bluuebunny/crossref_metadata_2025_split huggingface dataset:
The development of APS03118, a potent next-generation RET inhibitor for treating RET-inhibitor-resistant patients.
Authors: Subbiah Vivek , Zhong Jun , Lu Ying , Liu Yongbo , Chen Minchun , Chen Xiaohu , Wang Hao , Zhu John , Lu Shun , Drilon Alexander E. 
Published: June 2022

e15107 Background: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 < 15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited the proliferation of KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 < 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models at 10 mg/kg (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. The pharmacokinetic/pharmacodynamic relationship of APS03118 in Ba/F3 KIF5B-RET G810R and WT xenograft tumor model was investigated, and the sustained decrease of the phosphorylated RET were observed at 30 mg/kg with the plasma exposure exceed cell IC90. Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. APS03118 has received IND approval and Fast Track Designation from FDA, and a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.
Pan-Cancer analysis of the mutation frequency of genes in DDR pathway in Chinese population.
Authors: Zhang Zhe , Li Zhuoqi 
Published: June 2022

e15109 Background: The DNA damage repair (DDR) pathway is of vital importance to maintain human genomic stability. And the variation of DDR pathway related genes is closely related to tumorigenesis, tumor progression and therapeutic response. In order to comprehensively study the mutation status of DDR pathway related genes in human cancers, we evaluated the genomic features of Chinese pan-cancer patients and investigated the mutation frequency of genes in DDR pathway. Methods: A total of 5018 patients consisting of more than 22 cancer types were enrolled in this study. Utilizing target next-generation sequencing (NGS) platform, genomic profiling of 599 cancer-related genes was performed on tumor tissue or blood samples. And many DDR pathway related genes are included and detected mutations such as TP53, BRCA2, BRCA1, ATM, BLM, FANCA, POLE and so on. Results: We observed 91.23% (4578/5018) of cases harbored at least one alteration of the DDR pathway genes. The mutation frequency ranges from 71.88% to 100.00% among the 22 cancer types. Among them the DDR gene mutation frequency of lymphoma, esophagus and esophagogastric junction cancer and endometrial cancer are all 100%, and mutation frequency of bowel cancer, hepatobiliary cancer, melanoma, breast cancer, esophageal cancer, gastric cancer and central nervous system cancer are also more than 90% respectively. The highest mutation rate gene is a well-known tumor suppressor gene TP53, which mutated in 2650 patients and the mutation rate is 52.81%. And it primarily mutated in esophageal cancer, with a mutation rate of 81.43%. Besides the mutation rate of TP53 in gastric cancer, bowel cancer, breast cancer, ovarian cancer, pancreatic cancer, bladder cancer and hepatobiliary cancer are all more than 50%. Followed by is BRCA2 gene, which is also a tumor suppressor gene and the mutation rate is 16.04%. Next is ATM, BLM and FANCA, the mutation rate of which is 11.68%, 11.12% and 8.97% respectively. Conclusions: We find a unique genomic feature of DDR pathway in the comprehensively analysis of the mutation profile of the Chinese pan-cancer patients, which may provide potential therapeutic targets in the future.
Mapping the epidemiologic characteristics of cancer patients with NTRK gene fusions: A real-world analysis of the Cerner Enviza Eletronic Health Records (EHR) database.
Authors: Vikis Haris G. , Clark Otavio , Furegato Martina , Vavroch Nathan , Purinton Stacey , Haskell Tom , Boshears Tasha 
Published: June 2022

e15123 Background: Fusions in neurotrophic-tropomyosin receptor kinase (NTRK) genes occur in a vast array of tumors and are among the most important genetic alterations in cancer patients. Their presence warrants the use of specific agnostic therapy (AT) with TRK inhibitors Larotrectinib (L) and Entrectinib (E). AT is associated with high levels of tumor response rate in patients showing NTRKgenetic alterations. This mutation is rare and the epidemiologic profile and clinical characteristics of NTRK positive patients are not completely clear. Methods: Our aim was to identify and describe the characteristics of patients with NTRK fusions in a large EHR database. De-identified records of NTRK positive oncologic patients were retrieved from Cerner-Enviza EHR, a healthcare provider network with 100 different providers across the USA, between November 2018 to August 2021. Data extracted were primary tumor, gender, age, and treatment received. Results: We identified 123 patients with NTRK alterations. Major primary tumor locations are described in the table. Males were 56% of the population, median age at diagnosis was 59 years, 36% of the patients were treated with E and 64% with L. Conclusions: In this sample, NTRK mutations were more common in patients with Lung Cancer and Soft Tissue tumors. The median age at diagnosis was 59 years.[Table: see text]
Insights into mutational differences between upper tract urothelial carcinoma and urothelial carcinoma of the bladder.
Authors: Chen Yuanlei , Lu Zeyi , Wang Fangqin , Luo Yijie , Xu Liwei 
Published: June 2022

