bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of therapeutic targeting of the oncogene EMP2 in triple-negative breast cancer on tumor load.
Authors: Wadehra Madhuri , Kiyohara Meagan , Fu Maoyong , Gordon Lynn K , Braun Jonathan 
Published: March 2020

1052 Background: Understanding tumor induced angiogenesis is a challenging problem with important consequences for the diagnosis and treatment of cancer. In this study we define a novel function for the tetraspan epithelial membrane protein-2 (EMP2) in the control of neoangiogenesis. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple negative breast, ovarian, and endometrial tumors. In breast cancer, EMP2 is highly expressed on the majority of invasive tumors examined, and in particular 70% of triple negative breast tumors showed surface expression of this marker. In this study, we examine the control of EMP2 on the tumor microenvironment and further characterize its therapeutic efficacy in breast cancer. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels altered the tumor microenvironment. Cells were tested for their expression of pro-angiogenic proteins HIF-1a and VEGF-A as well as for their ability to induce endothelial cell migration and capillary like tube formation. Cells with modulated EMP2 levels were also tested in vivo for tumor formation and examined for histological changes in the tumor microenvironment. In addition, we recently constructed a fully human EMP2 IgG1 and determined its therapeutic efficacy in a number of triple negative breast cancer cells. Results: In vitro, upregulation of EMP2 promoted VEGF expression through a HIF-1a dependent pathway and resulted in successful capillary-like tube formation. In contrast, reduction of EMP2 correlated with reduced HIF-1a and VEGF expression with the net consequence of poorly vascularized tumors in vivo. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load with a significant improvement in survival. Conclusions: Clinically, EMP2 has been shown to correlate with poor survival, and these results suggest that this occurs in part through its control on tumor vasculature. In addition, we provide additional evidence on the potent cytotoxic effects of EMP2 treatment in vivo.
Prognostic significance of LINE-1 methylation level in the upper gastrointestinal cancer.
Authors: Baba Yoshifumi , Watanabe Masayuki , Iwagami Shiro , Shigaki Hironobu , Ishimoto Takatsugu , Iwatsuki Masaaki , Baba Hideo 
Published: March 2020

10523 Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in long interspersed nucleotide element-1 (LINE-1) is a good indicator of global DNA methylation level. Although LINE-1 methylation level is attracting interest as a useful marker for predicting cancer prognosis, the prognostic significance of LINE-1 hypomethylaiton in the upper gastrointestinal cancer [i.e., esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC)] remains unclear. Methods: Using 217 ESCC and 207 GC specimens, we quantified the LINE-1 methylation using bisulfite-pyrosequencing technology. During the follow-up, there were a total of 63 ESCC recurrences, 51 ESCC deaths and 56 GC deaths. The median follow-up time for censored patients was 2.8 years. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical, epidemiological, and pathological variables. The term “prognostic marker” is used throughout this study according to the REMARK Guidelines. Results: ESCCs and GCs showed significantly lower LINE-1 methylation levels compared to matched normal mucosa (p<0.0001). In ESCC, LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate HR= 2.32, 95% confidence interval (CI) 1.38-3.84, p=0.0017; multivariate HR=1.81, 95% CI 1.06-3.05, p=0.031] and cancer-specific survival (log-rank p=0.0020; univariate HR=2.21, 95% CI 1.33-3.60, p=0.0026; multivariate HR=1.87, 95% CI 1.12-3.08, p=0.018]. We found a significant modifying effect of the tumor stage on the relationship between LINE-1 methylation and the recurrence rate (P for interaction = 0.031). In GC, LINE-1 hypomethylation was significantly associated with cancer-specific survival (log-rank p=0.029; univariate HR=2.01, 95% CI 1.09-3.99). Conclusions: LINE-1 hypomethylation is associated with shorter survival in both ESCC and GC, suggesting that it has potential for use as a prognostic biomarker.
VEGF polymorphism may be associated with overall survival in lapatinib-treated breast cancer patients with brain metastases.
Authors: Spraggs Colin F. , Li Li , Briley Linda P. , Joshi Alaknanda , Florance Allison M. , King Karen , Parham Laura R 
Published: March 2020

