bluuebunny/crossref_metadata_2025_split huggingface dataset:
First report of ELUCIDATOR study: A prospective observational multicenter study on resistance mechanisms in patients with early disease progression during osimertinib.
Authors: Mizumori Yasuyuki , Tamiya Akihiro , Osuga Mitsuo , Isa Shun-ichi , Taniguchi Yoshihiko , Nakamura Keiichi , Harada Daijiro , Shinohara Tsutomu , Yanai Hidetoshi , Nakatomi Katsumi , Oki Masahide , Mori Masahide , Kuwako Tomohito , Yamazaki Koji , Tamura Atsuhisa , Ando Masahiko , Koh Yasuhiro 
Published: June 2023

3032 Background: Osimertinib (Osi) is the key standard therapy for patients (pts) with chemo-naive advanced non-small cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor ( EGFR) mutations. However, many of cases treated with Osi experience the disease progression (PD). Therefore, understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies. Here, we addressed the underlying mechanisms of resistance to Osi using paired plasma DNA samples and particularly focused on early PD (PD within 6 months) cases. Methods: This trial is the multicenter prospective research, and we prospectively collected plasma DNA samples prior Osi treatment and at PD. Next-generation sequencing (NGS) implemented with the molecular barcoding method was performed to analyze gene mutations in 197 cancer-associated genes. Then using these ct-DNA, we analyzed the Osi resistance by ultra-sensitive NGS. In this interim analysis, we specially analyze the early PD (PD within 6 months) cases. Results: One hundred eighty-eight pts were enrolled between May 2019 and January 2021. Among these pts, 125 (66%) pts were female, 96 (51%) were EGFR exon 19 deletion mutation, and 109 (58%) were never smoker. Seventy-eight pts experienced PD and 36 pts experienced early PD at interim analysis. Baseline shedders, patients with plasma positivity for EGFR-activating mutation were more frequently observed in early PD pts than non-PD (86.1% vs 63.4%, p = 0.009). Early PD patients had significantly more co-occurring gene mutations along with EGFR mutations than non-early PD patients (2.89±1.49 vs 1.97±1.37, p = 0.002). Most notably, 3 among 36 early PD pts and 8 among 78 PD pts had significant reduction of plasma EGFR mutant allele frequency at PD than that at baseline. Among those, 1 had germline BRCA1 mutation and 1 had BRINP3 mutation in 3 early PD pts, and 1 had germline BRCA2 mutation, and 1 had germline TP53 mutation in 5 PD pts excluding early PD pts. Co-occurring TP53 mutations were not relevant to early PD in this study cohort. Conclusions: Germline mutations in BRCA1/2, TP53 and BRINP3 may confer early and unprecedented resistance to Osi monotherapy. Plasma-based serial comprehensive gene profiling may help predict and identify patients unlikely to benefit from Osi treatment, though further study is warranted. Clinical trial information: jRCTs031180051 .
A novel three-biomarker signature (CA-62, CEA, CYFRA 21-1) and early-stage NSC lung cancer detection.