e15125 Background: Upper tract urothelial carcinoma (UTUC) is histologically similar to bladder urothelial carcinoma (BUC), yet several clinical, biological and molecular features are unique to UTUC. UTUC may have unique genomic factors compared to BUC, while major knowledge gaps remain in our understanding of the biology and genomic landscape of UTUC. Methods: We retrospectively sequenced tumor samples and matched germline DNA using targeted next-generation sequencing methods and analyzed at least 642 cancer-associated genes. The cohort included 35 UTUC patients and 36 BUC patients. Results: Among all cases, KMT2D and TP53 were the most common mutations (account for 66% and 75% in UTUC and BUC, respectively). The most frequently mutated genes in UTUC were KMT2D (37%), TP53 (29%), ELF3 (26%), FGFR3 (23%), ASXL1 (20%), DKN2A (20%), DKN2B (17%), REBBP (17%), MT3B (17%), GNAS (17%) and PIK3CA (17%). The most frequently mutated genes in BUC were KMT2D (36%), TP53 (39%), MUC17 (14%), ARID1A (22%), GNAS (19%), RB1 (19%), BCL6 (19%), E2F3 (19%), EIF4A2 (19%) and FGF3 (19%). However significant differences in the prevalence of mutations in individual genes were observed. FGFR3 (23% vs. 8%) and ELF3 (26% vs. 11%) were more frequently altered, whereas RB1 (6% vs. 19%), E2F3 (3% vs. 19%) and BCL6 (3% vs. 19%) were less frequently altered in UTUC (P < 0.05). FGFR3 mutations have been shown to be oncogenic and RB1 inactivation has been associated with genomic instability in urothelial cancer in previous researches, which represent potential therapeutic targets. Conclusions: Â UTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.
Integrated analysis of genomic alterations of Chinese lung adenocarcinoma with micropapillary component.
Authors: Wang Yongjie , Yang Ronghua , Wang Dong , Zhang Shanshan , Xuan Yunpeng , Li Peng , Wang Lingjie , Che Shuyu , Han Minghui , Yu Yi 
Published: June 2022

