bluuebunny/crossref_metadata_2025_split huggingface dataset:
A circulating miRNA-based AI prediction system to identify multiple types of cancer.
Authors: Wu Chih-Hsun , Hwang Ming-Jing , Chang Chia-Ming 
Published: June 2022

3050 Background: Cancer is a major problem for human health. Development of an early diagnostic tool can increase the survival of cancer patients. Liquid biopsies have many advantages over traditional tumor tissue biopsies. Circulating microRNAs (miRNAs) are one type of liquid biopsies in part because they regulate the expression and thus functions of their target genes. Circulating miRNAs are stable, non-invasive and changes in their expression are detectable in the early stage of cancer progression, often before clear evidence of tissue biopsy/image tests. To date, there are few liquid biopsy-based tools for multiple-cancer diagnosis and their performance is unsatisfactory. The development of a non-invasive, effective early detection system for cancers is urgently needed. Methods: We integrated and investigated circulating miRNA expression data of 5046 non-cancer samples along with 3856 cancer samples of 6 major cancer types downloaded from publicly available databases. We used these expression data along with gender to establish a multiple cancer type AI prediction system. Furthermore, we built comprehensive interaction networks (miRNA-drug, miRNA-target gene) and performed functional enrichment analysis. Results: We constructed high-performance AI prediction model that can detect and differentiate 6 cancer groups from one non-cancer group. A median of sensitivity of 93.84% in test data was achieved for the multiple cancer classification task. A panel of gender and 15 most important circulating miRNAs was further shown to achieve excellent performance (sensitivity = 90.44%), with just a bit of decrease in the sensitivity of using the full set (gender and 2565 miRNAs). The 15 key circulating miRNAs worked well for the early stage (stage 1: sensitivity = 88%), much better than other liquid-biopsy results reported in the literature. This is important because these miRNAs and the AI system can be used to significantly decrease clinical cost and increase efficiency of early diagnosis, not to mention it is non-invasive. Finally, we constructed comprehensive interaction networks (drug/ target gene) for these key miRNAs to explore potential therapeutic strategies and understand the underlying biological mechanisms. Conclusions: In the study, we constructed the multiple-cancer prediction AI system to classify groups of normal individuals and cancer patients of multiple types, while finding key circulating miRNAs. As several key circulating miRNAs were shown to be potential drug targets or serve as diagnosis biomarkers to fulfill the aim of cancer precision medicine, this work represents a significant step toward achieving the goal of developing a non-invasive tool for early diagnosis of cancers.
A large-scale, multi-center molecular characterization of MET fusions in a real-world Chinese population.
Authors: Liu Yutao , Xia Hui , Zhang Junhua , Si Tongguo 
Published: June 2022

3064 Background: MET is a driver gene notable in its diversity of clinically relevant aberrations, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under-reported, leaving unanswered a series of fundamental questions. In this study, we addressed this knowledge gap by screening for and characterizing MET fusions in a real-world, multi-center population of Chinese cancer patients. Methods: We retrospectively included patients with solid tumors and available genome profiles acquired between August 2015 to May 2021. MET fusion-positive ( MET+) patients were subsequently selected for clinical and molecular characterization. Results: A total of 79816 patients across 27 tumor types were screened. We detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver, biliary tract cancer, and renal cancer (range 0.52%-0.60%) and lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. The fusion partners also turned out to be highly heterogeneous, with ST7, HLA-DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma patients (n = 32) revealed high prevalence of aberrant TP53 in MET+ patients as well as EGFR L858R, L861Q and MET amplification as concurrent alterations. Conclusions: This study is, to our knowledge, currently the largest in characterizing MET fusions. Our findings warrant further clinical validation and mechanistic study that may translate into therapeutic avenues for MET fusion-positive cancer patients.
Real-world utilization of ctDNA in the management of colorectal cancer.
Authors: Savill Kristin M. Zimmerman , Gentile Danielle , Jeune-Smith Yolaine , Klink Andrew J. , Feinberg Bruce A. 