Authors: Tcherkassova Janneta , Tsurkan Sergei , Prostyakova Anna , Klinski Evgueni , Sekacheva Marina , Boroda Alexander , Moro Ricardo , Berz David 
Published: June 2023

3038 Background: A double-blind clinical study was conducted on 304 clinically verified blood serum samples, including 141 non-small cell lung cancer (NSCLC), 133 healthy volunteers and 30 patients with chronic obstructive pulmonary disease (COPD). The objectives of the study were: The assessment of various cancer markers and their possible combinations for detection of early (I-II) stages of non-small cell lung cancer (NSCLC) and evaluation of the best cancer markers panel as a pre-screening tool for NSCLC before Low-Dose CT scan. Methods: Quantitative measurement of various tumor markers for serum samples was carried out using electrochemiluminescent immunoassays Elecsys CA-125, ELECSYS CA 19-9, ELECSYS CYFRA 21-1 and ELECSYS SCC (COBAS, Roche Diagnostics GmbH, Germany, EU), enzyme immunoassay CA15-3-ELISA-BEST, CEA-ELISA-BEST, NSE-ELISA-BEST (JSC "VECTOR-BEST", RF) and immunochemiluminescent analysis CLIA-CA-62 (LLC "JVS Diagnostics", RF). The results were compared to the literature data for other biomarkers and their panels. Results: Unlike other tumor markers, which are expressed proportionally to tumor size, the marker for epithelial carcinomas CA-62 is expressed from Stage I and demonstrated the highest diagnostic results in detecting early stages (I-II) of NSCLC. The biomarkers CYFRA 21-1 and SCC do not have sufficient sensitivity and specificity to diagnose asymptomatic lung cancer. However, the addition of cytokeratin 19 CYFRA 21-1 to glycoproteins CA-62 and CEA increases the specificity by eliminating false positive results, which significantly improves the diagnostic value of the cancer marker signature (CA-62, CEA and CYFRA 21-1): 100% Specificity, 93% Sensitivity, 100% PPV, 94% NPV and 94% test accuracy. Conclusions: The results of the study demonstrated that using the biomarkers signature (CA-62, CEA and CYFRA 21-1) allows increasing the specificity of CT scan for patients with suspicious abnormalities on the tomogram, improving the interpretation of visualized localized lesion, and improving the accuracy of differential diagnosis at detecting early stages of LC up to 94%. In the prospective, adding cancer markers panel signature (CA-62, CEA and CYFRA 21-1) to the current lung cancer risk assessment system as a pre-screening tool for LDCT may improve the quality of early-stage Lung cancer detection by significant increasing the sensitivity and by reducing the proportion of false positive results. [Table: see text]
The detection of multiple cancer types with an extended set of methylation and protein markers.
Authors: Katerov Slava E. , Fleming Harrison L , Rugowski Debra E , Heilberger Justin , Duellman Tyler , Kirby Jillian M , Kirchner Nick , Melah Brittany , Hennek Jacquelyn , Allawi Hatim T. 
Published: June 2023

3040 Background: Cancer is the 2nd leading cause of mortality in the US, with an estimated 1.96M new cases expected in 2023. With guideline recommended screening unavailable for most cancers, multicancer early detection (MCED) tests in development may extend the reach of cancer screening. As part of an ongoing program examining multiple biomarker classes in cancer early detection, we examined the feasibility of combining blood DNA methylation and cancer protein markers for the detection of multiple cancer types. Methods: 236 samples from subjects with cancer (13 tumor organ types) were retrospectively collected and gender/age matched with 146 unscreened non-cancer control samples. Plasma and serum were used for cfDNA methylation analysis of 36 differentially methylated regions and 8 cancer-associated protein markers in a randomized, blinded fashion. Methylated DNA markers (MDMs) were assayed using target enrichment long-probe quantitative-amplified signal assays. Protein markers were assayed with commercial kits. Normalized methylation values/protein concentrations were used to develop a logistic regression model for cancer detection. The model was built with 5 random 0.7/0.3 training/validation splits, keeping case/control, cancer types, gender, and age distributions similar to the original data set. Models for MDMs and protein markers were created, and a combined model including both MDMs and protein markers was also evaluated for performance improvement. Results: A reduced subset of MDM and protein markers was identified to have robust detection of several cancer types. At 99% specificity, overall sensitivity for cancer detection was 68% (95% CI: 62%-74%) for MDMs, 43% (37%-50%) for proteins, and 75% (69%-80%) for MDMs and proteins combined. Conclusions: Building on promising results with mutation and protein biomarker analysis (Science 369:6499, 2020) this pilot study demonstrates the potential of combining DNA methylation and protein biomarkers and contributes to a larger scale effort to develop a multi-biomarker class MCED test (Ann Oncol 2022 Vol. 33:S575). [Table: see text]
ctDNA-based genomic landscape analysis to evaluate molecular brake and gatekeeper mutations in FGFR2 alterations.
