bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blocking pro-invasive signaling and inflammatory activation in triple-negative breast cancer with nucleic-acid scavengers (NASs).
Authors: Eteshola Elias , Landa Karenia , Hwang Eun-Sil Shelley , Nair Smita , Sullenger Bruce 
Published: May 2020

e13096 Background: Breast cancers remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortalities in the US. Subtype heterogeneity and aggressive invasive potential are believed to be the major contributors of these outcomes. Triple-negative breast cancer (TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Inflammation-driven tumorigenesis has been shown to correlate with cell-free DNA (cfDNA) and other damage-associated molecular patterns (DAMPs) in cancer patient sera. We showed that nucleic-acid scavengers (NAS) can block pro-inflammatory signals elicited by DAMP-activation of innate immune sensors (e.g. toll-like receptors). Treatment with the NAS PAMAM-G3 drastically reduced liver metastatic burden in an immunocompetent murine model of pancreatic cancer. Methods: TNBC cells lines were treated with a cocktail of standard-of-care chemotherapeutic agents and the conditioned media (CM) from these cells served as an in vitro DAMP source. Downstream function of TLR activation was tested via a HEK293-TLR reporter cell line measuring absorbance at 655nm. The in vitro invasive phenotype was tested and quantified using a Transwell-Matrigel invasion assay. Cytokine secretion was measured using a BioLegend cytokine array. Results: TNBC CM greatly increased TNBC cell invasion in vitro and that treatment with the NAS PAMAM-G3 significantly inhibits this effect. Treatment of human monocytes (THP-1) with TNBC CM elicited a strong pro-inflammatory response with elevated levels of IL-8, IL-6, CCL2, and IL-1β. Other biologically immune responders including human PBMCs will be tested to determine the potential impact on the tumor immune microenvironment during tumorigenesis and treatment. Conclusions: To elucidate the mechanism by which this NAS works in these tumor settings, our lab has developed several PAMAM-G3 derivatives, including biotin, IR-, and near-IR fluorophore labeled molecules. These molecules will allow us to capture and characterize DAMPs and do in vivo live imaging experiments to gain insight into NAS PK/PD properties. This insight into NAS capabilities will enhance our understanding of metastatic progression and its interplay with the immune system. Moreover, these principles will aid in the development of novel of anti-metastatic therapies to improve TNBC patient outcomes.
Evaluating progression-free survival in black and white women with triple-negative breast cancer in pooled clinical trials from a synthetic control database (SCD) and real-world electronic medical records (EMR).
Authors: Watson Mark Layton , Holcomb Kevin , Newman Lisa , Andrews Janna , Ensign Lisa , Galaznik Aaron , Fields Bryant , Diamond Sheila , Pollard Nicole 
Published: May 2020

e13102 Background: Previous studies have shown a lower survival rate in Black women with breast cancer compared with other ethnic groups, largely explained by the increased incidence of triple negative breast cancer (TNBC). In this study we further explore relative survival by race within a TNBC population. By using pooled clinical trial data, we seek to control for variation in patient assessment on outcomes. We further use a real-world electronic medical records (EMR) data source to compare the representativeness of pooled trial findings to patients receiving care not on trial. Methods: Phase II and III open-label breast cancer studies having completed their primary analysis were selected from the Medidata Enterprise Data Store (MEDS), comprised of over 19,000 historical clinical trials, for de-identified aggregate analyses. The Synthetic Control Database (SCD) for this study contains 749 patients with TNBC enrolled in second line and higher treatment trials between 2010 and 2017. De-identified Oncology EMR data was sourced from the Guardian Research Network (GRN) of integrated delivery systems from 2010 to 2018, and contained 1877 patients. Baseline characteristics were assessed between pooled trial and real-world data cohorts. Patients were stratified by race. Progression-free survival (PFS) was assessed using a Kaplan-Meier analysis. We conducted further analysis to assess the impact of additional factors that may influence the aggressive progression of TNBC response in Black women and TNBC disparity. Factors included, but were not limited to: age, stage at diagnosis, baseline benign neutropenia, Body Mass Index (BMI) and genetic factors (BRCA). Results: The TNBC SCD population was 73.0% White, 6.8% Black, and 20.2% Non-White Non-Black (NWNB). The real-world distribution, by contrast was 79%, 10%, and 11%, respectively, with patients predominantly stage 2 at diagnosis. Median BMI at diagnosis was 28.6, 32.6 and 27.1. Unadjusted progression-free survival (PFS) was directionally lower in Black patients in a Kaplan-Meier assessment with a Median PFS of 105 days vs 144 days for all others. Conclusions: A representative pool of cross trial TNBC patients demonstrated lower PFS in Black patients compared to their non-Black counterparts. Based on these findings, further investigation to explore potential biological and treatment factors associated with racial disparity in TNBC is warranted.
Dual TGF-β and AURKA targeting enhances chemosensitivity in triple-negative breast cancer.
Authors: Faruqi Fahad Ahmed , Jalalirad Mohammad , D'Assoro Antonino Bonaventura , Haddad Tufia C. , Carter Jodi M , Boughey Judy Caroline , Wang Leiwei , Goetz Matthew P. , Ingle James N. 
Published: May 2020