e15130 Background: Lung adenocarcinoma (LADC) with micropapillary component (MPC) is a special pathological subtype of LADC, which poses higher invasive with poor prognosis, regardless of proportion of MPC. The effectiveness of molecular targeted therapy in MPC-LADC patients is still being explored without sufficient clinical evidence. Herein, we comprehensive analyzed the genetic alterations of MPC-LADC in order to find effective potential drug-target genes and guide new therapeutic strategies. Methods: We enrolled 31 MPC-LADC patients at Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University from January 2019 to December 2020, and also randomly selected 89 non-MPC-LADC patients as a reference cohort. FFPE or fresh tumors and matched blood samples were performed for NGS-based target panel detection of at least 420 genes (range 420-638 genes), and we analyzed the genomic alterations of the genes with intersection in the above panels sequencing. Results: In our MPC-LADC cohort, the proportion of micropapillary component in 31 tumors were: 5 cases with MPC < 5%, 13 cases with MPC 5% - 20%, 10 cases with MPC ≥20% and other 3 cases unclear. The most frequently mutant genes were EGFR (61.3%, 19/31), TP53 (41.9%, 13/31), ALK (19.4%, 6/31), CTNNB1 (16.1%, 5/31), KRAS (12.9%, 4/31) and SMAD4 (12.9%, 4/31). Moreover, 90.3% (28/31) patients harbored genomic alterations in RTK/RAS/MAPK pathway, 54.8% (17/31) in cell-cycle pathway, 38.7% (12/31) in Wnt pathway, and 19.4% (6/31) in PI3K/AKT/mTOR pathway. Notably, the median age of patients with ALK fusions were younger than wild-type patients (53 vs 60 years, p < 0.05). Patients with KRAS mutations had larger tumor sizes than wild-type patients (Median: 3.4 vs 2.2 cm, p < 0.05), and their lesions are more prone to vascular invasion (p < 0.05). Compared with the reference group of non-MPC-LADC patients, three mutant genes were significantly enriched in MPC-LADC group, namely, CTNNB1 (16.1% vs 1.1%, p < 0.01), ALK (16.1% vs 2.2%, p < 0.05) and SMAD4 (12.9% vs 2.2%, p < 0.05). Finally, we obtained the date of micropapillary lung adenocarcinoma in Memorial Sloan-Kettering Cancer Center (MSK) from cBioPortal database, and survival outcome analysis displayed that EGFR mutations were significantly associated with poor overall survival (OS) (p < 0.05). Conclusions: In this study, we comprehensive revealed the genomic alterations of Chinese MPC-LADC patients and their association with clinicopathological characteristic. Several MPC-enriched genes including EGFR, ALK, KRAS, CTNNB1 and SMAD4 were identified which may be potential genetic drivers of micropapillary lung tumors and could help us to reveal distinct therapeutic avenues of MPC-LADC.
Utilization of nano-hmC-seal technology to detect epigenetic signatures of peritoneal metastasis in cell-free DNA (cfDNA) in patients with colorectal and high-grade appendiceal cancer.
Authors: Dhiman Ankit , Malina Yuri , Gao Lu , West-Szymanski Diana , Rivas Marco , Cui Xiao-Long , Witmer Hunter D. D. , Berger Yaniv , Ulrich Leah , Dougherty Urszula , Kwesi Akushika , Zhang Wei , He Chuan , Bissonnette Marc , Turaga Kiran 
Published: June 2022

e15510 Background: Peritoneal metastases from lower GI tumors are common and cause significant morbidity. Assays of circulating-tumor DNA (ctDNA) to identify peritoneal recurrence after curative-surgical intent are limited due to the low abundance of DNA shed by these tumors, especially mucinous tumors. We demonstrate for the first time an ultra-sensitive test to detect biomarkers modified by the epigenetic mark 5-hydroxymethylcytosine (5hmC) in human cfDNA utilizing nano-hmC seal technology to identify patients with peritoneal metastases (PM) after curative-intent resection. Methods: Patients treated with curative intent resection of colorectal (CRC) and high-grade appendiceal (HGA) cancers underwent prospective plasma collection. Peritoneal disease was documented by direct visual inspection (laparoscopy/laparotomy). Plasma samples were analysed using nano-hmC-seal technique to obtain 5hmC signatures. Genome-wide differential analysis was used to identify significant 5hmC- differentially modified gene body regions (p-value < 0.01 and log-fold change > 10%). Functional annotation analysis was performed to further characterize differentially 5hmC -modified genes noted on multivariate logistic models. Results: Of 64 patients included in the study (CRC = 26; HGA = 38), 47 (73%) were PM+. The median DNA extracted per sample was 23.5 ng (IQR: 15.8-38.3), and no sample failed sequencing criteria. After genome-wide analysis, 39 gene body regions were identified as differentially 5hmC-modified, and 14 genes remained significant after multivariate adjustment. The signatures for PM+ patients were distinguishable from PM- patients using hierarchical clustering and principal component analyses. Functional annotation analysis based on the 14 genes point to alterations in immune and microbiome-related pathways in PM+ group (Table). Conclusions: We report for the first time the detection of peritoneal metastasis in cfDNA from human lower GI cancers using nano-5hmC seal epigenomic technology. This technology could be exploited to detect recurrences in tumors that shed very low levels of cfDNA. This signature is being validated in a prospective clinical trial (NCT 04157322).[Table: see text]
Survival analysis of patients with early and standard onset colorectal cancer: A single center study.
Authors: Patel Dhruv , Martins Maia Catarina , Lyudmer Michael , Tolu Seda , Chergui Adel , Patel Riya Jayesh , Kim So Yeon , Gali Radhika , Acuna Villaorduna Ana , Goel Sanjay 
Published: June 2022