Authors: Severson Paul , Sytnikova Julia , Mohan Adithi , Zhang Nicole , Donderici Elifnur Yay , Williams Richard Thomas 
Published: June 2023

3049 Background: FGFR2 and FGFR3 (FGFR2/3) gene alterations are oncogenic drivers found across various cancer types and have been successful targets of drug development. Several FGFR inhibitors (FGFRi) are approved for clinical use, and most are ATP-competitive, reversible inhibitors (1st-gen). Efficacy of the 1st-gen FGFRi can be limited by acquired resistance mutations in the FGFR kinase domain, typically molecular brake or gatekeeper mutations, which disrupt compounds binding through conformational changes or through direct steric hindrance, respectively. Irreversible (covalent) FGFRi, such as futibatinib, are in development to overcome kinase domain resistance mutations. However, preclinical evidence indicates that some of the known resistance mutations (eg. V564L) remain insensitive to futibatinib. Methods: To assess the landscape of FGFR-driven cancers and to better understand the prevalence of molecular brake and gatekeeper mutations, we analyzed the distribution of FGFR2/3 alterations in a large clinical genomic research database. This ctDNA-based genomic database was selected for the analysis given that liquid biopsy is a fit-for-purpose method to detect acquired resistance mutations. Results: We identified over 2,100 patients with FGFR2/3 alterations. Non-small cell lung cancer (NSCLC), breast, bladder, and cholangiocarcinoma (CCA) had the highest number of patients with FGFR2/3 alterations. 36% of all FGFR2 alterations across all cancer indications consisted of molecular brake or gatekeeper mutations. This finding was most enriched in CCA and breast cancer where 51% and 57%, respectively, of FGFR2 alterations were molecular brake or gatekeeper mutations. In breast cancer patients, molecular brake mutations were common and represent activating mutations in FGFRi-naïve patients. A small number of FGFR3 gene fusions were detected in CCA patients who had significantly shorter time on 1st-line treatment and trended toward shorter overall survival when compared to patients with FGFR2 fusions. We also identified CCA patients with FGFR2 fusions and one or more concurrent FGFR2 SNVs; primarily those in the kinase domain and associated with FGFRi resistance. Most of these putative cases of acquired resistance were polyclonal, with 2 or more (up to 8) FGFR2 SNVs coexisting with the fusion. Bladder cancer and NSCLC had the highest numbers of FGFR3 alterations. FGFR2/3 alterations were typically found without other driver mutations in CCA, bladder, and NSCLC patients. However, in breast there was a large overlap between FGFR2/3 alterations and other drivers. Conclusions: Herein, we identify a cohort of patients with FGFR2/3 molecular brake and gatekeeper mutations that may benefit from next-generation FGFR2/3-targeted therapies designed to inhibit a broad spectrum of both primary and secondary resistance mutations.
Detection of early-stage cancers using circulating orphan non-coding RNAs in blood.
