bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive analysis of germline and somatic BRCA1/2 mutations in ovarian cancer population: Interim results of OVATAR prospective study.
Authors: Tyulyandina Alexandra , Kekeeva Tatiana , Karaseva Vera , Gorbunova Vera , Kolomiets Larisa , Filipenko Maxim , Demidova Irina , Lyubchenko Liudmila , Imianitov Evgenii , Cherdyntseva Nadezhda , Moliaka Yuri , Vodolazhky Dmitriy , Andreev Sergei , Statsenko Galina , Saevets Valeria , Khokhlova Svetlana , Tkachenko Svetlana , Koroleva Irina , Lisyanskaya Alla , Tjulandin Sergei 
Published: September 2018

e23109 Background: The most promising method for the detection of BRCA 1/2 mutations is next-generation sequencing (NGS). There is no enough data about prevalence of large deletions of BRCA mutations and somatic alterations in ovarian cancer (OC). NGS technology is important approach for somatic mutations search in tissue samples. Methods: 498 pts with serous and endometrioid OC were enrolled in OVATAR study (NCT02122588). NGS testing of BRCA1/2 in blood and tumor tissue, multiplex ligation-dependent probe amplification (MLPA) for large deletions in blood were employed. Results: Interim analysis included pair tumor and blood samples from 336 pts (median age 54 (22 - 84) years; family history in 79 (23.5%). The total rate of BRCA1/2 mutations was 29.2% (98/336) pts including 80.6% (79/98) germline mutations and 19.4% (19/98) somatic mutations. Hotspot mutations were detected in 42/98 (42.8%) pts, among them 5382insC mutation was observed in 29.6% (29/98). Blood MLPA was performed in 142 (42.2%) pts; germline large deletions were found in 2 (1.4%) cases. Differences in NGS results for tumor and blood are listed in the table. Conclusions: Application of NGS revealed rare mutations in 57.2% among all detected mutations in OC pts; moreover, NGS in tumor tissue provided a significant increase in BRCA mutations of 19% due to somatic alterations. Large deletions in BRCA1/2 are rare event in OC in our study. [Table: see text]
Enhancing targeted therapy of tumors with activating FGFR alterations.
Authors: Bockorny Bruno , Rusan Maria , Piccioni Federica , Tan Li , Bass Adam Joel , Hammerman Peter S. 
Published: September 2018

e23134 Background: Emerging evidence points to the Fibroblast Growth Factor Receptor (FGFR) kinase family as a promising target in multiple cancer types including lung squamous cell carcinoma, cholangiocarcinoma, gastric, bladder and breast cancer. Although several FGFR kinase inhibitors have entered clinical trials, single agent clinical efficacy has been modest and resistance invariably occurs. A comprehensive understanding of the molecular basis of resistance to FGFR inhibitors is urgently needed to enable the successful application of anti-FGFR therapy in the clinic. Methods: We utilized a systematic genome-wide open reading frame (ORF) screen to identify genes whose upregulation confers resistance to the FGFR inhibitors BGJ398 and FIIN-3 in FGFR1-amplified H2077 lung cancer cells. In an orthogonal approach, we established resistant clones of FGFR1-amplified and FGFR3-translocated cell lines by chronic exposure to BGJ398, and characterized these by high-throughput gene expression analysis. Results: We identified 34 candidate genes, including expected findings such as a mutant KRAS allele and MET overexpression. Intriguingly, we also identified novel candidate resistance mechanisms involving the genes of the TAM family, which encode the transmembrane receptors Tyro3, Axl and Mertk. These tyrosine kinases may serve as a secondary target to augment FGFR therapy. We validated that the TAM family confers resistance to FGFR inhibitors in different FGFR dependencies including FGFR1-amplified lung cancer, FGFR2-amplified gastric and colon cancer and FGFR 3-translocated bladder cancer, with AXL having the greatest rescue. Notably, gene profiling of resistant clones also implicates the TAM family, with both receptors and their ligands upregulated in the majority cases. Moreover, concurrent TAM blockade augments the response to FGFR inhibition in vitro and provides a promising therapeutic strategy to overcome resistance. Conclusions: TAM kinases are important mediators of resistance to FGFR inhibitors and the dual blockade of FGFR and TAM provides a novel approach to enhance the efficacy of anti-FGFR therapy.
Comprehensive analysis of tumor NGS data to demonstrate pathways pointing to therapeutic targeting options.
Authors: Krishnan Subha , Perlina Ally , Thomas Alex , Kakaradov Boyko , Delport Wayne , Nehring Ramlah B , Shinbrot Eve , Natarajan Thanemozhi G , Lau Corine K , Gylfe Alexandra E , Sainger Rachana , Pelak Kimberly , Smith Heather L , Biggs William , Perkins Brad , Cohen Ezra E.W. , Bloom Kenneth Joel 
Published: September 2018