e13106 Background: Chemotherapy resistance remains a significant barrier in the effective treatment of patients with triple negative breast cancer (TNBC). TGF-β signaling is a well characterized oncogenic pathway in TNBC that promotes chemoresistance by inducing epithelial to mesenchymal transition (EMT) and tumor stemness. Aurora-A kinase (AURKA) is a serine/threonine kinase responsible for chromosomal stability during mitosis. Significantly, aberrant expression of AURKA induces breast cancer progression. We hypothesized that aberrant activation of TGF-β and AURKA signaling pathways contributes to chemoresistance in TNBC by promoting EMT and tumor stemness and that dual-targeting of these oncoproteins will enhance chemosensitivity. Methods: RNA-Seq data were analyzed from patient derived xenografts (PDx) established from patients with Stage I-III TNBC who received pre-operative taxane and anthracycline based chemotherapy. Chemoresistance was defined as an RCB score of 1-3, and chemosensitivity was defined as an RCB score of 0. Unique TNBC cell lines developed from brain metastasis PDxs (TNBC M14, TNBC M25) were treated in vitro with 10nM docetaxel (DTX), 50nM LY2157299 (TGF-β inhibitor) and 50nM MLN8237 (AURKA inhibitor). EMT reprogramming was determined by measuring the expression of vimentin, ALDH activity and mammosphere growth. Apoptotic cells following drug treatment were labeled with Red Annexin-V marker and monitored in real time using the IncuCyte instrument. Results: RNA-Seq revealed that there was no baseline difference in expression of AURKA between chemoresistant and chemosensitive TNBC PDxs. However, there was a 2.7-fold increase in AURKA expression in the post-treatment PDx models compared to pre-treatment PDx models. In vitro treatment of the M14 and M25 cell lines with DTX demonstrated no significant increase in apoptotic cells compared to control, whereas treatment with the combination of DTX, LY2157299 and MLN8237 resulted in a two-fold increase in apoptosis compared to treatment with DTX alone (p = 0.0068 M14, p = 0.003 M25). Dual-targeting with LY2157299 and MLN8237 reduced the expression of vimentin and ALDH activity. Conclusions: TGF-β and AURKA play a central role inducing EMT and a stem-cell-like phenotype in TNBC that confers chemoresistance. AURKA is up-regulated after exposure to chemotherapy in chemoresistant TNBC PDx models. LY2157299 and MLN8237 reduce TNBC stemness in M14 and M25 cell lines and enhance DTX chemosensitivity. Dual-targeting of TGF-β and AURKA is a potentially promising approach in chemoresistant TNBC.
Deoptimized influenza virus for treatment of TNBC and induction of anticancer immunity in the EMT6 mouse model.
Authors: Stawowczyk Marcin , Stauft Charles Brandon , Wang Ying , Mueller Steffen , Coleman John Robert 
Published: May 2020

e13109 Background: Triple negative breast cancer (TNBC) is resistant to classical hormone-based therapy, prone to relapse and aggressive metastasis. Oncolytic viruses (OVs) when injected into the tumor, can promote local lysis of tumor cells and drive presentation of tumor antigens, thereby making tumors visible to the immune system. CodaLytic is a re-coded influenza A virus that has a high frequency of disfavored codons and codon pairs which attenuate the virus yet preserve all antigens and immune stimulation properties of the wild type influenza virus. CodaLytic is produced from the same master virus seed as CodaVax, a universal influenza vaccine candidate currently in Phase I clinical trials under a US IND. Methods: BALB/c mice were implanted with EMT6 mouse TNBC cells into a mammary fat pad. Six days post-implantation, when tumors became palpable, treatment was initiated by intratumoral administration of PBS (mock) or CodaLytic (108 PFU in 50 µL). Mice were treated three times a week for a total of three weeks. Tumor growth was monitored daily for 33 days and animals were euthanized if the tumor volume exceeded 500 mm3. Survivors were challenged via flank or intravenous (IV) injection of EMT6 cells. Two weeks after IV challenge, lungs were removed and compared to the lungs of control mice. Results: At the end of the initial experiment (day 33), 80% of CodaLytic-treated mice were alive with 70% of survivors being tumor-free as compared to mock, of which none survived. Survivors on day 33 had a median decrease in tumor size of 75%. CodaLytic stimulated lasting anti-tumor immunity as 100% of CodaLytic-treated survivors failed to establish tumors following challenge with EMT6 cells via flank injection. To model metastasis, surviving treated mice were also challenged with EMT6 cells delivered 2x104 cells IV. IV challenged mice had over 10-fold fewer nodules in their lungs as compared to naïve controls and 40% of the animals remained tumor free, whereas 100% of the control animals developed tumors. Additionally, CodaLytic-treated survivors showed no weight loss after IV re-challenge compared to controls which lost an average of 12% body mass. Conclusions: CodaLytic OV treatment of TNBC increased survival, led to complete tumor clearance in the EMT6 mouse model, and induced systemic anti-tumor immunity that has potential for preventing and treating metastatic disease.
Triple-negative and non–triple-negative breast cancer in a south Indian cohort.
Authors: Warrier Narayanankutty Edavalath , Sankar Uma V , P S Sreedharan , Sherif Ajmal 
Published: May 2020