Authors: Karimzadeh Mehran , Wang Jeffrey , Cavazos Taylor B. , Schwartzberg Lee S. , Multhaup Michael , Ku Jeremy , Zhao Xuan , Wang Jieyang , Wang Kathleen , Hanna Rose , Arensdorf Patrick , Chau Kimberly H , Li Helen , Goodarzi Hani , Fish Lisa , Hormozdiari Fereydoun , Alipanahi Babak 
Published: June 2023

3051 Background: Orphan non-coding RNAs (oncRNAs) are a novel category of small RNAs (smRNAs) that are present in tumors and largely absent in healthy tissue. We investigated the utility of oncRNAs extracted from serum for early cancer detection across seven cancer types. Methods: We collected 2,882 serum samples from individuals with known cancers of the bladder ( n=152), breast (220), colon and rectum (141), kidney (283), lung (281), pancreas (287), and stomach (280) as well as donors with no history of cancer (1,238). We used 0.5 mL serum aliquots to generate and sequence smRNA libraries at an average depth of 20 million 50-bp single-end reads. Samples were split into age-, sex-, and smoking status-matched training (1,232 cancer; 922 control) and validation (412 cancer; 316 control) cohorts. A large catalog of oncRNAs specific to each cancer was created using tumor and adjacent normal samples from The Cancer Genome Atlas (TCGA) smRNA-seq database. Using TCGA-derived oncRNAs, we trained a machine learning model to predict cancer presence and tissue of origin (TOO) in a 5-fold cross validation setup using our training cohort. For the validation cohort, we averaged the predictions from the five training cohort models. Results: The model ROC-AUC for detecting cancer was 0.95 (95% CI: 0.94–0.95 for training and 0.94–0.97 for validation cohorts). Sensitivities for detecting cancer at 95% specificity were 0.74 (0.70–0.76) for early stage (I/II) and 0.80 (0.76–0.84) for late stage (III/IV) cancers in the training cohort, and 0.77 (0.71–0.81) and 0.81 (0.73–0.87) in the validation cohort. Sensitivities of detection for each cancer type are shown. For samples with cancer and TOO predictions, our top 1 and top 2 TOO accuracy was 0.76 (0.68–0.84) and 0.83 (0.76–0.90) for the validation set. Conclusions: These results demonstrate that oncRNAs detected in serum can be used for accurate, early detection, and localization of multiple cancers. [Table: see text]
NMR metabolomics in bladder cancer: Identification and monitoring of serum biomarkers during Pt-based treatment.
Authors: Giorgione Roberta , Gambale Elisabetta , Rossi Virginia , Mela Marinella Micol , Doni Laura , Roviello Giandomenico , Renda Roberta , Venturi Giulia , Pasqui Adriano , Zenoni Andrea , Bernini Andrea , Pillozzi Serena , Antonuzzo Lorenzo 
Published: June 2023

3057 Background: To date, predictive and prognostic biomarkers for Bladder Cancer (BC) are lacking. Metabolomics, the study of small molecules involved in metabolism, aims to identify diagnostic, predictive and prognostic biomarkers. Overall, BC shows perturbations of various metabolic pathways, involved in biochemical reactions essential for energy production and for the maintenance of the REDOX balance, as well as in the metabolism of purines and pyrimidines. The main objective of this study is to characterize the serum metabolic profile of patients with BC undergoing platinum-based chemotherapy (Pt-CT), to identify the alterations induced by CT and evaluate the associated deregulated metabolic pathways, in order to identify potential biomarkers, prognostic and predictive of response to treatment. Methods: We enrolled patients with BC undergoing Pt-CT in different settings (neoadjuvant, adjuvant or metastatic). For each patient, a blood sample was collected before the start of each CT cycle (T0, T1, Tn). Metabolomic analysis was performed using the Bruker Avance 600 spectrometer. At baseline (T0), the metabolomic profiles of BC patients were compared with that of age- and sex-matched healthy controls. Major metabolites up- or down-regulated in patients with BC at baseline, were then monitored during CT (T1, Tn). Results: 14 patients were enrolled. When compared with age- and sex-matched healthy controls, patients with BC had elevated levels of acetate and acetone (ketone bodies), hypoxanthine, trimethylamine N-oxide (TMAO), glutamate, lactate, phenylalanine, and ornithine, and decreased levels of carnitine, choline, betaine, aspartate, threonine, 2-hydroxybutyrate, 2-aminobutyrate and histidine. When monitored during CT, hypoxanthine, glutamate, and aspartate levels increased; acetone, acetate and TMAO instead had a decreasing trend. Conclusions: The results of our pilot study confirm perturbations in several metabolic pathways: up-regulation of lactate, ketone bodies, hypoxanthine, phenylalanine, and glutamate levels in BC patients reflects altered glycolysis, fatty acid, purine, and amino acid metabolism, respectively. In addition, TMAO may play a role in the development of BC by promoting a pro-inflammatory and oxidative stress state. Furthermore, monitoring these metabolites could be a useful tool for predicting response to treatments. To our knowledge, there are no metabolomic studies that evaluated BC patients receiving CT and that included longitudinal monitoring to identify any changes in the metabolic profile induced by treatment.