Published: June 2022

3075 Background: The utilization of circulating tumor DNA (ctDNA) as a non-invasive biomarker for the detection of minimal residual disease, prediction of recurrence in the post-operative setting, and real-time monitoring of treatment efficacy has the potential to vastly improve the care and outcomes of patients with colorectal cancer (CRC). In August of 2020, ctDNA testing first gained approval for use in solid tumors and its prognostic benefit after curative intent surgery has been demonstrated to exceed that of prior standard of care clinicopathological criteria in CRC patients. The comprehensive integration of validated ctDNA approaches into the routine clinical care of patients with CRC would not only fundamentally change how risk of recurrence is assessed but could also reduce treatment with unneeded/unwarranted toxic therapies and allow for earlier recognition and treatment in cases with a high risk of relapse. This survey-based study aimed to evaluate the utilization of ctDNA testing in the management of CRC among practicing community oncologists in the U.S. Methods: Questions related to ctDNA utilization for patients with CRC were presented to community oncologists during a virtual meeting held in July 2021. Descriptive statistics were used to analyze the results. Results: Of 55 participating oncologists geographically distributed across the U.S., 49% indicated not using ctDNA to make treatment decisions in CRC. A proportion of physicians reported using ctDNA to detect recurrence (27% of physicians); make decisions around post-resection adjuvant therapy (25%); monitor disease progression/relapse (18%); and track tumor resistance during treatment (9%). The most frequently cited barriers to ordering ctDNA testing for patients with metastatic CRC were reimbursement issues (reported by 56% of oncologists), insufficient clinical evidence (46%), and limited familiarity with ctDNA use (28%). Oncologists reported that the following would increase their utilization of ctDNA testing: more clinical evidence of the utility of ctDNA (reported by 66% of physicians), increased education on methodology (60%), more education on the use of ctDNA (57%), more financial aid and reimbursement support for patients (49%), more decision support tools (47%), and better communication between physicians and vendors (26%). Conclusions: These findings demonstrate limited adoption of ctDNA testing by community oncologists in the care of CRC patients. Insufficient demonstration of clinical utility, limited familiarity with methodology, and reimbursement issues were cited as barriers to uptake. Education for community oncology providers about ctDNA testing and its demonstrated clinical utility, and increased financial support for patients may improve its utilization and adoption in CRC to improve patient outcomes and care.
Updated analysis of the efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (NTRK-fp) solid tumors.
Authors: Krzakowski Maciej Jerzy , Lu Shun , Cousin Sophie , Smit Egbert F. , Springfeld Christoph , Goto Koichi , Garrido Pilar , Chung Christine H. , Lin Jessica Jiyeong , Bray Victoria J. , Pitcher Bethany , Zeuner Harald , Patel Siddhartha , Bordogna Walter , Gelderblom Hans 
Published: June 2022

3099 Background: NTRK gene fusions, coding for chimeric TRK proteins, are oncogenic drivers in many solid tumors. In an integrated analysis of three phase 1/2 trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]), entrectinib, a potent CNS-active TRK inhibitor, showed durable systemic and intracranial responses in pts with NTRK-fp solid tumors. We report updated data from a larger cohort with longer follow-up (clinical cutoff 2 Aug 2021). Methods: Pts with locally advanced/metastatic NTRK-fp solid tumors and ≥12 months’ follow-up from first tumor assessment were efficacy evaluable. The safety cohort also included pts from TAPISTRY (NCT04589845). Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every 8 weeks thereafter. Primary endpoints: objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR and safety were also assessed. Results: The efficacy-evaluable cohort comprised 150 adults (vs 121 previously) with 17 different solid tumor types. Median age was 58.5 years; 91% of pts had ECOG PS 0–1 and 37% had received ≥2 prior lines of therapy. Median survival follow-up was 30.6 months. ORR was 61.3% (n = 92/150; 95% CI: 53.1–69.2), including 25 complete responses. Responses were observed in all tumor types with n>1 (Table). Median DoR, PFS and OS were 20.0 months (95% CI 13.2–31.1), 13.8 months (95% CI 10.1–20.0), and 37.1 months (95% CI 27.2–not estimable [NE]), respectively. In pts with and without investigator-assessed baseline CNS metastases (n = 31 / n = 119), ORR was 61.3% (95% CI 42.2–78.2) and 61.3% (95% CI 52.0–70.1) respectively. IC-ORR was 69.2% (n = 9/13) in pts with BICR-assessed measurable CNS metastases; median IC-DoR was 17.2 months (7.4–NE). In the safety population (N = 235: all treated pts), most treatment-related adverse events (TRAEs) were grade 1/2 and not serious; the most frequent were dysgeusia (36.6%), diarrhea (29.8%) and weight increase (28.5%). TRAEs led to dose interruption, reduction and discontinuation in 32.8%, 24.3% and 7.2% of pts, respectively. Conclusions: In this updated analysis, entrectinib continued to demonstrate deep and durable responses and was well tolerated in pts with NTRK-fp solid tumors with or without baseline CNS metastases. Clinical trial information: STARTRK-2 [NCT02568267]. [Table: see text]
The distribution of genetic mutations correlated with resistance to KRASG12C inhibitors in Chinese patients with lung cancer.
