bluuebunny/crossref_metadata_2025_split huggingface dataset:
TOOme: A novel computational framework to infer cancer tissue-of-origin by integrating both gene mutation and expression.
Authors: Gao Wei , Yang Jianwei , Zhuo Changhua , Yang Jialiang , Huang Sha , Tian Geng , Lin Jinyuan 
Published: May 2020

3591 Background: Metastatic cancers require further diagnosis to determine their primary tumor sites. However, the tissue-of-origin for around 5% tumors could not be identified by routine medical diagnosis according. With the development of machine learning techniques and the accumulation of big cancer data from TCGA and GEO, it is now feasible to predict cancer tissue-of-origin by computational tools. Methods: Developed a computational framework to infer tumor tissue-o. Results: Applied TOOme to the TCGA data containing 7,008 non-metastatic samples across 20 solid tumors including BLCA, BRCA, CESC, COAD, GBM and so on. 74 genes by gene expression profile and 6 genes by gene mutation are selected by the random forest process, which can be divided into two categories: (1) cancer type specific genes, which are highly expressed or mutated only in one specific cancer and (2) those expressed or mutated in several cancers with different levels of expression or mutation rates. Function analysis indicates that the selected genes are significantly enriched in gland development, urogenital system development, hormone metabolic process, thyroid hormone generation prostate hormone generation and so on. According to the multiple-label classification method, random forest performs the best with a 10-fold cross-validation prediction accuracy of 96%. We also use the 19 metastatic samples from TCGA and 256 cancer samples downloaded from GEO as independent testing data, for which TOOme achieves a prediction accuracy of 89%. The cross-validation validation accuracy is better than those using gene expression (i.e., 95%) and gene mutation (83%) alone. Conclusions: TOOme provides a quick yet accurate alternative to traditional medical methods in inferring cancer tissue-of-origin. In addition, the methods combining somatic mutation and gene expressions outperform those using gene expression or mutation alone.
Tumor-targeted oncolytic adenovirus demonstrates high cytotoxicity for human lung and renal cell carcinomas independently of the level of tumor PD-L1 expression.
Authors: Yao Jia , Atasheva Svetlana , Young Cedrick , Master Viraj A. , Shayakhmetov Dmitry 
Published: May 2020

3596 Background: Immuno-checkpoint (IC) inhibitors targeting PD1-PD-L1 pathway have proven highly effective at extending survival of cancer patients. However, the clinical benefits of IC inhibitors are limited to only about 20% patients who have moderate to high levels of tumor PD1 and/or PD-L1 expression. To develop therapeutics that would provide clinical benefits to a larger proportion of cancer patients, we engineered oncolytic adenovirus for targeted infection of human tumor cells via CD46 and integrins of α3β1 or α6β4 classes, overexpressed on many epithelial human cancers. Methods: Here, we analyzed the infectivity and cytotoxicity of this novel oncolytic virus in a panel of human non-small cell lung cancers (NCSLC) cell lines, primary patient derived NSCLC xenografts, and tumor surgical explants from patients with renal cell carcinoma (RCC). Results: The in vitro analysis of NSCLC cells lines (N = 17) demonstrated that over 60% of them were highly sensitive to virus infection. The genome-wide transcriptional profiling showed that only 3 out of 12 cell lines that were sensitive to oncolytic virus infection, expressed PD-L1 ( > 4.5 Log2 RPMK). Furthermore, although the pre-treatment of these cell lines with IFN-I activated PD-L1 expression, IFN-I treatment did not reduce the efficacy of tumor cell infection by the oncolytic virus. The analysis of virus infectivity on primary human tumor cells from patients with NSCLC (N = 4) and RCC (N-24) demonstrated that primary tumors were highly sensitive to oncolytic virus infection. Specifically, tumor-targeted oncolytic virus demonstrated strong cytotoxicity in 22 out of 24 analyzed primary isolated RCC cell samples. Next, we subcutaneously grafted PD-L1-negative NSCLC A549 cells to NSG mice, treated them with oncolytic virus intravenously, and the kinetics of tumor growth and animal survival was monitored. This analysis showed that after intravenous administration, oncolytic virus was able to infect tumor cells and suppress tumor growth. Whereas the median survival in mock-treated group was 26 days, all mice survived up to 100 days post oncolytic virus therapy (endpoint). Conclusions: Our study showed that tumor-targeted oncolytic adenovirus infects human tumor cell lines independently of their PD-L1 expression status and is not sensitive to IFN-I inhibition. This novel tumor-targeted oncolytic virus has the potential to provide clinical benefits to cancer patients, who do not respond or became resistant to ICI drugs.
Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886 Hydrogen Sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).
Authors: O'Sullivan Coyne Geraldine Helen , Gross Andrea M. , Dombi Eva , Tibery Cecilia , Carbonell Amanda , Takebe Naoko , Derdak Joanne , Pichard Dominique , Srivastava Apurva K. , Herrick William , Parchment Ralph E. , Martin Staci , Wolters Pamela , Whitcomb Patricia , Rubinstein Lawrence , Doroshow James H. , Chen Alice P. , Widemann Brigitte C. 
Published: May 2020

3612 Background: NF1-related PN are locally invasive tumors characterized by increased activation of the RAS pathway causing significant morbidity including disfigurement, pain and functional limitations. Selumetinib has received breakthrough designation for NF1 PN based on phase I / II trials in children. We present results for the ongoing phase II study of selumetinib in adults with NF1 PN, which includes pharmacodynamic (PD) evaluation of serial tumor biopsies as well as functional/patient-reported outcomes (PROs). Methods: Open-label Simon 2-stage design. Eligibility: NF1 patients (pts) ≥18 years old with inoperable/symptomatic/progressive PN. First 2 pts received selumetinib 75 mg BID; subsequent pts received selumetinib 50 mg BID. Primary objective: response rate by volumetric MRI analysis (partial response [PR]; ≥20% volume decrease). Secondary objectives: PD studies on pre/on-treatment biopsies of PN and cutaneous neurofibromas, assessment of clinical benefit using PROs (Numeric Rating Scale-11, Pain Interference Index), and PN-specific functional assessments. Validated, fit-for-purpose, isozyme-specific measurements of pERK/ERK/pMEK/MEK performed using SOPs designed for labile phosphoproteins (PMID 27001313). Results: As of February 2020, 27 pts have enrolled. Outcomes are reported for 23 pts (74% male; median age 33 years, range 18-60). Most common PN-related morbidity: pain (19 pts). Sixteen pts achieved PR (69%), with 13/16 confirmed; no disease progression. Time to response: 11 months (range 5-25); median change in PN volume at best response: -22% (range -41% to +5.5%); median duration of treatment: 28 months (range 2-50). Selumetinib suppressed tumor pERK1,2/ERK1,2 but not pMEK1,2/MEK1,2 ratios from 1-10 hours following oral dosing (one t½). Pt-reported target tumor pain intensity and pain interference scores significantly improved (both p < 0.03). Pts 1 and 2 were dose-reduced due to grade 3 intolerable rash (n = 2) and pain (n = 1). Grade ≥3 drug-related toxicities on 50 mg (21 pts) include transaminitis (5 pts), rash (1 pt) and pancreatic enzyme elevation (1 pt). Two pts were dose reduced (rash = 1 pt, transaminitis = 1 pt). Two pts discontinued by choice, 2 pts withdrawn by PI (best interest of patient), and 1 pt each removed for transaminitis, surgical resection, serious concurrent medical illness, and non-compliance. Conclusions: Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit. Clinical trial information: NCT02407405 .
Quality of life of adults and children with TRK fusion cancer treated with larotrectinib compared to the general population.
Authors: Kummar Shivaani , Van Tilburg Cornelis M. , Albert Catherine M. , Berlin Jordan , Farago Anna F. , McDermott Raymond S. , Bielack Stefan S. , Doz Francois P. , DuBois Steven G. , Lassen Ulrik Niels , Leyvraz Serge , Mascarenhas Leo , Nagasubramanian Ramamoorthy , Keating Karen N , Chirila Costel , Childs Barrett H. , Laetsch Theodore Willis , Drilon Alexander E. , Hong David S. 