e23153 Background: Recent advancements in NGS technology have enabled precision medicine based on tumor-specific genomic alterations. However, the complex nature of tumor biology demands an integrative analysis of genomic variations to identify converging downstream targets potentially regulated by multiple pathways. Methods: Genomic alterations from whole-genome sequencing results were interpreted in the context of pathways. Beyond listing the implicated known pathways based on genomic alterations, we explored protein interactions cross-linking the pathways to converging downstream targets. An in-house analytical pipeline was used to prioritize candidate pathways from MetaBase™, which contains manually curated pathways and interactions based on published experimental results. Custom pathway diagram was then designed manually to depict the most actionable pathways. The manual review consists of context-checking and addressing the concordant/discordant nature of all interactions. Factor such as mutational impact, directionality, mechanism of interaction and known targeted action are taken into account. Results: Comprehensive analysis of the genomic variations in three tumors types revealed activation of multiple oncogenic signaling pathways. Key events driving the tumor in a melanoma sample were NF1/RAS/MEK/ERK, WNT/beta-catenin pathway, and MITF signaling. Three interconnected signaling pathways, WNT, PI3K/AKT, and P53 were impacted by genomic alterations in a colorectal sample, which point to activation of converging downstream targets- CDK6, VEGFA, and COX-2. Integrated discovery of genomic alterations in an esophageal adenocarcinoma sample suggested potential activation of PI3K/AKT/MTOR and p16/Cyclin D1/CDK pathways. This could synergistically activate downstream converging targets- VEGFA, Cyclin D1, CDK6, CDK4, AURKA; some of which also showed relative RNA overexpression, supporting our pathway findings. Conclusions: Comprehensively analyzing the genomic alterations in context of cell signaling pathways provides us insights on how the pathways synergistically affect downstream targetable events, which in turn can impact therapeutic decisions.
Association of activated B-cell infiltration in the tumor microenvironment with regulatory T-cell (Treg) infiltration, but not macrophages polarization in immunogenic human cancers.
Authors: Chae Young Kwang , Bae William Han , Kim Young Suk , Anker Jonathan Forrest , Matsangou Maria , Giles Francis J. 
Published: September 2018

e23174 Background: We reported an inverse association between tumor-infiltrating B and CD8 T cells in human cancers. Preclinical studies suggested that B cells regulate T cell activities via activation of Treg cells and alternative polarization of macrophages. In this study, we investigated the relationship between B cell infiltration, Treg cell infiltration, and macrophage polarization in five human cancers approved for the use of immune checkpoint inhibitors by the FDA. Methods: mRNA expression scores of 812 immune-related genes from the TCGA database were analyzed to calculate tumor infiltrating cells in 2951 patients with bladder urothelial carcinoma, renal cell carcinoma, skin melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (Angelova et al., 2015). Expression patterns of Treg markers and M1/M2 phenotypic macrophage polarization markers were compared in relation to the presence of activated B cells (ActB) in human tumor tissues. Odds ratios (OR) of the numbers of tumors with versus without Treg cell infiltration by the presence of ActB cells were calculated. Results: Infiltration by ActB cells was significantly correlated with Treg cell infiltration in human cancers (OR=10.86, p<0.001). In lung adenocarcinoma, ActB cells also demonstrated a significant association with myeloid derived suppressor cells (MDSCs, p<0.05). Tumors infiltrated by ActB cells had significantly elevated expressions of Treg markers and suppressive cytokines (Table), but not macrophage polarization markers. No significant changes in survival outcomes were noted. Conclusions: We report for the first time an association between B cells and Treg cells in human immunogenic cancer tissues. ActB cell infiltration in the tumor microenvironment was positively correlated to Treg cell infiltration, but not macrophages polarization in immunogenic human cancers. [Table: see text]
The correlation between immune status of patients and their prognosis in non-small cell lung cancer.
Authors: Ding Xiao , Cui Jiuwei , Yan Xu , Niu Chao , Tian Huimin 
Published: September 2018