Diagnostic application of circulating CDH17 biomarker for screening GI malignancies.
Authors: Ng Lui , Iyer Deepak , Wong Tony K , Hon Tsz Chun , Sun Stella , Luk John Moon , Foo Dominic Chi-Chung 
Published: June 2023

3058 Background: Colorectal cancer (CRC) is the most common and treatable gastrointestinal (GI) cancer, yet it remains the second leading cause of cancer associated deaths globally. Cadherin-17 (CDH17) is a biomarker for GI cancers characterized by its overexpression in stomach, liver, and colorectal cancers but controlled expression in normal tissues from healthy adults. Although an improvement in the detection strategy of CDH17 is essential to apply it for large scale CRC screening. We have developed a novel diagnostic immunoassay using a panel of highly specific antibodies (PCT/US2019/032752) that unveiled CDH17 as a potential diagnostic maker with high detection sensitivity and specificity in CRC. Methods: The study recruited 150 patients (Retrospective specimens - 50 colorectal adenomas and 100 colorectal cancer) and 50 asymptomatic 18-80 years old blood donors (prospective specimens). CDH17 expression levels were measured within the individual blood-plasma samples using an enzyme-linked immunoassay. Results: The novel CDH17 diagnostic assay showed a wide operating dynamic range extending from 90ng to a lower limit of detection at 123pg. Using the assay, we observed a progressive and a significant increase in the plasma CDH17 concentration from the asymptomatic individuals to the colorectal adenoma group, while the CRC patients showed the highest expression of the circulating protein (median: 2.5ng/mL vs 4.5ng/mL vs 8.0ng/mL, P<0.0001). Within the CRC group, a higher CDH17 expression was associated with advanced tumor invasion, occurrence of nodal or distant metastases, as well as a clinical presentation of an advanced stage disease. The diagnostic power of the assay in terms of ROC AUC values was higher than 0.9 with an overall sensitivity of 82% that extended to 100% for metastatic CRC, while the specificity was at 94% for all stages combined (P<0.0001). Plasma CDH17 outperformed the clinically applied CEA and CA19-9 markers in differentiating the CRC patients from the asymptomatic population. Conclusions: The CDH17 immunoassay is potentially a diagnostics tool aid for the detection of CDH17 within blood samples prompting the early diagnosis of CRC. [Table: see text]
ctDNA analysis of NTRK fusion and mechanisms of acquired resistance to TRK inhibitors.
Authors: Sivaprakasam Karthigayini , Harada Guilherme , Choudhury Noura J. , Savin Casey , Shah Ronak H. , Berger Michael F. , Drilon Alexander E. 