e13110 Background: The heterogeneity of breast cancer explains in part the differences in the morbidity and mortality of this disease. Triple-negative breast cancer (TNBC) is a specific subset of tumors characterized by the absence of the 3 most commonly targeted biomarkers considered for breast cancer treatment: Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). TNBC accounts for 15% to 20% of all breast cancer diagnoses and usually has a more aggressive clinical course, with worse evolution within the first 3 to 5 years after diagnosis; early and higher rates of distant recurrences, typically visceral; and poor survival. Methods: To analyze the clinical, pathological, and sociodemographic aspects between triple-negative breast cancer (TNBC) and non-TNBC in a Kerala cohort and identify potential prognostic factors. This hospital-based retrospective cohort study (From January 2017 till December 2018) included 465 women with breast cancer treated at MVR Cancer Centre & Research Institute in North Kerala. Overall and disease-free survival was compared; prognostic factors were evaluated. Results: Triple-negative breast cancer corresponded to 16.3% of breast cancer diagnosis and was more prevalent among rural women. The patients with TNBC tended to present with stage III cancer, high p53 expression, lymphocytic infiltration, and multifocality and treated with radical surgery and chemotherapy. The 2-year overall and disease-free survival were 52.1% and 43.5% for TNBC and 83.8% and 73.4% for non-TNBC, respectively ( P < .001). The TNBC recurrence was associated with multicentricity, whereas lymph node involvement increased the risk of both recurrence and death. Non-TNBC worse clinical course was associated with rural women, younger age, lymph node involvement, and advanced stage. Conclusions: Triple-negative breast cancer exhibited a more aggressive behavior, earlier and more frequent recurrence, and worse survival compared with non-TNBC. While biological and social variables were associated with poorer prognosis in non-TNBC, only lymph node involvement and multicentricity were correlated with worse clinical outcomes in TNBC.
Next generation sequencing reveals the phylogenetic relationship of multi-organ metastatic colon cancer and molecular determinants of metastasis.
Authors: Hu Dandan , Chen Gong , Zhang Yaojun , Chen Minshan 
Published: May 2020

e13502 Background: The clinical manifestation of metastatic colorectal cancer (mCRC) varies from patient to patient, with the underlying genetic alterations and expression profiles deceptive. We aim to investigate the phylogenetic relationships of the multi-organ mCRC and the possible biomarkers of disease progression. Methods: Whole Extron Sequencing (WES) was performed in CRC and their matched multi-organ metastases from three patients with different clinical manifestations. Sciclone calculation between individual lesions illustrated the evolutionary origins of each metastatic sites. Genomic divergence between primary and metastatic sites were identified and their potential role in the metastatic process were annotated. Following the WES results, the significantly correlated genes were validated by immunohistochemistry. Results: The evolutionary tree showed that the distant metastasis could originated from either the primary colon cancer or the other metastatic site. Organotropism exists in both mCRC and protein levels in terms of APOB, and a number of driver mutations potentially decide the disease progression. Moreover, the expressive change of APOB between primary CRC and CRC liver metastasis indicates worse long-term outcomes. Conclusions: Metastatic routes of multi-organ mCRC are highly heterogeneous. We identified previously unreported gene alterations might facilitate metastatic and organotropic progression, providing potential biomarkers for diagnosis and treatment.
Association of rs28714259 polymorphism with a risk of early-onset chronic anthracycline-mediated cardiotoxicity in patients with breast cancer.
Authors: Gvaldin Dmitry Yu. , Timoshkina Natalya N. , Omelchuk Ekaterina P. , Vashchenko Larisa N. , Ratieva Anastasia S. , Vladimirova Liubov Yu , Kit Oleg I. , Lisutin Aleksandr E. 
Published: May 2020