e15512 Background: While more aggressive clinical/pathological features have been consistently described in between patients with early-onset (EO) and standard-onset (SO) colorectal cancer (CRC), survival data have been conflicting. While some studies report better survival rates for EO-CRC; others found that outcomes among groups are not different. In a prior study, using the Surveillance, Epidemiology and End Results (SEER), we reported that cancer-related survival did not differ between EO-CRC and SO-CRC; however, a main limitation was the lack of molecular status and treatment details among groups. This study aims to compare the survival of EO-CRC and SO-CRC patients at Montefiore Medical Center. Methods: Retrospective cohort among 690 patients diagnosed with metastatic colorectal cancer (CRC) at Montefiore Medical Center between 2010 and 2018. Patients were identified using the software Clinical Looking Glass and charts were reviewed manually to gather information about demographics (race/ethnicity defined as Non-Hispanic White [NHW], Non-Hispanic Black [NHB] and Hispanic [H], gender, comorbidity index, calculated using the Charlson comorbidity score), clinicopathological features (grade, tumor sidedness, K-ras mutation) and treatment-related characteristics (metastatectomy, lines of chemotherapy and use of biologics). EO-CRC was defined as CRC diagnosis before age 50 and SO-CRC as CRC diagnosed at 50 years or older. Overall survival was compared between EO-CRC and SO-CRC using Kaplan Meier and Cox regression analyses. Stata v15.1 was used for statistical analysis. Results: Of 690 patients with CRC, 139 (20.1%) had EO-CRC and 551 (79.9%) had SO-CRC. Participants with EO-CRC had a higher frequency of poorly-differentiated tumors (35.5% vs. 23.8%, p = 0.02), a lower comorbidity index (6 vs. 7, p < 0.001). and a higher use of biologics (70.5% vs. 60.8%, p = 0.03) compared to SO-CRC. K-ras mutation was available for 377 (54.5%) of cases and did not differ among groups (45.9% vs. 45.9%, p = 0.99). In a model adjusted for race/ethnicity, gender, comorbidity index, sidedness, use of biologics and metastatectomy, there was no difference in mortality among groups (HR:0.9, 95%CI: 0.58 – 1.43, p = 0.68). This result remained unchanged in a model restricted to patients with available K-ras-status (n = 75), adjusted for all these variables. Conclusions: Despite more aggressive clinical/pathological features in patients with EO-CRC, survival does not differ compared to SO-CRC.
Diagnostic accuracy of the CxPREVENTIVE Colon model for early detection of colorectal cancer.
Authors: Calleja Sergio J , Patiño Édgar C 
Published: June 2022

