bluuebunny/crossref_metadata_2025_split huggingface dataset:
Approaches and data needed for real-world evaluation of multicancer early detection tests.
Authors: Tunis Sean , Parmar Mahesh K. B. , Burris Howard A. , LeBeau Michelle M. , Kessler Larry 
Published: June 2023

e15069 Background: The MCED Consortium is a group of volunteers, advisors, and companies from the US and the UK spanning a wide range of expertise in biomarker evaluation and implementation, with a special focus on clinical practice, health equity, and communication. The development of Multi Cancer Early Detection (MCED) markers may herald a new approach to screening and detection of multiple cancers at one time via various biological assays. Methods: The Consortium is developing recommendations for the evaluation of test utility, appropriate population targets for screening or early detection, downstream actions in health systems, issues of health equity, and communication challenges related to this new, potentially revolutionary generation of tests. While randomized controlled trials with cancer-specific endpoints have been the gold standard for the evaluation of cancer screening tests for decades, and have successfully shown effectiveness of breast, colorectal, cervical and lung cancer screening, there are compelling reasons not to rely entirely on those approaches to guide the evaluation and clinical use of MCEDs. Results: A large number of MCED products are likely to reach the market well before trials with mortality endpoints can be completed. The release of tests in clinical practice in the US via the laboratory-developed-test pathway means data could be available many years before data is available from trials. The MCED Consortium proposes approaches for the structure, systematic collection of real-world data that will complement such trials. This includes adopting shared definitions of RWD & RWE, definition of core data elements to be collected from all patients undergoing MCED testing, and the need for collaboration strategies across test developers, health systems, payers, clinicians, and others. Conclusions: We will present a framework for learning from clinical experience through data collection that will move MCEDs forward in the context of sensible clinical practice.
Molecular characteristics of KRAS mutations in Chinese patients with cancer.
Authors: Yan Hui , Li Mengmeng , Luo Ningning , Qi Yingxue , Sun Tingting , Qi Chuang 
Published: June 2023

e15070 Background: Sotorasib, the first KRAS G12C inhibitor, has been approved for the treatment of non-small cell lung cancer (NSCLC) patients with KRAS G12C mutation-positive. Understanding the molecular characteristics of KRAS in Chinese patients with cancer is imperative, which is conducive to screening the beneficiary groups. Here, we focus on the molecular characterization of KRAS in NSCLC, colorectal cancer (CRC), pancreatic cancer (PC), and gastric cancer (GC). Methods: This study enrolled 17,775 pan-cancer patients detected by next-generation sequencing (NGS) from June 2021 to February 2022, in which NSCLC, CRC, PC and GC were 48.67% (8651/17775), 10.87% (1933/17775), 1.92% (342/17775) and 5.37% (955/17775), respectively. Results: The KRAS mutation rate in pan-cancer is 16.28% (2893/17775). In NSCLC, CRC, PC and GC cohorts, the mutation rates of KRAS were 13.28% (1149/8651), 50.34% (973/1933), 66.67% (228/342) and 7.64% (73/955), respectively. In NSCLC cohort, 1274 KRAS mutations were detected, and the subtypes were concentrated in G12C (346;27.16%), G12D (205;16.10%), G12V (194;15.23%), G12A (86;6.75) and Q61H (57;4.47%). In CRC cohort, 1094 KRAS mutations were detected. The subtypes were mainly distributed in G12D (350;31.40%), G13D (184;16.82%), G12V (180;16.45%), A146P (66;6.03%) and G12C (49;4.48%). In PC cohort, 251 KRAS mutations were detected, and the subtypes were concentrated in G12D (109;43.43%), G12V (70;27.89%), G12R (32;12.75%), G12C (9;3.59%) and Q61H (9;3.59%). In GC cohort, 82 KRAS mutations were detected. The subtypes of these mutations were concentrated in G12D (23;28.05%), G13D (12;14.63%), Q61H (7;8.54%), G12V (5;6.10%) and Q61R (5;6.10%). Conclusions: In NSCLC, CRC, PC and GC cohorts, K RAS mutations were concentrated in exon 2, accounting for 78.41% (999/1274), 81.63% (893/1094), 91.63% (230/251) and 64.63% (53/82), respectively. In NSCLC cohort, KRAS G12C was the molecular subtype with the highest mutation rate. However, in other cohorts, KRAS G12D was the predominant molecular subtype. G12D mutation will become the next research hotspot, and the breakthrough will help to further expand the beneficiary population of KRAS mutations.
