CDKN2A and 9p21 loss. No significant difference in immune biomarkers in MTAP loss versus wildtype (WT) was seen. PD-L1 low positive at 13.2% vs 19.2%, PD-L1 high positive at 2.9% vs 6.5%, median tumor mutational burden at 2.5 vs 2.5 and MSI high at 0.0% vs 1.6% in MTAP loss vs WT, respectively. There were no significant differences between MTAP loss and WT in potentially actionable mutations including FGFR1/2 mutations (12.4% vs 10.7%), PIK3CA (6.40% vs 6.60%), ERBB2 (4.10% vs 5.30%) and KRAS G12C (1.20% vs 1.10%) in MTAP loss vs WT, respectively. The table depicts significant genomic differences between these subgroups. Conclusions: This represents the largest iCCA cohort with MTAP loss to our knowledge. Given the historical data regarding 9p21 loss and poor response to immunotherapy, efforts targeting MTAP loss through synthetic lethality or other novel combinational therapeutics are justified.[Table: see text]
Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) and capecitabine plus temozolomide (CAPTEM) for pancreas and midgut neuroendocrine tumours (pNETS, mNETS)—Final results.
Authors: Pavlakis Nick , Ransom David Turner , Wyld David , Sjoquist Katrin Marie , Wilson Kate , Gebski Val , Murray James , Kiberu Andrew Ddembe , Burge Matthew E. , Macdonald William , Roach Paul , Pattison David A. , Butler Patrick , Price Timothy Jay , Michael Michael , Lawrence Benjamin James , Bailey Dale L. , Leyden Simone , Zalcberg John Raymond , Turner Harvey 
Published: June 2022

4122 Background: CAPTEM is an accepted regimen for patients (pts) with advanced pNETs. Single agent PRRT is now a standard of care for progressive WHO Grade 1/2 mNETs. High activity was seen with PRRT/CAPTEM in a single arm Phase I/II trial. This study aims to determine the activity of combining CAPTEM with PRRT in mNETs and pNETs pts. Methods: Non-comparative randomised open label parallel group phase II trial with 2:1 randomisation to PRRT/CAPTEM (experimental arm) vs. PRRT (mNETs control) and CAPTEM (pNETS control). PRRT/CAPTEM: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 10 every 8 weeks for 4 cycles, with concurrent oral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 every 56 day cycle, up to 4 cycles. PRRT alone: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 1 every 8 weeks for 4 cycles. CAPTEM alone: Oral capecitabine 750mg/m2 b.i.d. days 1-14 and days 29-42; Oral temozolomide 75mg/m2 b.i.d. days 10-14 and 38-42 every 56 day (8w) cycle. Primary endpoint: Progression free survival (PFS). mNETS: At 15 months, assuming PFS 66.4% in control arm; target PFS ³ 80%; pNETS: At 12 months, assuming PFS 60% in control arm; target PFS ³ 75%. Secondary endpoints: Objective tumor response rate (complete or partial) (OTRR), overall survival (OS), adverse events (AEs). Results: 75 pts enrolled (Dec 2015 – Nov 2018): mNETs 33 PRRT/CAPTEM, 14 PRRT, median follow up (mFU) 60.3 months; pNETS 19 PRRT/CAPTEM, 9 CAPTEM, mFU 57.5 months (mo). Late Grade 3/4 haematologic AEs: mNETS: 2/32 (6%) PRRT/CAPTEM pts and 4/13 (31%) PRRT pts. Events included myelodysplastic syndrome (40 mo), leukaemia (60 mo), pancytopenia (50 mo), anaemia (32 mo), thrombocytopenia (7 mo). No late haematologic G3/4 AEs were reported in the pNETS cohort. No late renal toxicity was identified in all study arms. Conclusions: CONTROL NETs is the first randomized trial to demonstrate efficacy for PRRT in pNETs, in addition to a standard of care. Extended follow up confirms durable CAPTEM/PRRT activity, with superior PFS in pNETs. Late haematologic toxicity was seen in both mNET PRRT arms but was not higher with additional CAPTEM. The activity of CAPTEM/PRRT in pNETs should be tested in the phase III setting. Clinical trial information: ACTRN12615000909527. [Table: see text]
Comparative analysis of the targetable landscape in KRAS-mutant and wild-type pancreatic adenocarcinoma.
Authors: Knepper Todd C , Kim Dae Won , Mauer Elizabeth , Ronski Karyn , Gulhati Pat 
Published: June 2022

4155 Background: Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer deaths, with increased incidence among patients (pts) younger than 50 years old (yo). Small cohort studies suggest early-onset PC (EOPC, diagnosis at < 50 yo) tumors may have a unique biology, harboring a higher proportion of KRAS wild-type status ( KRASWT) and enrichment of targetable mutations/fusions compared to non-EOPC. In addition, therapy targeting oncogenic fusions in KRASWT tumors has shown meaningful responses in PC pts. Here, we investigate the prevalence of fusions, mutations, and homologous recombination deficiency (HRD) in KRASWT PC to identify potential targets for therapeutic intervention, and compare EOPC to non-EOPC to better characterize EOPC differences. Methods: De-identified records from 4,956 PC pts with tumor biopsies sequenced using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq) were retrospectively reviewed. Fusions were detected from RNA-seq data via the Tempus bioinformatics pipeline. Mutations identified included germline and/or somatic single-nucleotide variants and insertions/deletions. HRD status was determined from RNA-seq data by the Tempus HRD test. Significance was determined as FDR-corrected p-values < 0.05. Results: Across the entire cohort, 21% tumors were KRASWT. HRD was more frequent in KRASWT (7.9%) compared to KRASMUT (3.1%) tumors ( P< 0.001). Significant somatic mutational differences between the KRASWT and KRASMUT cohorts included BRAF (5.0% vs 0.2%) , CDKN2A (5.4% vs 25%), ARID1A (3.6% vs 8.6%), CTNNB1 (1.3% vs 0.3%), and TSC2 (1.2% vs 0.1%) (all P< 0.001). Actionable rearrangements were enriched in the KRASWTcohort (10% vs 2.1%, P< 0.001); the most common fusion partners include NRG1, MET, RAF1, BRAF, NTRK1-3, FGFR 1-4, and RET. TMB-high (10 muts/Mb) and MSI-high were more common in KRASWT (2.9% and 1.0%) compared to KRASMUT (1.7% and 0.4%) tumors ( P= 0.015). Additionally, 382 pts were classified as EOPC. KRASWT tumors comprised 30% of EOPCs, 22% of the 50-70 yo cohort, and 17% of the > 70 yo cohort. Germline (pathogenic/likely pathogenic) alterations in BRCA1 and BRCA2 were more frequent in EOPCs (2.0% and 4.5%) compared to the 50-70 yo (0.4% and 1.7%) and > 70 yo (0.4% and 0.8%) cohorts ( P= 0.015 and < 0.001, for BRCA1 and BRCA2 respectively). There were no statistical differences in actionable genes detected in EOPC vs non-EOPC. HRD was found at higher frequency in EOPC (5.4%) and decreased in age cohorts 50-70 yo (4.7%) and > 70 yo (2.5%) ( P = 0.047). Rearrangements were more common in EOPC compared to non-EOPC (10% vs 1.1%, P< 0.001). Conclusions: HRD, TMB-H/MSI-H and oncogenic rearrangements are more prevalent in KRASWT PC when compared with KRASMUT. These molecular analyses may provide additional therapeutic options for PC pts, warranting comprehensive genomic and transcriptomic profiling for this population.