e13504 Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to assess the prevalence of rs28714259 polymorphism and to study possible correlation with anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 173 Caucasian patients (median age 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular pathology who underwent treatment in the RRIO, Rostov-on-Don in 2019. For genotyping of SNP rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by Sanger sequencing with a Genetic Analyzer 3500 (ABI, USA). The obtained results were compared with European population (1000 Genome). Results: 13 patients (7.5%) with an early-onset of chronic AMC were founded after three courses of chemotherapy. The allelic frequency rs28714259 was 0.079, the frequency of AG genotypes was 0.135, and AA was 0.012. It was shown that the presence of this SNP leads to an increase risk of cardiovascular pathology at an early stage by more than 4 times (OR = 4.186, p = 0.006). In addition, when comparing with the European population, the highest probability of developing early-onset chronic AMC was determined for patients with the AA genotype (more than 22 times, p = 0.001). Conclusions: In this study, a statistically significant association of rs28714259 presence with developing early-onset chronic AMC was revealed, which seems promising for the early determination of the risk group in the management of cancer patients.
Genomic characterization of preclinical models derived from primary and metastatic sites from rapid autopsy patients in PDMR.
Authors: Chen Li , Patidar Rajesh , Das Biswajit , Evrard Yvonne A , Karlovich Chris Alan , Vilimas Tomas , Nair Nikitha , Peach Amanda , Lee Fong Anna , Romero Luis , Jiwani Shahanawaz , Dutko Lindsay , Benauer Kelly , Radzyminski Marianne , Dougherty Kelly , Eugeni Michelle , Newton Dianne , Hollingshead Melinda G. , Williams Paul M. , Doroshow James H. 
Published: May 2020

e13506 Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.
NGS-based molecular profiling (a multi-center collaborative, observation study in Japan) highlights pathogenic variants of DNA-repair genes in advanced or recurrent endometrial cancer.
Authors: Fujiwara Hiroyuki , Oda Katsutoshi , Takahashi Nobutaka , Sakata Jun , Taneichi Akiyo , Ikeda Masae , Tanikawa Michihiro , Kusakabe Misako , Mitsuhashi Akira , Kobayashi Yoichi , Yamashita Hiroshi , Suzuki Nao , Akiyama Azusa , Tokunaga Hideki , Tanaka Naotake , Mikami Mikio 
Published: May 2020

e13510 Background: Although tumor molecular profiling has now become prevalent, next-generation sequencing (NGS)-based molecular profiling with adequate annotation is limited in recurrent endometrial cancers. We investigated the frequency of alterations in cancer-related genes in a Japanese cohort of incurable endometrial cancer patients. Methods: We enrolled 102 endometrial cancer patients, who had discontinued standard therapy, and extracted tumor DNA from their formalin-fixed paraffin-embedded specimens. Oncomine Comprehensive Assay v3 (ThermoFisher), which covers 161 cancer genes, was used as a comprehensive NGS assay. We only defined variants with the annotations “pathogenic” or “likely pathogenic.” Oncogenicity and actionability were defined with the Oncomine Knowledgebase and “Chrovis database” ( https://chrov.is/ ). The protocol was approved by the institutional ethics committee at each institute, and written informed consent was obtained from all patients before enrollment. Results: The ratios of pathogenic mutations in the PI3K-AKT pathway were 34.3%, 15.7%, and 3.9% for PIK3CA, PTEN, and AKT1, while those in the receptor tyrosine kinase-RAS-MAPK pathway were 3.9%, 2.0%, 3.9%, and 1.0% for FGFR2, KRAS, NF1, and BRAF, respectively. The pathogenic mutation ratios of TP53, ATM, CTNNB1, and FBXW7 were 21.6%, 3.9%, 10.8%, and 9.8%, respectively. In addition to 5.9% of MSH2 variants (five patients with 5-20% and one patient with 56% variant allele frequency (VAF)), pathogenic variants of BRCA1 and/or BRCA2 were identified in 7.8% (seven patients with 5-20% and one with 40% VAFs). Three fusion genes were identified in three patients ( TPR- NTRK1, ESR1- CCDC170, and TBL1XR1- PIK3CA). “Actionable” gene variants (applicable for clinical trials or approved drug available in Japan) were identified in 49.0% of patients. Candidate drugs for patients with actionable variants included ROS1/TRK, AKT, immune checkpoint, and PARP inhibitors. Conclusions: Molecular profiling in poor-prognostic endometrial cancer highlighted the significance of DNA-repair related genes ( TP53, ATM, BRCA1, and BRCA2) and Wnt-beta catenin signaling pathway, and the infrequent alterations in PTEN and KRAS genes, although PIK3CA was frequently mutated. Our data suggest that targeting DNA repair pathway (including PARP inhibitors), may be a treatment option in certain endometrial cancer patients. Clinical trial information: UMIN000027294.