e23192 Background: In order to investigate the association of immune status with the prognosis in patients with lung cancer and to screen the potential prognostic markers, the immune status including the expression levels of tumor surface molecules, tumor infiltrating lymphocytes (TIL) and cytokines, sMICA and sMICB in serum were detected in this study. Methods: Tissue and serum samples of 125 patients with NSCLC were obtained from the First Hospital of Jilin Universtiy. 50 serum samples of healthy volunteers were obtained as controls. Surface molecules of cancer cell, such as MHC-I, PD-L1, MICA/B and CD8+ TIL were detected with immunohistochemistry. Cytokines such as IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α levels in serum were detected with Luminex. sMICA and sMICB levels were examined by ELISA. The association between their expression levels and patients’ prognosis was analyzed by SPSS 17.0 software. Results: MHC-I was down-expressed, PD-L1 and MICA/B were up-regulated in NSCLC. CD8+ TIL could be seen in tumor stroma and nest. In univariate analysis, we found that patients with down-expression of MHC-I and up-regulation of PD-L1 had a poor prognosis (P < 0.05). MICA/B expression had no correlation with patients’ prognosis (P > 0.05). Patients with more stromal CD8+ TIL might have better prognosis. In multivariate analysis, we found that MHC-I and stromal CD8+ TIL might be independent prognostic factors in NSCLC (P < 0.05). TNF-α and IFN-γ were significantly decreased, IL-6 was increased in NSCLC patients (P < 0.05). There were no connections between the cytokines levels with patients’ prognosis (P > 0.05). Serum sMICA was significantly higher in NSCLC patients than healthy controls (P < 0.05). sMICB tented to be elevated in NSCLC compared with health controls, but there was no significant difference (P > 0.05). High sMICA expression had an association with poor prognosis (P < 0.05). There was no connection between the sMICB level with patients’ prognosis (P > 0.05). Conclusions: The immune status of patients with NSCLC had a close association with their prognosis in this study. It worths further study to confirm the clinical value of MHC-I expression, stromal CD8+ TIL and serum sMICA as prognostic marker in the patients with NSCLC.
A new unsupervised clustering algorithm applied to genome-wide profiles of breast cancers in The Cancer Genome Atlas proper subsets triple-negative samples.
Authors: Mezey Jason , Schwager Steven , Shenoy Sushila , Benbanaste Jef , Elashoff Michael , Kelkar Anuja , Somashekar Pramod , Lee David S. 
Published: September 2018

e23195 Background: Clustering algorithms have identified subtypes of major cancers from analysis of genome-wide gene expression (GE) and somatic mutation (SM) profiles. These algorithms almost never discover a proper subset cluster, a recovered cluster that includes all the samples of a specific subtype. For breast cancer (BC), clustering of genome-wide profiles has been unable to proper subset triple negatives (TNs), TN subtypes, or other major subtypes. Methods: To search for a proper subset cluster for TNs, we applied a new clustering algorithm to the public domain GE and SM data of BC samples in The Cancer Genome Atlas (TCGA). A module of Medidata’s Clinical Trial Genomics (CTG) platform for automated clinical and genomic data integration and analysis, it uses a hierarchical component with tree learned cut points applied to a principal component dimension reduced similarity matrix calculated from a genome-wide data profile. Results: Our analysis of 540 TCGA BC samples run without human supervision produced a proper subset cluster that included all 55 TN samples and only 74 non-TN samples. GE data have previously indicated TN status, but this is the first demonstration that these TCGA BC data contain enough information to proper subset TNs, implying that this broad BC subtype has a strong, quantifiable impact on GE. We show that the genome-wide SMs of TCGA BC samples can be used to proper subset 4 novel subtypes distinguished as classes “TP53 mutated”, “PIK3CA mutated”, “both TP53 and PIK3CA mutated”, and “neither mutated”, signifying an important role for these known driver mutations in producing the subtypes’ genome-wide mutation profiles. We find that most ( > 80%) TN BCs are in “TP53 mutated” but only 1 TN sample ( < 2%) is in “PIK3CA mutated”, indicating distinct biology for these TNs with potential implications for TN therapy. Conclusions: CTG clustering achieves proper subset cancer subtype clustering of TCGA BC samples. These results illustrate the therapeutic discovery potential possible from genomic data of the high quality present in TCGA if combined with detailed clinical data with the Medidata CTG integration and annotation platform.
Molecular classification with NanoString nCounter system in triple-negative breast cancer.
Authors: Ahn Sung Gwe , Kim Seung Joon , Lee Hak Woo , Yoon Hyo Jeong , Kim Chungyeul , Jeong Joon 
Published: September 2018