10532 Background: Lapatinib is a dual HER2/EGFR tyrosine kinase inhibitor (TKI) approved in combination with capecitabine or letrozole for patients with HER2+ metastatic breast cancer (MBC). Consistent with TKI therapies, patient response is variable and suggestive of additional determinants of sensitivity and resistance. This exploratory pharmacogenetic study sought to identify germline genetic variants that associate with lapatinib treatment outcomes in HER2+ MBC patients. Methods: Fifty five functional single nucleotide polymorphisms (SNPs) in 24 candidate genes were evaluated in a subset of MBC patients participating in two clinical trials: EGF105084: lapatinib monotherapy in HER2+ MBC patients with recurrent brain metastases following trastuzumab and cranial radiotherapy (n=120) and EGF104900: lapatinib plus trastuzumab (n=92) and lapatinib monotherapy (n=103) in HER2+ MBC patients with disease progression following trastuzumab. Testing for associations of SNPs with progression free survival (PFS) and overall survival (OS) during lapatinib treatment was performed using Cox proportional hazards methods, with covariate adjustment. Markers were considered to be significantly associated if they achieved a predefined multiple testing threshold of p<0.0003. Results: No SNPs were significantly associated with PFS in either study. A SNP in VEGFA (rs3025039, 936C>T) was significantly associated with improved OS (p=0.0002) for the T allele carriers, with an allelic hazard ratio of 0.21 (0.08-0.52) in EGF105084. The association was not seen in EGF104900. This SNP is located in the 3’ UTR gene region, the T allele is associated with lower serum VEGFA levels and reduced breast cancer risk [Krippl et al, 2003, Int J Cancer 106: 468; Kataoka et al, 2006, Cancer Epidemiol Biomarkers Prev, 15:1148]. Conclusions: A germline variant in VEGFA may be associated with survival outcome in MBC patients with brain metastases who are treated with lapatinib. This may represent activation of VEGF angiogenic pathways to overcome HER2 inhibition in patients carrying the higher expression genotype. These associations are considered exploratory and require confirmation in an independent dataset.
Prognostic and diagnostic value of Ewing family of tumors (EFTs)-associated fusion transcripts detected in peripheral blood specimens.
Authors: Przybyl Joanna , Kosela Hanna , Wiater Katarzyna , Ptaszynski Konrad , Szumera-Cieckiewicz Anna , Falkowski Slawomir , Lugowska Iwona A. , Debiec-Rychter Maria , Siedlecki Janusz A , Rutkowski Piotr 
Published: March 2020

10538 Background: EFTs are characterized by chromosomal translocations leading to formation of oncogenic EWSR1-FLI1 fusion gene in 85-90% of cases. The aim of the study was to detect circulating tumor cells (CTCs) carrying EWSR1-FLI1 fusion transcript in peripheral blood and assess their added value to standard diagnostic procedures and utility as a prognostic marker in EFTs. Methods: 10mL of whole blood was collected from 35 untreated adult EFTs patients at the diagnosis (period: 2008-2011, median age 27 years) and 13 healthy controls. 13 patients presented metastatic disease (M1) at the diagnosis. Nested RT-PCR was applied in triplicate for the detection of EWSR1-FLI1 transcript. Blood specimen was regarded CTC-positive when at least 2 out of 3 nested RT-PCR assays were positive and results were confirmed by sequencing. FISH assay for EWSR1 rearrangement was performed on FFPE tumor tissue in 28 available cases. Median follow-up was 16 months. Results: EWSR1-FLI1 transcript was detected in peripheral blood of 71.4% (n=25) of patients. FISH assay was positive for EWRS1 rearrangement in 58% of cases. In 10 patients, where FISH assay could not be performed due to insufficient quality or lack of material, nested RT-PCR provided confirmation of immunopathological diagnosis. Specificity of RT-PCR blood test in healthy control was 91.4% (12/13 negative; p=0.0001). Median overall survival (OS) was 18 months. CTC-positive patients showed the trend for longer OS than CTC-negative patients (1-year OS: 89% vs. 58%; p=0.07), but longer follow-up is needed. Conclusions: Our results show that the fusion transcript detection in peripheral blood specimens may be a useful additional test to the standard clinicopathological diagnosis of EFTs. High detection rate of EWSR1-FLI1 transcript in peripheral blood of EFTs patients at the diagnosis may imply EFTs as a systemic disease with clinically evident metastases or micrometastases at presentation. Prognostic significance of CTCs in EFTs warrants further studies.
Detection and HER2 expression of circulating tumor cells in advanced gastric cancer patients.
Authors: Matsusaka Satoshi , Chin Keisho , Ogura Mariko , Suenaga Mitsukuni , Shinozaki Eiji , Mizunuma Nobuyuki , Sano Takeshi , Yamaguchi Toshiharu , Yamamoto Noriko , Ishikawa Yuichi , Mishima Yuji , Terui Yasuhito , Hatake Kiyohiko 
Published: March 2020