The analysis of BRAF fusions characteristics in Chinese solid tumor patients.
Authors: Ma Fang , Zhao Yaping , Wang Chenxi , Han Tiantian , Ding Ran , Deng Wanglong , Bu Fanfeng 
Published: June 2023

e15073 Background: BRAF encodes a RAF kinase, which signal downstream of RAS and activate the MAPK pathway, and has emerged as a major oncogenic driver and a potential therapy target. BRAF V600E base substitution is an approved target for the BRAF inhibitors in solid tumors. BRAF gene fusions represent a different mechanism of BRAF activation. BRAF fusions have shown responses to MEK inhibitors and non-specific RAF inhibitors (eg, sorafenib) in Melanoma (NCCN). We sought to analysis of BRAF fusions characteristics in Chinese solid tumor patients to explore the possibility of therapeutic intervention in solid tumors. Methods: We comprehensively characterized BRAF fusions from next-generation sequencing (NGS) data from May 2019 to January 2023 in 80083 various solid tumors. Considering the characteristics of the receptor tyrosine kinase, we focused on the BRAF fusions which contain the kinase domain. Results: A total of 164 unique cases (70.1% (115/164) glioma and 29.9% (49/164) non-glioma with BRAF fusions) were identified. The non-glioma cohort consisted up mainly lung tumors (49%, 24/49), colorectal tumors (18.4%, 9/49), pancreatic tumors (10.2%,5/49), melanoma (9.2%, 4/49) and biliary tumors (4.1%, 2/49). In the glioma cohort, the median age of the 115 patients was 12 with a range of 0–66; 43 (37.4%) of the patients were female and 72 (62.6%) were male. On the other hand, the median age was 64 with a range of 33–82; 23 (46.9%) of the patients were female and 26 (53.10%) were male in the non-glioma cohort. In the glioma cohort, 82.4% of the partners were KIAA1549. However, the most common fusion partners were AGK (14.04%), TRIM24(14.0%), SND1(12.28%), TPK1(8.77%) in the non-glioma cohort. These BRAF fusions comprised 49 unique 5′ fusion partners, of which 51% (25) were known and 49.0% (24) were novel. 14 novel partners were TMEM176B, HMBOX1, SEMA3E, LOC441204, PDE4D, DENND2A, STIM1, TNS3, PRRC2B, BCR, MET, COL4A3BP, TPM4, ZBTB16 and 10 novel partners were intergenic region. 130 patients with BRAF fusions could be evaluated for concurrent mutations. Of interest is that no KRAS and BRAF V600E mutations were identified in the 130 cases. Conclusions: BRAF fusions were detected in 0.2% (164/80083) of Chinese solid tumor patients. 70.1% of BRAF fusion positive cases were diagnosed with glioma and 29.9% were diagnosed with non-glioma. 14 novel BRAF fusion partners were discovered. BRAF fusion is an important driver genomic alteration and occur in a mutually exclusive pattern with other activating mutations in the MAP kinase signaling pathway. BRAF fusion targeted therapies should be further explored in solid tumors.
CDK4/6 inhibitors and cardiovascular toxicity: Real-world evidence.