Published: May 2020

3614 Background: NTRK gene fusions occur in diverse tumor types in adults and children. The selective TRK inhibitor, larotrectinib, has shown high response rates, durable disease control, and a favorable safety profile in patients (pts) with TRK fusion cancer. We report an expanded quality of life (QoL) analysis for pts treated with larotrectinib. Methods: QoL data were collected in two trials of larotrectinib in pts with TRK fusion cancer using EORTC QLQ-C30 (adults) and PedsQL (children) questionnaires, and were analyzed descriptively and longitudinally. EORTC QLQ-C30 global health scores (GHS) and PedsQL total scores range from 0 to 100, with higher scores indicating better QoL. We calculated the proportion of pts with normal/above and below normal QoL scores compared to values in the literature for the US general population. Results: By July 2019, 126 pts with TRK fusion cancer (74 adults, 24 children ≥2 yrs, and 28 infants <2 yrs) had received larotrectinib and completed baseline (BL) and ≥1 post-BL questionnaire. Most pts had clinically meaningful QoL improvements that reached or exceeded the minimally important difference (Table); a positive change from BL was also seen in infants: mean best change of 12.0 (SD 13.8). Of 52 adults with BL EORTC QLQ-C30 GHS at or above the population norm, 51 remained in this category on treatment and 1 moved into the below normal category. Of 22 adults with BL scores below the population norm, 20 moved into the normal/above normal category. All 9 children aged ≥2 yrs with BL PedsQL scores at or above the population norm remained in this category on treatment. Of 15 children with BL scores below the population norm, 10 moved into the normal/above normal category. Sustained QoL improvements (change from BL ≥0) occurred by 2 months of treatment in 69% of adults and 75% of children. Median duration of sustained improvement in EORTC QLQ-C30 GHS and PedsQL total score was 12.0 months (range 1.7–20.3) and not estimable (range 1.1–23.0), respectively. Conclusions: Adults and children with TRK fusion cancer treated with larotrectinib had rapid, clinically meaningful, and sustained improvements in QoL. Clinical trial information: NCT02576431, NCT02637687 . [Table: see text]
Pan-cancer analysis of FGFR1-3 genomic alterations to reveal a complex molecular landscape.
Authors: Krook Melanie A. , Silverman Ian M. , Murugesan Karthikeyan , Ernst Gabrielle , Reeser Julie , Wing Michele , Frampton Garrett M. , Newton Robert C , Jackson Jeffery Richard , Albacker Lee A. , Burn Timothy , Roychowdhury Sameek 
Published: May 2020

3620 Background: Activating genomic alterations (GAs) in the fibroblast growth factor receptor (FGFR) gene family occur in many tumor types. FGFR1-3 mutations and rearrangements are of particular interest given evidence of clinical activity of selective FGFR inhibitors in patients (pts) with susceptible alterations. We queried FGFR1-3 GAs in patient tumor samples analyzed using comprehensive genomic profiling (CGP) and performed in vitro characterization of select novel alterations. Methods: Tumor samples were assayed by hybrid capture based CGP on 0.8-1.2 Mb of the genome to identify GAs in exons and select introns in up to 404 genes (Foundation Medicine, Inc, Cambridge MA). Cell lines were stably transduced with alterations of interest and transformation assays and drug sensitivity assays were performed to determine oncogenic potential and sensitivity to FGFR inhibition by pemigatinib. Results: GAs in FGFR1-3 were present in 6314 of 274,694 pt specimens (2.3%), of which 4091 (64.8%) were short variants and 2269 (35.9%) were rearrangements. Tumor types with the highest frequency of FGFR1-3 alterations were bladder cancer (17.9%), cholangiocarcinoma (11.1%), endometrial cancer (7.9%), and glioma (5.5%) (Table). We identified 270 unique FGFR1-3 short-variants, including 144 missense mutations and 94 truncating alterations. Of short variants, the most frequent were FGFR3 p.S249C (18.3%), FGFR2 p.S252W (9.9%) and FGFR1 p.N546K (6.9%). Truncating alterations were largely identified in exon 18, downstream of the kinase domain. We identified 476 unique FGFR1-3 rearrangement pairs ( FGFR1; n=77, FGFR2; n=338, FGFR3; n=61). FGFR3-TACC3 was the most prevalent FGFR rearrangement (29.0%), followed by FGFR2-BICC1 and FGFR2-N/A (both 9.7%). In vitro analysis of the transforming potential and drug sensitivity for select alterations will be reported. Conclusions: FGFR1-3 mutations and rearrangements are highly diverse and present at low to moderate frequencies across many cancers. Therefore, cataloging and characterizing these diverse alterations has the potential to facilitate precision medicine. Tumor-specific and -agnostic trials of selective FGFR inhibitors in pts with susceptible alterations are ongoing. [Table: see text]
Tumor genomic analysis for biomarker identification in a phase I trial of the Wee 1 inhibitor adavosertib (AZD1775).