10541 Background: This study was aimed at detecting and HER2-expressiong circulating tumor cells (CTC) in peripheral blood of chemo-naïve or chemo-resistant patients with advanced gastric cancer. Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital in the Japanese Foundation for Cancer Research and provided informed consent. The study population consisted of patients of age 18 years or older with histologically proven advanced gastric cancer. A total of 140 patients with advanced gastric cancer were enrolled into a prospective study. We used CellSearch system for detection and HER2 expression for CTC. Results: We detected ≥1 CTC/7.5ml in 80 of 140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 CTC-positive patients (23.8%), including 6 patients with HSR2-negative primary tumors. 21 patients with HER2-positive primary tumors administered trastuzumab in combination with chemotherapy (Xeloda+cisplatin; 15, weekly Paclitaxel; 5). We detected ≥1 CTC/7.5ml at the baseline in 11 of 20 patients with trastuzumab treatment. HER2-positive CTCs were observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2-positive CTC at the baseline were shorter PFS than those with HER2-negative CTC at the baseline. Conclusions: HER2 expression on CTC was associated with chemo-resistance. Information on the HER2 status of CTC might be helpful for stratification of HER2-directed therapies.
Serum hepatocyte growth factor and interleukin-6 as prognostic markers for stage III non-small cell lung cancer.
Authors: Ujiie Hideki , Tomida Mikio , Akiyama Hirohiko , Okada Daisuke , Nakajima Yuki , Sakai Hiroshi , Takiguchi Yuichi , Tanzawa Hideki 
Published: March 2020

10542 Background: We surveyed prognostic biomarkers for resectable non-small cell lung cancer (NSCLC). Methods: We obtained preoperative serum from 109 patients admitted to our facility, and measured the levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and nicotinamide N–methytransferase (NNMT) in the sera by the ELISA method. We also examined the clinical backgrounds of the patients. Results: The median HGF and IL-6 contents in sera from 109 patients were 860 pg/ml and 2.7 pg/ml, respectively. Analysis of survival curves indicated that HGF or IL-6 levels higher than the median were associated with poor overall survival (HGF, P = 0.019; IL-6, P = 0.002). On the other hand, carcinoembryonic antigen (CEA), a known tumor marker, and NNMT, which we found to be a candidate tumor marker, exhibited no correlation with the prognosis. The tumor status (pT factor) and stage were strong prognostic indicators (P < 0.001). In addition, we analyzed stage III lung cancer alone. Higher HGF or IL-6 levels were associated with poor overall survival (HGF, P = 0.016; IL-6, P = 0.013). Disease-free survival was also affected by these cytokine contents, but not statistically significantly. The prognosis of patients with adenocarcinomas (ADC) was better than that of patients with other histological types. However, the pT factor and nodal status (pN factor) were not associated with the survival of stage III patients. Conclusions: The levels of HGF and IL-6 in serum could be useful prognostic indicator of the survival of stage III NSCLC patients undergoing surgery and chemotherapy.
Preclinical evaluation of selective inhibitors of nuclear export (SINE) in basal-like breast cancer (BLBC).
Authors: McCauley Dilara , Landesman Yosef , Senapedis William , Kashyap Trinayan , Saint-Martin Jean-Richard , Plamondon Louis , Sandanayaka Vincent , Shechter Sharon , Froim Doriana , Nir Raphael , Williams Jennifer , Chin Lynda , Benes Cyril , Mirza Mansoor Raza , Kauffman Michael , Shacham Sharon 
Published: March 2020