Authors: Lin Shengcheng , Ma Kai , Xu Yafei , Liu Xinyi , Huang Xiaochun , Huang Mengli 
Published: June 2022

3141 Background: In lung cancer, p.G12C is the most frequent variant in Kirsten rat sarcoma viral oncogene homologue (KRAS) gene. KRASG12C inhibitors have shown promising efficacy in lung cancer in recent clinical trials, acquired resistance, however, eventually occurred in most patients. Preliminary studies revealed that a number of genetic mutations were correlated with resistance to this type of drugs, including KRAS secondary mutations, KRAS activating mutations, mutations in RTK-RAS-MAPK signaling pathways members, oncogene rearrangements and copy number gain. To clarify the potential clinical application of KRASG12C inhibitors, herein we analyzed the distribution of reported resistance gene alterations in a large and natural group of Chinese lung cancer, as well as the gene mutation landscape of the subset of patients with suspected resistant mutations. Methods: A total of 32878 Chinese lung cancer including early-stage, late-stage without treatment or late-stage with previously treated were analyzed in this study. Wide NGS panel testing was used to detected single nucleotide variants (SNV), copy number variants (CNV) and oncogenic gene rearrangements. Results: KRAS mutations were detected in 2767 (8.4%) cases, of which KRAS G12C was the most common variant (30.86%). Among 854 patients (2.6%) harbored KRAS G12C, 75 (10%) carried the above resistance mutations, such as G12D/R/V (n = 7). Fusions (20%) which previously observed only in coloretal cancer were unexpectedly detected in this corhort, including EML4-ALK (n = 1), FGFR1-MECOM (n = 1), EWSR1-CHEK2 (n = 2), SPEN-KAZN (n = 2), MET-KCNB2 (n = 1), NOTCH2-NOTCH2NLA (n = 5), SMARCA4-DNAH8 (n = 1), and LIPM-FAS (n = 1). Furthermore, KRAS (46.7%), MYC (25.3%) and MET (10.7%) were amplified. Among this subset of patients with resistant mutations, TP53 (66%), LRP1B (25%), and STK11 (22%) were the most frequently mutated genes. It is noteworthy that STK11/KEAP1 /NFE2L2 gene mutation was detected in nearly 30% in this group of patients. Conclusions: The results of our analysis suggested that about 10% KRAS G12C-mutated Chinese lung cancer patients would be resistant to KRAS G12C inhibitors. Moreover, a small number patients have co-mutated genes which were negatively related to immunotherapy in NSCLC, indicating they were also inappropriate for immunotherapy.
Updated survival follow-up for phase I study of abexinostat with pazopanib in patients with solid tumor malignancies.
Authors: Tsang Erica S , Aggarwal Rahul Raj , Thomas Scott , Dhawan Mallika Sachdev , Pawlowska Nela , Bartelink Imke Heleen , Grabowsky Jennifer A. , Jahan Thierry Marie , Truong Thach-Giao , Ryan Charles J. , Munster Pamela N. 