e23198 Background: Previous studies have shown that several distinct subtypes identified by gene expression profiling (GEP) consisted of triple-negative breast cancer (TNBC). Compared with the subtypes defined by GEP, we developed molecular classification with NanoString nCounter system in TNBC. Methods: GEP was conducted on 188 FFPE containing chemotherapy-naïve TNBC tumors collected at Gangnam Severance Hospital. To select core genes for classification, other 120 samples from public GEP database were used. Correlation between nCounter system and GEP using identical RNA was done. In a part of tumors, BRCA1 methylation, homologous recombination deficiency (HRD) assay, and drug response assay with ATP was comprehensively assessed. Results: To classify TNBC into 4 major subtypes (Basal-like: BL, Luminal androgen receptor: LAR, Mesenchymal: M, and Immune-modulatory: IM) according to the Vanderbilt classification, we selected 110 genes in 220 samples with GEP (100 from Gangnam Severance Hospital and 120 from public database). In other 88 samples, the classification with the 110 genes were validated. In 149 tumors excluding UNS subtype by the Vanderbilt, a correlation between 110 genes-classification and the Vanderbilt system was 74.4% (111 of 149, Pearson’s R = 0.726). In 180 tumors with GEP and nCounter assay, a correlation between them was 85.0% (153 of 180, Pearson’s R = 0.827). Compared with tumors of the IM type by 110-genes, the recurrence-free survival was significantly reduced in tumors of the non-IM type by 110-genes ( P= 0.049). In cases with BRCA1 methylation test (n = 147), a significant higher rate of BRCA1 promoter methylation was found in BL type by nCounter system (BL: 41.0% vs. non-BL: 19.4%). In cases with HRD test, a significant lower rate of HRD was found in nCounter-identified LAR type (LAR: 0% vs. non-LAR: 79.3%). In patients with in vitro drug response assay with cisplatin (n = 36), tumors with nCounter-BL had a significant higher responsiveness than tumors with others ( P= 0.028). Conclusions: Our work shows the feasibility of molecular classification with nCounter system in TNBC. Future study warrants the clinical utility of this classification to guide the subtype-specific therapy in patients with TNBC.
PI3K mutation and effect of aspirin use in breast cancer.
Authors: Tang Shou-Ching , Raval Priyanka , Sonbol Mohamad Bassam , Simmons Josh David , Chintalapally Rohini , Savage Natasha , Kolhe Ravindra B. , Kitamura Eiko , Chang Chang-Sheng , Keaton Mark Robert , Maihle Nita J. , Kim Sangmi 
Published: September 2018

e23209 Background: Increasing literature suggests a protective role of aspirin in breast cancer. PI3K mutation is prevalent in 30% of estrogen receptor positive and 50% of HER2 receptor positive breast cancers. Aspirin inhibits prostaglandin-endoperoxide synthase 2 (PTGS2) through down-regulation of phosphatidylinositol 3-kinase (PI3K). A study in colorectal cancer demonstrated that regular use of aspirin was associated with superior survival among patients with PI3K mutated tumors. The aim of this study was to retrospectively examine the presence of PI3K mutation in breast cancer tissue in patients who used aspirin during treatment, and compare survival between those with and without PI3K mutations. Methods: Among 1259 patients diagnosed with breast cancer between year 2002 to 2013 at Augusta University (AU), 47 patients who used at least 81 mg of aspirin daily during cancer treatment were identified, and their breast cancer tissue blocks were analyzed for PI3K mutation by gene sequencing technique. Genomic DNAs were extracted from formalin fixed paraffin-embedded tissues using GeneRead DNA FFPE kit (Qiagen) and sequenced on Miseq sequencer (Illumina). We selectively analyzed five genes involved in the PI3K pathway, including PIK3CA, AKT, PIK3R1, PTEN, and TP53. The presence of mutation was correlated to overall survival, using Kaplan-Meier and Cox Regression analyses. Results: Of the 47 patients, 53% were Caucasian and 47% were African American. 70% were early stage (TNM stage I, II) and 30% were late stage (TNM stage III, IV). 69% were never smokers, 31% were current or former smokers. ER, PR and HER2 were expressed in 84%, 79%, and 86% patients respectively. 66% had PI3K mutation, and 34% were PI3K wild type. There was no significant difference (log-rank test p = 0.28) in overall survival (OS) of patients with PI3K mutation versus those without, although the former group had longer survival numerically. The multivariable-adjusted hazard ratio (HR) for PI3K mutation was 0.53 (p = 0.29). Conclusions: Our project supports justification for a larger study to explore the role of aspirin in prevention, treatment and prognosis of breast cancer, and to validate biomarkers such as PI3K and related genes mediating the aspirin effect.
RNA turbulence by tumor type: Overexpression of actionable mRNA signaling pathways by histology.
Authors: Patel Sandip Pravin , Morris Scott , Chae Young Kwang , Clarke Jeffrey Melson 
Published: September 2018