1055 Background: Basal-like breast cancers (BLBC) compose up to 15% of breast cancer (BC) and are usually triple negative characterized by lack of ER, PR, and HER-2 amplification. In addition, most BRCA1-associated BCs are BLBC and TNBC, expressing basal cytokeratins and EGFR. BLBC is characterized by an aggressive phenotype, high histological grade, and poor clinical outcomes: high recurrence and metastasis rates. CRM1 (XPO1) is the exclusive nuclear exporter of multiple Tumor Suppressor Proteins (TSP) including p53, p21, BRCA1&2, pRB, FOXO. CRM1 inhibition forces nuclear accumulation of TSPs, inducing apoptosis in cancer cells. KPT-SINE are novel, small molecule, irreversible inhibitors of CRM1 with potent anti cancer activity. Methods: The Cancer Genome Atlas (TCGA) and BC cell line databases were used for mRNA analyses. MTT assay was used to determine the cytotoxic effect of KPT-SINE (KPT-185 and KPT-330) on 44 breast cell lines including luminal A, luminal B, HER2 positive, BLBC and TNBC cells. The effect of KPT-330 treatment on tumor growth was tested in vivo in the TNBC model MDA-MB-468 xenograft. Results: Analyses of nuclear pore complex (NPC)-related mRNA levels (including CRM1) showed clear separation of BCs into high and low NPC expression. BLBC subtype was enriched with high NPC transcripts while luminal BC was enriched in low NPC levels (p<1.53e-20). High NPC levels had higher mutation levels in BRCA2 (cor=0.33, p=1.83e-8) and ABL1. NPC expression was inversely correlated with ER mRNA expression (cor=-0.58, p=1.37e-7). KPT-SINE showed potent cytotoxicity on >75% of the cell lines (IC50 values <1 μM). Only three of 24 TNBC cell lines displayed IC50 values >1.5 μM upon KPT-SINE treatment. Genomic analyses on all BC lines indicated that p53, PI3K/AKT and BRCA1 or 2 status did not affect cytotoxicity. In MDA-MB-468 xenograft, KPT-330 displayed efficacy in a dose-dependent manner inhibiting nearly 100% of tumor growth compared with vehicle treated animals, and was well tolerated. Conclusions: These data show that NPC/CRM1 mRNAs are overexpressed in BLBC/TNBC and that CRM-1 mediated nuclear export inhibition by SINE represents a potentially novel and well tolerated therapy for BLBC / TNBC.
Hybrid PET-MRI of the breast: A promising tool for the characterization of breast tumors.
Authors: Pinker-Domenig Katja , Bickel Hubert , Bogner Wolfgang , Magometschnigg Heinrich , Gruber Stephan , Dubsky Peter Christian , Pluschnig Ursula , Rudas Margaretha , Bago-Horvath Zsuzsanna , Helbich Thomas 
Published: March 2020

10570 Background: To evaluate if PET-MRI of breast tumors improves staging of breast cancer and obviates unnecessary breast biopsies. Methods: 106 patients with breast tumors detected by mammography or ultrasound and classified as BIRADS 3-5 were included in this IRB approved prospective study. All patients were examined with dedicated 18FDG-PET-CT and 3T multiparametric MRI of the breast. Examinations were scheduled no longer than 7 days apart. MRI protocol included: a diffusion-weighted sequence (DWI), a T2-w sequence and a contrast-enhanced combined high temporal and spatial resolution 3D-T1-w sequence before and after application of a standard dose Gd-DOTA. For PET-CT patients fasted at least 6 h before injection of approx. 300 MBq 18F-FDG based on the patients weight. Scanning was started 45 min after injection. Blood glucose levels were <150 mg/dl. A prone PET dataset over the breasts was acquired using a positioning device allowing the same patient geometry as the breast MRI coil. CT data was used for attenuation correction. Co-registration of imaging data and image fusion were performed. PET-MRI was assessed for lesion morphology and EH-kinetics according to BI-RADS and restricted diffusivity with an ADC threshold 1.25 x10-3mm2/s set as the cut-off for malignancy. Lesions were assed for 18F-FDG–avidity and classified as positive when 18F-FDG-uptake was greater than blood-pool activity. Additionally, nodal status was recorded for each technique and patient. Histopathology was used as the standard of reference. Results: PET-MRI achieved an excellent sensitivity of 100%. Specificity was increased from 68% to 80% as compared to routinely used MRI. Diagnostic accuracy of PET-MRI for diagnosis of breast cancer was 95%. PET-MRI would have obviated unnecessary breast biopsies in 80% of benign breast lesions without missing any cancers. Additionally, PET-MRI increased sensitivity in the detection of lymphnode metastases from 70% to 87% compared to MRI alone. Conclusions: With PET-MRI unnecessary breast biopsies can be obviated without missing any cancers. PET-MRI increases overall diagnostic accuracy in the diagnosis of breast cancer and lymphnode metastases for an accurate staging.
Antagonistic activity of acolbifene, fulvestrant, tamoxifen, and raloxifene on cancer-associated genes in the mouse mammary gland.
Authors: Calvo Ezequiel , Luu-The Van , Martel Céline , Labrie Fernand 
Published: March 2020