Published: June 2022

3150 Background: Histone deacetylase (HDAC) inhibition downregulates HIF-1a, which may be effective in overcoming resistance to VEGF-targeting tyrosine kinase inhibitors. We report the updated survival follow-up for patients treated with abexinostat and pazopanib in a phase Ib trial. Methods: Patients with solid tumor malignancies were enrolled in this phase Ib, open-label trial (NCT01543763) of abexinostat in combination with pazopanib (3+3 design), with a dose expansion restricted to renal cell carcinoma (RCC). Patients received a 1-week run-in period with abexinostat alone, and then combination abexinostat with pazopanib during a 28-day treatment cycle until disease progression, unacceptable toxicity or study withdrawal. Plasma samples from 29 patients were sent for metabolomics analysis. Results: 51 patients were enrolled: N = 36 patients in dose escalation, N = 15 in dose expansion. At the time of last report in 2017, 5 patients remained on study treatment: N = 4 with RCC, and N = 1 with thymic neuroendocrine carcinoma. 4 of these patients have now had disease progression. Median duration of therapy measured 44.9 months (range 39.8-102.2). One patient with metastatic RCC (patient 1) remains on study treatment, after progression on 5 prior lines of systemic therapy. With updated survival follow-up, median OS measured 12.4 months in the dose escalation arm and 27.65 months in the RCC dose expansion cohort. Overall median duration of therapy in all 51 patients measured 5.6 months (range 1-103 months). Progression-free survival among patients with high PBMC HDAC2 expression (> 0.4) remains longer compared to those with low expression (median 6.3 vs. 3.7 months, p = 0.0041). Metabolomics analysis demonstrated a negative correlation between HDAC2 and N6-acetyllysine, suggesting that baseline HDAC2 may impact efficacy of HDAC inhibition. Conclusions: The combination of abexinostat with pazopanib appears promising, with the potential for long-term responses particularly in patients with metastatic RCC. This has led to an ongoing phase III trial examining this combination in RCC. Clinical trial information: NCT01543763. [Table: see text]
Cell-free DNA (cfDNA) fragmentomes predict tumor burden in metastatic colorectal cancer (mCRC).
Authors: Leal Alessandro , van 't Erve Iris , Lumbard Keith , Keefer Laurel , Carey Jacob , Wu Tony , Jakubowski Debbie , Butler Denise , Rongione Michael , Chesnick Bryan , Punt Cornelis J. A. , Meijer Gerrit A. , Dracopoli Nicholas C , Maddala Tara , Scharpf Robert , Bach Peter Brian , Velculescu Victor E. , Fijneman Remond 
Published: June 2022

3541 Background: Measurement of plasma mutant allele fraction (MAF) in patients with cancer provides prognostic information, but this approach typically relies on prior tumor tissue analyses or knowledge of specific mutations. There is a clinical need to develop rapid and accurate noninvasive plasma-only approaches to estimate disease burden dynamics. Comprehensive genome-wide analyses of cfDNA fragmentomes has become a useful tool for noninvasive cancer characterization. Here we present a novel application to predict MAF from genome-wide fragmentation-related profiles (fMAF) as a prognostic marker in mCRC patients with initially unresectable liver-only metastases enrolled in the phase III CAIRO5 study (NCT02162563). Methods: 693 longitudinal plasma cfDNA samples were obtained from patients with RAS/BRAF-mutant mCRC (training arm, N = 78) and patients with RAS/BRAF wild-type mCRC (validation arm, N = 75) treated with first-line fluoropyrimidine-based chemotherapy were collected. MAFs as measured by digital droplet PCR (ddPCR) were obtained for patients in the training arm. We trained an initial regression model to predict MAFs with genome-wide fragmentation features using subject-level random intercepts. Out of sample predictions for participants in the RAS/BRAF-mutant mCRC arm were obtained through cross-validation. Cox proportional hazards models were used to evaluate the association between fMAF and PFS and overall survival (OS) at pre- and first post-treatment blood draws. Standardized hazard ratios (sHR) and 95% confidence intervals (CI) are reported. Results: There were 68 and 61 evaluable participants with median (range) age of 62 y (41-79 y) and 58 y (27-76 y), and 38% and 36% female in the training and testing arms, respectively. Median time between pre- and post-treatment blood draw was 8 weeks. In the training cohort, median fMAFs dropped from pre- to post-treatment initiation (17.8% to 1.8%). Median PFS was 9 months. For both fMAFs and RAS/BRAF MAFs, the association with PFS was stronger for the pre-treatment than the post-treatment timepoint (Table). Post-treatment fMAFs were not associated with PFS in the training cohort and similar trends were observed for OS. Conclusions: Initial modeling demonstrates the ability of cfDNA fragmentomes to estimate cell-free DNA tumor burden with performance comparable to standard approaches. Ongoing modeling efforts will result in evaluation of a final model in the testing arm. The development of a noninvasive tissue-independent diagnostic approach that does not rely on mutation detection in the circulation has the potential to expand the use of liquid biopsies for advanced disease monitoring. Clinical trial information: NCT02162563. [Table: see text]
Association between environmental quality index and young onset colorectal cancer.