Authors: Naqash Abdul Rafeh , Mittra Arjun , O'Sullivan Coyne Geraldine Helen , Chen Li , Das Biswajit , Kummar Shivaani , Do Khanh T , Chang Ting-Chia , Bruns Ashley , Juwara Lamin , Miller Brandon , Kinders Robert J. , Parchment Ralph E. , Rubinstein Larry V , Ji Jiuping Jay , Wilsker Deborah , Dull Angie B , Doroshow James H. , Chen Alice P. , Takebe Naoko 
Published: May 2020

3624 Background: Adavosertib, a first-in-class Wee1 kinase inhibitor, abrogates G2/M cell cycle arrest causing premature mitosis and DNA replication stress, yielding enhanced DNA damage. Here we report on potential biomarkers of response from tumor genomic analysis in patients (pts) with solid tumors treated with adavosertib. Methods: Adavosertib was administered once daily on days 1-5 and 8-12 of a 21-day cycle. RECIST 1.1 was used to evaluate clinical response. Paired tumor biopsies were obtained for RNASeq gene expression profiling (GEP) and for whole-exome sequencing (WES) to evaluate gene mutation and copy number amplification (CNA). Fold change (FC) was calculated to define gene overexpression. To identify the frequency of CNA and mRNA overexpression for the genomic biomarkers of interest, cBioPortal analysis using TCGA and MSK-IMPACT datasets was performed. Differential GEP analysis of tumor and paired normal tissue was performed using the gene expression profiling interactive analysis (GEPIA) interface (Tang et al. 2017). Results: Out of 35 pts evaluable for response, 6 (17%) had partial response (PR; 4 ovarian carcinoma [OVC], 2 endometrial carcinoma [EC]). The median duration of response was 5.2 months (range 4.0-23.1). Eighteen pts (51.4%) had stable disease. Genomic analysis of tumor biopsies was available for 9 pts; 7 of these pts were evaluable for response, and 3 had PR (2 OVC, 1 EC). WES revealed TP53 mutations in 6 pts (66.6%; 3 pts with PR, 2 with progressive disease,1 not evaluable). On WES, tumor Cyclin E1 ( CCNE1) CNA was present in 1 of 3 PR pts while tumors from all 3 PR samples showed relatively high CCNE1 expression by RNAseq (FC = 4.07). In the MSK-IMPACT 2017 dataset, CCNE1 CNA was identified in 1.8% of pts (194 of 10336); of which, OVC (10.3%) and EC (8.7%) had the highest incidence of CCNE1 CNAs. In separate tumor-specific (OVC, EC) TCGA datasets having CCNE1 overexpression and/or CNA, overlap in CCNE1 overexpression with CCNE1 CNA was 35.5% (OVC) and 25.2% (EC). Compared to normal ovarian/ endometrial tissues, GEPIA analysis revealed significantly higher CCNE1 mRNA expression in OVC (FC = 3.5) and EC (FC = 3.8). Conclusions: CCNE1alterations (overexpression and/or CNA) tend to be enriched in OVC and EC with a limited fraction showing both overexpression and CNA. Tumor genomic analysis of additional OVC and EC pts treated with adavosertib is required to determine whether CCNE1 mRNA overexpression, regardless of CCNE1 CNA, is a potential biomarker of response to this drug in these tumor types. Funded by NCI contract No. HHSN261200800001E. Clinical trial information: NCT01748825 .
The landscape of predictive biomarkers for ATR inhibition in Chinese solid-tumor patients.