Authors: Fiste Oraianthi , Liontos Michael , Gavriatopoulou Maria , Dimitrakakis Constantine , Evangelou George , Nikolaidou Vasiliki , Kotteas Elias A. , Syrigos Kostas N. , Dimopoulos Meletios A. , Zagouri Flora 
Published: June 2023

e15074 Background: Cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) have fundamentally transformed the therapeutic landscape of hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer, either as monotherapy (abemaciclib) or combined with classic endocrine therapy (ribociclib, abemaciclib, and palbociclib). However, evidence regarding treatment-related cardiovascular complications, beyond the context of clinical trials, remains scarce. Methods: We retrospectively explored the FDA Adverse Events Reporting System (FAERS) to gain insight into both frequency and spectrum of cardiovascular toxicities of these novel targeted agents in real-world setting. Results: For the period January 2018 - September 2022, a total of 90,999 adverse events (AEs) in patients under CDK4/6i have been reported, with 2,739 (3.01%) and 5,176 (5.69%) records being submitted as cardiac and vascular events, respectively. The incidence of these AEs was higher in the case of ribociclib, with arrhythmia representing the main cardiac complication (512 cases), followed by palpitations (120 cases), and acute coronary syndrome (115 cases). Interestingly, there was only one report of QT prolongation; of note, ribociclib has labeling guidance for QTc assessment. Hypertension/hypertensive crisis (302 cases), flushing (251 cases), and thrombotic events (226 cases) -with the exception of pulmonary embolism which was categorized as respiratory AE- comprised the foremost vascular toxicities associated with ribociclib. Conclusions: FAERS displays a public, post-market safety evaluation database with reports from healthcare professionals as well as consumers, yet it may include duplicates, inaccurate information, and fails to confirm causal relationship between the AEs and the medicinal product. In the light of CDK4/6i long-term usage, pharmacovigilance studies are warranted to elucidate their potential cardiovascular hazard. [Table: see text]
The genomic landscape of adolescent and young adult (AYA) malignancies using DNA and RNA-based next generation sequencing.
Authors: Lustberg Maryam B. , Kaneva Kristiyana , Teslow Emily , Mauer Elizabeth , Federman Noah , Eisfeld Ann-Kathrin 
Published: June 2023

e15091 Background: Survival for adolescents and young adult (AYA) cancer patients (defined as age 15-39 years by the NCI) has not improved compared to survival outcomes in pediatric and older adult patients. Several factors contribute to the outcomes disparity, including lack of access to novel treatments. Currently, only a fraction of AYA cancer patients receive advanced genomic testing. Herein, we aim to characterize the molecular landscape of AYA cancers. Methods: De-identified records of 2,706 AYA patients diagnosed with solid tumors and hematologic malignancies who received Tempus xT next-generation sequencing (NGS) were identified. The prevalence of pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs), insertions/deletions (indels), fusions, and copy number alterations were assessed to describe the somatic landscape. Tumor biomarkers, such as microsatellite instability (MSI) and tumor-mutational burden (TMB) were also analyzed. Results: The cohort consisted of 2,706 AYA patients diagnosed with: central nervous system (N = 779), breast cancer (N = 700), bone and soft tissue sarcomas (N = 226), hematologic (N = 198), and gastrointestinal (GI) (N = 803) malignancies. Among 407 high-grade gliomas (HGG WHO Grade 3 & 4), variants in TP53 167 (41%), 136 (33%) IDH1, 125 (31%) ATRX, and 48 (12%) TERT were seen. Among the 82 patients with low-grade glioma (LGG, WHO Grade 1 & 2), 42 (51%) had a variant in IDH1, 40 (49%) TP53, and 35 (43%) ATRX. Among 269 patients with HR+ HER2- breast cancer, 82 (30%) had variants in TP53, 66 (25%) PIK3CA, 46 (17%) GATA3, 43 (16%) FGFR1 and 34 (13%) in ESR1. In triple-negative breast cancers (TNBC), 95 (77%) had a variant in TP53, and 9 (7.3%) in BRCA1. In ewing sarcomas (N = 36), 28 (78%) patients had a fusion with EWSR1, with TP53, STAG2, FGFR2, and RET altered in 2 (5.6%) patients. Within osteosarcomas (N = 46), 12 (26%) patients had a variant in TP53 and 9 (20%) in RB1 . In the AML subgroup (N = 34), WT1 was altered in 5 (15%) and FLT3 in 4 (12%) cases. Finally, in the GI cohort (806), 22 (5%) cases were MSI-H. Within colorectal cancer patients (N = 446), 247 (55%) patients had a variant in TP53, 150 (34%) in KRAS, 64 (14%) in PIK3CA, and several with NRG1 (8, 1.8%) and NTRK (3, 0.7%) fusions. Conclusions: We describe the somatic landscape of common malignancies in one of the largest AYA datasets. Additional analyses will focus on how this landscape differs from non-AYA age groups.
A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive, heavily pretreated solid tumors: Results from a phase Ⅰa/Ⅰb, first-in-human, open-label, single-center study.