Authors: Goksu Suleyman Yasin , Khatib Jude , Reddy Sarah , Ozer Muhammet , Maxwell Mary Claire , Khosama Leticia , Kainthla Radhika , Sanford Nina Niu , Pogacnik Javier Salgado , Chilakamarry Sitaram , Huang Emina , Beg Shaalan Shaalan , Kazmi Syed Mohammad Ali 
Published: June 2022

3548 Background: The factors associated with the rise of young-onset colorectal cancer (YOCRC) remain unclear. However, environmental exposures are believed to be associated with YOCRC in addition to hereditary factors. Therefore, we evaluated the association between the national level Environmental Quality Index (EQI) and YOCRC in the US. Methods: We queried the SEER database to identify adult colorectal cancer patients diagnosed between 2010-2016. YOCRC was defined as age at diagnosis < 50 years. EQI (2005-2010) is a measure of county-level cumulative environmental exposures that includes 5 domains: sociodemographic, built, air, land, and water. A higher value represents a lower environmental quality. We distributed the total EQI and each EQI domain into five quintiles. Multivariable logistic regression analysis was used to assess the relationship between YOCRC and quintiles (upper-most vs. lowest) of EQI after adjusting by race (White, Black, and Others), gender, and stage at diagnosis. The age-adjusted incidence rate was also calculated using the SEER*Stat, and correlation efficiency was estimated between EQI domains and incidence rate. Results: A total of 261,417 CRC patients were included; 11% were YOCRC. In the adjusted multivariable analysis, poor built EQI (OR 1.15 [1.11-1.20]) and water EQI (OR 1.08 [1.03-1.12]) were more likely to be associated with YOCRC. Poor built EQI was more strongly associated with Black YOCRC (OR 1.21 [1.09-1.35]) as compared to White YOCRC (OR 1.14 [1.09-1.19]). Poor sociodemographic EQI was more strongly associated with Others (OR 1.47 [1.25-1.72]) compared to Black YOCRC (OR 1.14 [1.03-1.25]). In addition, poor built EQI (OR 1.19 [1.12-1.27]) and water EQI (OR 1.12 [1.05-1.19]) were more strongly associated with the metastatic disease among YOCRC patients. However, the total poor EQI was not associated with YOCRC (OR 0.99 [0.95-1.03]). On incidence analysis, there was a positive correlation between the incidence rate of YOCRC and sociodemographic EQI (rho = 0.49, p < 0.001), air EQI (rho = 0.30, p < 0.001), and land EQI (rho = 0.18, p < 0.001). Conclusions: This study evaluated a population-based ecological approach and showed that YOCRC was associated with lower environmental quality, including built and water domains. EQI domains were also associated with different racial groups among YOCRC. Instead of studying single environmental exposures, the impact of the cumulative environmental index should be recognized and studied further to understand the mechanism of cancer development.