Authors: Shen Rong , Yang Qiuan , Liu Zimin , Wang Yongjie , Fan Xinglong , Li Lei , Hu Bo , Xiao Wenjing , Ma Meili , Chen Wei , Liu Xiaoyan , Shi Weiwei , Liu Angen 
Published: May 2020

3626 Background: Ataxia Telangiectasia and Rad3-related (ATR) is one of the core regulators participating in DNA damage response as a sensor of replication stress. Besides, ATR also plays a role in cell cycle checkpoint activation and DNA replication regulation. Several ATR inhibitors (ATRi) have been demonstrated in anti-cancer clinical trials. Herein, we describe the distribution of selected biomarkers, which have been shown to predict a higher sensitivity to ATRi according to preclinical data, in Chinese cancer population. Methods: FFPE tumor tissues and matched blood samples from 10,194 Chinese patients with 25 different types of solid tumors were collected. NGS based 450 cancer genes panel assay were performed to detect genomic alterations, including SNV, short and long insertions/deletions, CNV and rearrangements/fusions. The testing was carried out by a CAP accredited and CLIA certified laboratory. Results: The prevalence of ARID1A mutations, ATM mutations, BRCA1/BRCA2 mutations, MYC amplification, and CCNE1 amplification accounted for 9.5%, 4.7%, 6.0%, 3.5% and 3.3% of this cohort respectively. The most common tumors with ARID1A mutations were endometrial carcinoma (EC, 34.4%), gastric carcinoma (GC, 19.4%), small bowel carcinoma (SBC, 19.3%), intrahepatic cholangiocarcinoma (19.3%), extrahepatic cholangiocarcinoma (17.7%) and urothelial carcinoma (UC, 16.7%). For ATM mutations, the prevalence was colorectal carcinoma (CRC, 8.9%), SBC (8.8%), pancreatic cancer (7.8%), UC (7.3%), gallbladder carcinoma (GBC, 7.1%) and GC (6.8%). For BRCA1/BRCA2 mutations, the prevalence was ovarian carcinoma (29.5%, Germline 23%), breast carcinoma (13.3%, Germline 7.1%), EC (11.5%, Germline 3.3%), UC (10.4%), melanoma (8.5%) and CRC (7.9%). For MYC amplification, the prevalence was breast carcinoma (10.2%), ovarian carcinoma (9.2%), esophageal carcinoma (7.2%), thymic tumor (6.1%), cancer of unknown primary (CUP, 5.8%) and gastrointestinal neuroendocrine tumor (GI-NET, 5.4%). For CCNE1 amplification, the prevalence was GC (11.9%), GBC (8.8%), bone sarcoma (7.7%), ovarian carcinoma (6.9%), CUP (4.2%) and GI-NET (4.1%). Conclusions: Our study reported the prevalence of gene mutations of ATRi sensitivity determinants in a large cohort of Chinese cancer patients. The results revealed the high prevalence and different distribution of these biomarkers across a wide spectrum of cancers. The genomic profile study also provided information for ATRi sensitivity assessment and the drug combinations with ATR inhibition.
Comprehensive analysis of HER2 status through genomic, transcription, and translation among 5,305 patients with diverse malignancies.
Authors: Mesleh Shayeb Akram , Kurzrock Razelle , Kato Shumei 
Published: May 2020

3632 Background: HER2 alterations is a predictive biomarker for anti-HER2 regimen. Success in breast and gastric cancers with anti-HER2 therapies translated to explore their efficacy in other tumors. Currently, measurement of HER2 can be done by assessing the expression of protein [e.g. immunohistochemistry (IHC)] or gene amplification of copy number variation (CNV) [e.g. fluorescence in situ hybridization or next-generation sequencing (NGS)]. But little is known about the transcription level (mRNA) of HER2. Herein, we investigated HER2 mRNA expression and its association with gene and protein expressions among diverse cancer types. Methods: Between 2015-2019, HER2 status was evaluated using IHC, qRT-PCR and NGS by Paradigm Diagnostics (CLIA-certified laboratory). All tumors in the database were included for analysis. Correlations between all 3 tests were done. An illustrative patient who was treated with anti-HER2 therapy base on the mRNA testing is presented. Results: HER2 testing was performed on 5305 patients (pts) with diverse cancers including NSCLC (n=1175), breast (n=1040) and colon (n=566); 4.1% (161/3926) had amplification through NGS, 33.3% (615/1848) had mRNA overexpression and 9.3% (236/2533) had overexpression by IHC. Of 723 pts who had all three tests performed, we found 7.5% (54/723) of pts with all three HER2 markers being positive (CNV [+]/mRNA [+]/ IHC [+]). Meanwhile, variety of amplification/ expression patterns were seen (see Table). CNV positivity translated to protein expression in 95% of cases. While only 4% of pts were IHC positive when CNV and mRNA were negative. 20% (144/723) of pts had mRNA overexpression alone among diverse cancer types. Representative case of 70yo female with metastatic cholangiocarcinoma harboring mRNA overexpression (but negative for CNV, IHC unclear due to sample insufficiency) who had near complete response to anti-HER2 therapy with progression-free survival of 24+ months is presented. Conclusions: HER2 status can be discordant with different assays but NGS positivity has excellent correlation with mRNA and protein expression. Of importance, HER2 mRNA can be overexpressed in 20% of pts even when gene amplification and protein expression are negative. Further studies are warranted to determine the clinical utility of mRNA as a biomarker for HER2 and potential use for anti-HER2 targeted therapies. [Table: see text]