Authors: Song Na , Teng Yuee , Teng Zan , Shi Jing , Jin Bo , Qu Jinglei , Zhang Lingyun , Yu Ping , Zhao Lei , Wang Jin , Li Aodi , Tong Linlin , Liu Yunpeng , Qu Xiujuan 
Published: June 2023

e15098 Background: IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which possessing the same binding properties to HER2 as trastuzumab and improving antibody-dependent cellular cytotoxicity (ADCC) activity and superior anti-tumor efficacy. We present results from patients with advanced HER2 positive malignant solid tumors including trastuzumab resistant and ineffective patients to establish the recommended dose of IAH0968 for phase II trials, as well as to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of the drug. Methods: This was a single institution investigator-initiated phaseⅠa/Ⅰb study, using 3+3 design. The primary endpoint was safety, tolerability and preliminary clinical activity. Secondary endpoints included PK, recommended phase II dose, and anti-drug antibody (ADA). PK detection used ELISA to quantitatively determine blood drug concentration of IAH0968. Results: Eighteen pts were evaluable for safety and fifteen pts were suitable for efficacy analysis. The primary cancer sites included breast (8/18), colon (3/18), stomach (2/18), rectum (2/18), biliary tract (2/18), and pancreas (1/18). Median age was 54.2±9.7, ECOG 1/2 = 17/1, and 72.2% received anti-HER2 therapy in prior lines. Doses escalation were 6mg/kg (N = 3), 10mg/kg (N = 6), 15mg/kg (N = 5), and tolerable up to 20mg/kg (N = 4). Only one DLT was found at dosage 10mg/kg, and no MTD was reached. No ADA against IAH0968 was detected. The main PK parameters included mean T1/2 for doses 6~20 mg/kg ranging from 105 to 118 hours. The volume of distribution (Vz-obs) ranged from 4110.16 mL to 5395.64 mL. EC50 of ADCC activity of IAH0968 was 17.75~63.25 ×10-3 µg/mL. All grade treatment-related adverse events (TRAEs) occurred in 100% of pts, including grade 3 in 16.7%, and grade 4 in 5.6% of pts. The most common grade 3 TRAEs were hypokalemia (5.6%), arrhythmia (5.6%), QTC interval extension (5.6%), and infusion reaction (5.6%). The grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or G5 were reported. 22.2% of pts had a TRAE leading to dose adjustment and 16.7% leading to discontinuation of IAH0968. After a median follow-up of 56.5 days (range, 0-479), objective response rate (ORR) was 13.3% (2/15), disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (PFS) was 57.5 days (range, 42-236), with 4/15 responses ongoing. Conclusions: In heavily pretreated metastatic pts with HER2 positive, IAH0968 demonstrated promising clinical activity and tolerable safety profiles. IAH0968 will be further assessed in Phase Ⅱ study in combination treatment. Clinical trial information: NCT04934514 .
MELK and Del-1 as druggable targets in TNBC.
Authors: Lee In Hee , Lee Soo Jung , Kang Byeongju , Lee Jeeyeon , Park Ho Yong , Park Ji-young , Park Jee-Young Nora , Chae Yee Soo 
Published: June 2023

e15100 Background: In our previous study, the researchers found that Del-1 was a promising predictive marker for breast cancer. However, the Del-1 downstream targets and biological effectors remain unknown and undruggable in breast cancer. We used RNA-seq to analyze the transcriptome and investigate the mechanism of Del-1 in regulating the course of breast cancer to uncover a druggable target. Methods: To evaluate the expression levels of Del-1 and MELK, mRNA levels in several breast cancer cell lines were analyzed. Due to the heterogeneity of TNBC, eight different TNBC cell lines were analyzed (BT20, TNBC; MDA-MB-468, basal-like 1; HCC-1806, basal-like 2; DU4475, Immunomodulatory; BT549, mesenchymal-like; MDA-MB-231, mesenchymal stem-like; HS578T, mesenchymal stem-like; MDA-MB-453, TNBC Luminal androgen receptor). Total RNA was isolated using RNAiso Plus (TaKaRa, Otsu, Shiga, Japan). Libraries were prepared from total RNA using the NEBNext Ultra II Directional RNA-Seq Kit. High-throughput sequencing was performed as paired-end 100 sequencing using NovaSeq 6000 (Illumina, Inc., USA). OTS167 was treated for inhibition of MELK. The effects of MELK on cell proliferation and invasion were determined using MTT and Matrigel Transwell assays. To further investigate the relationship between DEL-1 and MELK, the researchers performed dual inhibition of DEL-1 & MELK. Results: Del-1 and MELK expression were