e23213 Background: Overexpression of mRNA provides an oncogenic mechanism, downstream of DNA level changes detected by sequencing, that can be treated with targeted therapies. It is still unknown why a subset of patients experience substantial responses to targeted therapies, while others experience minimal benefit. We hypothesize that the occurrence of multiple mRNA drivers may segment by cancer type in a similar manner to mutation burden. Methods: We examined results from 2088 patients with the 23 most common histologies that had received molecular testing at Paradigm Diagnostics by a panel of 56 mRNA targets, including 21 from the MAPK pathway, 14 from the P53 pathway, and 18 from the PI3K pathway. We calculated RNA turbulence, defined as the number of mRNA overexpressed in each case, as well as the pathway-specific RNA turbulence for the MAPK, PI3K and TP53 pathways. Results: Significant differences in overall and pathway-specific RNA turbulence across cancer types was observed. Colon and rectal cancers had high turbulence in the MAPK and TP53 pathways, with 87% having multiple putative drivers in the MAPK pathway and 29% having multiple drivers in the PI3K pathway. Small cell lung cancer and kidney cancers had high turbulence in the PI3K pathway, with 33% and 39% having multiple RNA drivers respectively. Overall, pancreatic, kidney and colon cancers had the highest turbulence and GIST, melanoma and cholangiocarcinoma had the lowest. There was a slight inverse relationship in tumor type when ranked by mutation burden vs. RNA turbulence Conclusions: RNA turbulence represents a unique mechanism by which to analyze tumors and correlates with disease type. Multiplex diagnostics assaying DNA, RNA, and protein level tumor changes will likely be needed to guide cancer therapeutics.
Phase II study of apatinib plus vinorelbine, a novel combination of all-oral regimen in heavily pretreated patients with metastatic HER2-negative breast cancer.
Authors: Zhu Anjie , Yuan Peng , Wang Jiayu , Ma Fei , Luo Yang , Fan Ying , LI Qing , Zhang Pin , Xu Binghe 
Published: September 2018

TPS1123 Background: Antiangiogenic therapy in combination with chemotherapy is effective in control advanced breast cancer(ABC). Apatinib is an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Phase II clinical trials of Apatinib single agent had presented objective response and manageable toxicity in heavily pretreated, metastatic breast cancer. The median progression free survival (PFS) and median overall survival (OS) of single agent in both triple-negative and non-triple-negative breast cancer were 3.3-4.0 months and 10.3-10.6 months, respectively. The overall response rate and disease control rate (DCR) reached 16.7% and 66.7%, respectively. This all-oral phase II study aims to investigate the efficacy and safety of the oral vinorelbine-Apatinib combination in pre-treated metastatic breast cancer(MBC). Methods: This single arm prospective study enrolled patients with HER2(Human epidermal growth factor receptor-2 ) negative advanced breast cancer, pretreated with anthracycline and taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimen. The estimated Enrollment was 40 patients.The primary end point of this study was PFS. Secondary end points included objective response rate (ORR), DCR, OS and safety. Patients were treated with apatinib 500/425mg daily plus oral vinorelbine 60-80 mg/m2 day1,8,15 every 3 weeks/cycle. Starting doses of Apatinib were chosen according to age, weight and patient status. Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles (6 weeks) there after until disease progressed. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs, version 4.0. Clinical trial information: NCT02768415.