e15518 Background: Despite different available methods for colorectal cancer (CRC) screening and their proven benefits, morbidity, and mortality of this malignancy are still high, partly due to technical limitations and low compliance with screening. The aim of the present study was to assess the diagnostic accuracy for early detection of CRC using a modeling algorithm based on multiple blood and urine biomarkers. Methods: In this retrospective cohort study, clinical and blood and urine markers-based algorithms with predefined cutoff values were applied to a generally healthy asymptomatic outpatient cohort of adults aged 50 years or older undergoing colonoscopy and histopathology for routine colorectal cancer screening. We used a modeling algorithm based on two different frameworks (Multiple Biomarkers Disease Activity Algorithm MBDAA [Bioprognos], and Artificial Intelligence Recursive Algorithm AIRA [Mintlot] both in Barcelona, Spain). Both algorithms compute information from a wide number of analytes, tumor markers (AFP, CA 19.9, CA 72.4, CA 125, CEA, Cyr61, NGAL, EGFR and 8-OHdG), and additional clinical data (age, weight, height, and BMI). MBDAA includes Barcelona Criteria (four criteria to correctly interpret the cause of the increase in tumor markers, benign or malignant, defined by the Spanish Society of Clinical Biochemistry and Molecular Pathology, Commission of Biological Markers of Cancer). To assess the association between the modelling algorithm and downstream diagnosis we used logistic regression to compute receiver operating characteristic curves (ROC). Exact binomial confidence limits were calculated to test accuracy, sensitivity, and specificity. Results: 221 people (median age 63 yr. [IQR 49-77]; 107 [49%] women and 114 [51%] men) who underwent colonoscopy at the Juan Ramón Jiménez Hospital (Huelva, Spain), were included in this analysis. Based on colonoscopy and histopathologic findings, CRC was diagnosed in 45 (20%) patients, colonic polyposis in 56 (25%), inflammatory bowel disease in 37 (17%), and absence of pathological findings (control group) was seen in 83 (38%). The diagnostic intervention for CRC yielded an area under the curve (AUC) of 1 among the entire specimen set, accuracy 1 (95% CI 0.996,1), Se 1 (0.988, 1) and Sp 1 (0.997, 1). Besides, the algorithm also performed very well in the identification of polyps with an accuracy 1 (95% CI, 0.967 to 1), Se of 1 (0.991, 1) and of Sp 1 (0.996, 1), as well in the diagnosis of inflammatory bowel disease with an accuracy of 1 (0.968 to 1), Se of 1 (0.986, 1) and Sp of 1 (0.997, 1). Conclusions: Using colonoscopy as a gold standard, our data suggest that an innovative newly designed non-invasive blood and urine-based biomarker algorithm CxPREVENTIVE Colon may provide a timely diagnosis of CRC with very high accuracy. Our findings warrant further investigation, and we are planning large-scale (n 10,000), fully powered study to inform clinical practice.
A RAS-independent biomarker panel pedicts response to MEK-inhibitors in colorectal cancer.
Authors: Pfohl Ulrike , Loskutov Jürgen , Bashir Sanum , Kühn Ralf , Templin Markus , Mamlouk Soulafa , Belanov Sergei , Vetter Marcus , Reinhard Christoph , Wedeken Lena , Regenbrecht Christian RA 
Published: June 2022

e15524 Background: Biomarker discovery and development are essential for stratifying cancer patients in order to improve treatment outcomes. In colorectal cancer (CRC), mutations in the TGF-β/BMP pathway, especially in the SMAD4 gene have been correlated with decreased overall survival and are suspected to modulate drug sensitivity on the cellular level, hence SMAD4 mutations are worthwile targets for novel targeted therapy aproaches. Methods: In the present study, we uncover the mechanistic role of a loss-of-function mutation in SMAD4 in syngeneic patient-derived organoids (PDOs). CRISPR-engineered SMAD4R361H PDOs were subjected to a comparative drug screening, RNA-Sequencing and multiplex protein profiling analysis (DigiWest®). We have confirmed the response towards MEK inhibition of the initial model in an additional set of 62 PDOs with known mutational status. Results: We show that acquisition of SMAD4 loss-of-function mutations renders PDOs sensitive to MEK-inhibitors. Further, an activation of the TGF-β/BMP signaling pathway, specifically of the BMP branch was observed in SMAD4wt PDOs; indicating that BMP signaling is likely responsible for the resistance towards MEK inhibition. It is plausible that functional loss of SMAD4 and thus loss of BMP signaling renders SMAD4 mutated tumors more sensitive to MEK-inhibitors. By looking at additional genes involved in TGF-β/BMP signaling that are frequently mutated in CRC, we identified the novel gene mutational SFAB-signature ( SMAD4, FBXW7, ARID1A, or BMPR2), when at least one pathogenic mutation is present in these genes. The frequency of SFAB in CRC patient cohort (TCGA, n = 594) was comparable to the frequency of SFAB in our PDOs. For PDOs with SFAB-signature, we found up to 95% and 70% significant positive prediction for cobimetinib and selumetinib, respectively and also up to 70% positive prediction for trametinib. Thus, the SFAB-signature predicts response to MEK inhibition in PDOs with a very high confidence. We further investigated whether the RAS status of CRC PDOs does predict sensitivity to MEK inhibition. The RAS status alone and in combination with SFAB-signature failed to yield better prediction sensitivity to MEK-inhibitors. Conclusions: The present study is a significant step forward to more personalized treatment regimens for CRC patients by early inclusion of MEK-inhibitors. The SFAB-signature should be put to clinical testing as a RAS-independent biomarker for stratification of patients providing a valuable alternative treatment option against CRC, thus ensuring that all patients receive effective and specific therapies as early as possible.