significantly increased in TNBC cell lines compared to luminal or HER 2 positive breast cancer cell lines. Expression of Del-1 and MELK was dramatically enhanced in MB 468, HCC-1806, and MB 231 TNBC cell lines. Three TNBC cell lines were transfected with Del-1-specific siRNA to examine the effect of Del-1 downregulation on breast cancer. Del-1 knockdown HCC-1806 & MDA-MB 231 cells significantly decreased MELK expression, suggesting the possible relation between Del-1 and MELK. OTS 167, a MELK inhibitor, significantly inhibits breast cell proliferation and promotes cell apoptosis (MBA-MB-468, p < 0.001). Furthermore, when the OTS 167 was treated, the cell viability decreased as the dose of the MELK inhibitor increased, and the degree was the greatest in MBA-MB 468, basal-like 1 TNBC cell line. To further investigate the relationship between DEL-1 and MELK, the researchers inhibited DEL-1 and then MELK in MTT assay. Dual inhibition significantly reduced cell viability in MDA-MB468 and MDA-MB 231 cell lines, with the basal-like 1 cell lines showing the most significant effect. Conclusions: In this study, we sought to investigate the association between De1-1 and MELK in TNBC cell lines and tumor tissue. We found that MELK is downstream of del-1 and is a promising target, especially in the basal-like 1 subtype. Further research is warranted.
Retrospective evaluation of erlotinib and gefitinib used in the military health system from the perspective of drug-drug interactions.
Authors: Shou Karen J , Luong Thu-Lan T. , Powers Chelsea N. , Reinhardt Brian J. , McAnulty Mike J. , Weina Peter J. 
Published: June 2023

e15108 Background: Erlotinib and gefitinib are epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) approved primarily for non-small cell lung cancer treatment, with pharmaceutical drug-drug interactions (DDIs) that are vague and poorly understood. Previous studies show that concomitant use of EGFR-TKIs with fluoxetine or losartan results in inhibition of both fluoxetine and losartan. Since DDIs can cause significant clinical ramifications, drugs that may interact with erlotinib or gefitinib must be identified. Methods: Data review was performed by Military Health System (MHS) data experts with data provided by the Joint Pathology Center (JPC) from the Department of Defense (DoD) Cancer Registry, the comprehensive ambulatory/professional encounter record (CAPER) and the pharmacy data transaction service (PDTS). Patients treated for cancer were identified, and the CAPER database was used to identify comorbidities. The PDTS database identified prescription drugs filled during erlotinib/gefitinib use, for all cancers. Patients were sorted into subgroups, (1) completed treatment (erlotinib or gefitinib was the last drug that patients completed, without recorded side effects), or (2) discontinued treatment (patients were treated with erlotinib or gefitinib but had recorded side effects and/or switched treatment). PDTS data and retrospective analysis of encounter notes, were used to sort medications into those that were taken before or after (“.”, “,”, “/”, or space between drugs) and those that were taken at the same time (“+”, “-/+”, or “and” between drugs). Results: 348 patients had diagnosis data, with 234 patients having completed treatment and 114 patients having discontinued treatment. Patients who discontinued treatment were diagnosed with more health issues than patients who completed treatment. A total of 258 patients had pharmacy data filled for erlotinib (240 patients) or gefitinib (18 patients). Of these, 177 patients completed treatment and 81 patients discontinued treatment. Patients in the completed treatment group filled 1 to 75 drugs, median range 11-20 drugs. Patients in the discontinued treatment group filled 3 to 103 drugs, median range 31-40 drugs. Patients who discontinued treatment filled more drugs than patients who completed treatment. The 20 most filled drugs, associated with side effects during erlotinib or gefitinib usage and the specific associated side effects were identified. Conclusions: This review cannot conclude that any drug resulted in erlotinib or gefitinib discontinuation. However, associations between top filled drugs and side effects have been made. Proof of concept in vitro laboratory testing should be done with these identified drugs, to confirm mechanistic interactions that may lead to clinical effects.