10583 Background: The efficacy and exceptionally good tolerance of estrogen blockade in the treatment of breast cancer is well recognized. Acolbifene (ACOL) is a novel and unique SERM completely free of estrogen-like activity in both the mammary gland and uterus. To better understand the specificity of ACOL, we have investigated its effect on the expression of a set of genes modulated by estradiol (E2) in the mouse mammary gland. Methods: ACOL, tamoxifen (TAM), raloxifene (RALOX) and fulvestrant (FULV) were administered (0.01 mg/mouse; sc) to ovariectomized (OVX) mice or to OVX mice simultaneously treated with E2 (0.05 µg/mouse; single sc injection). Microarray screening followed by Q_RTPCR was used to identify a reproducible set of E2 responsive genes. Results: From 128 genes significantly modulated by E2, 108 genes were up-regulated and 20 were down-regulated. Forty-nine of these genes were associated with tumorigenesis while 22 are known to be associated with breast cancer. This set of 49 genes were used to determine the specificity of ACOL compared to another pure antiestrogen in the mammary gland and uterus, namely FULV, as well as to the mixed estrogen antagonists/agonists TAM and RALOX, in their ability to block the effect of E2. Efficacy of reversal of the effect of E2 was 94%, 63%, 45% and 90% for ACOL, FULV, TAM and RALOX, respectively. The overlap between all treatments was 30.6% (15/49). ACOL reversed the effect of E2 on 42 of the 49 (85.7%) cancer-related genes. Between the genes up-regulated by E2 and reversed by ACOL, seven are considered as prognostic markers in breast cancer, namely Fgfr3, Fos12, Junb, Jdp2, Gdf15, Greb1 and Tgm2. On the other hand, two genes down‑regulated by E2, namely Foxa1 and Fgfr2, were restored by ACOL. Conclusions: Taken together, these data offer new information for a better understanding of the previously demonstrated potent tumoricidal action of ACOL in human breast cancer xenografts. The data also suggest, under the tested conditions, superiority of ACOL over TAM and the other compounds to reverse the effect of E2 on specific gene expression, thus supporting the interest of this new 3rd generation SERM for the hormonal therapy and prevention of breast cancer.
Multiplex TaqMan assays for a 7-gene prognostic immune response score to differentiate risk among women with ER-negative breast cancer.
Authors: Sninsky John J. , Christopherson Cindy , Lagier Robert , Chang Monica , Kwok Shirley , Tandon Vickram , Moore Dan H. , Waldman Frederic , Degnim Amy C. , Ingle James N. , Yau Christina , Benz Christopher , Gillett Cheryl , Tutt Andrew , Wang Alice M. , Esserman Laura 
Published: March 2020

10586 Background: Teschendorff et al. (Breast Cancer Res 2008) reported a 7-gene, immune response-enriched gene expression classifier using microarrays that was prognostic in women with ER-negative breast cancer. To facilitate further evaluation of the prognostic value of a classifier in archival fixed tumor tissue, we developed two multiplex TaqMan assays to quantify the expression levels of these genes, then trained and validated a 7-gene immune response score (IRS). Methods: RNA was extracted from FFPE sections of 185 ER-negative breast cancer patient samples from Mayo Clinic (n=81), Guy’s Hospital (n=50) and California Pacific Medical Center (CPMC) (n=27). Patients (N+ and N-) did not receive adjuvant therapy and were followed for a minimum of 5 years. Amplification of i) LY9, TNFRSF17, HLA-F, and IGLC2 and ii) XCL2, SPP1, C1QA and two reference genes NUP214 and PPIG were carried out in two multiplex RT-PCR TaqMan reactions and relative expression levels were determined using the DDCT method. The training set, comprised of the Mayo Clinic samples, was used to develop an IRS by using a summation of expression levels of the 7 genes. Association of the IRS with distant metastasis was assessed using a Cox proportional hazards model. The score was subsequently tested in a validation set (Guy’s + CPMC). Results: The amplification efficiency of each gene within the multiplex reactions was comparable to singleplex reactions. Duplicate amplifications showed excellent assay reproducibility and sensitivity (R2=0.98). The hazard ratio for a single standard deviation decrease in the IRS was 1.45 (95% CI 0.99-2.12, p=0.056) in the training set and 2.18 (1.32-3.61, p=0.002) in the validation set. ROC curves of continuous IRS to predict distant metastasis within 5 years had AUC of 0.74, 95% CI = 0.60-0.88. Conclusions: Robust multiplex TaqMan assays for FFPE tissue extracted RNA were developed for a 7-gene IRS. Increases in risk are associated with decreases in the IRS. Immune related gene expression clearly plays an important role in the spectrum of risk of ER-negative tumors. Additional signatures are in development that further support this conclusion.