Published: June 2023

3062 Background: The regulatory approval of TRK tyrosine kinase inhibitors (TKIs) represented a landmark in tissue-agnostic drug development. Adult and pediatric patients harboring NTRK fusions derive meaningful clinical benefits from the first-generation TRK TKIs larotrectinib and entrectinib. However, characterizing NTRK fusions and resistance mechanisms to TRK TKIs by circulating tumor DNA (ctDNA) remains to be studied. Methods: Patients with NTRK-fusion-positive tumors who received TRK TKIs and had ctDNA analyzed using next-generation sequencing (NGS) were retrospectively identified. Samples were collected at multiple time points, including pre-TRK TKI, on-treatment, and post-progression. Mechanisms of resistance to TRK TKIs were examined when post-progression ctDNA samples were available. Results: Twenty-seven patients, with a median age of 57 years (range 28-81) and 11 different cancer types were identified. Twenty-two patients (81%; 22/27) had at least one ctDNA-positive sample (tumor burden greater than 0). A total of 67 ctDNA samples were analyzed by MSKCC ACCESS ctDNA pipeline, of which 10 samples (15%; 10/67) were collected before any TRK TKI. Forty-two samples (63%; 42/67) had positive ctDNA and NTRK fusion was detected in 16 ctDNA samples (24%; 16/67), including 9 (56%) NTRK1 fusions and 7 (44%) NTRK3 fusions. Among the pre-TRK TKI samples (n=10), 2 samples (20%, 2/10) had NTRK fusions detected. A total of 8 patients had post-progression samples with a resistance mechanism identified, of which 5 patients received larotrectinib and 3 entrectinib. The ctDNA samples revealed 7 patients (88%; 7/8) with on-target resistance and 1 patient (12%; 1/8) with off-target resistance. Among on-target mutations identified, the most common involved the solvent front residue (86%, n=6/7: n=2 NTRK3 G623R, n=2 NTRK1 G595R, n=1 NTRK3 G623E, n=1 NTRK3 623L) followed by the xDFG motif (14%, n=1/7: n=1 NTRK1 G667C). Regarding off-target alterations, one patient developed a BRAF V600E mutation. Conclusions: The use of plasma ctDNA can improve the identification of NTRK fusions through non-invasive techniques and potentially identify subsequent resistance mechanisms after the administration of the TRK TKIs.
Potential improvement in the diagnostic accuracy in detecting the estrogen receptor status in metastatic and recurrent breast cancer using 18F-FES PET/CT in the US.
Authors: Fuentes-Alburo Adolfo , DiGregorio Nicholas , Neeser Kurt , Jin Jiran , Young Regina 
Published: June 2023

3063 Background: ER status helps classify BC for the most appropriate treatment pathway. Biopsy (Bx) and immunohistochemical (IHC) are established procedures to determine the ER status in metastatic BC (mBC, i.e., first occurrence of metastases) and recurrent BC (rBC, i.e., progression of mBC). In some cases, the accuracy of Bx/IHC to inform ER status may be challenged (e.g. difficult to access lesions; ER discordance within/across lesions and due to temporal heterogeneity; and when a Bx fails to obtain representative tissue). 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) is a radiolabeled form of estrogen that binds to ER. For use with positron emission tomography /computed tomography imaging (PET/CT), it allows an assessment of whole-body ER+ status. In prospective trials and meta-analyses, 18F-FES PET/CT provided high diagnostic accuracy (DA) of ER+ disease. This study evaluated the potential increase in accuracy in determining ER+ status when 18F-FES PET/CT was added to IHC in mBC and rBC. Methods: An Excel based decision model was developed to estimate the impact on DA for ER+/HER2- US mBC and rBC patients over a five-year period by introducing 18F-FES PET/CT. The model assumed that 18F-FES PET/CT was added to Bx/IHC to classify ER status in three cases: (i) for mBC patients when Bx failed or was inconclusive, (ii) for mBC patients when Bx was not possible, or (iii) for all rBC patients. The DA between two scenarios was compared: scenario A, DA of Bx/IHC only and scenario B, 18F-FES PET/CT + Bx/IHC. Results: Scenario B, adding 18F-FES PET/CT, may lead to an increase in the initiation of appropriate endocrine- and chemotherapies, as defined by clinical practice guidelines, in all comparisons. The largest increase in DA was in rBC and, when BX is not possible, in mBC patients. Also, results indicate that introducing 18F-FES PET/CT decreases the number of re-biopsies performed except when Bx was not possible (ii). Conclusions: Adding 18F-FES PET/CT to Bx/IHC is expected to improve the DA of a patients’ ER status thereby increasing the information available to inform treatment, thus reducing the need for re-biopsies in mBC and rBC patients. By far the largest increase in DA of ER status using 18F-FES PET/CT was seen among patients with rBC (iii). [Table: see text]