bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-02-08: Initial circulating tumor cell count and venous thrombosis-free interval in the course of metastatic breast cancer
Authors: Beinse G , Berger F , Cottu PH , Dujaric M-E , Kriegel I , Guilhaume M-N , Dieras V , Beuzeboc P , Pierga J-Y , Bidard F-C 
Published: May 2016

Abstract
Background: Circulating tumor cells (CTC) count is a major prognostic factor in metastatic breast cancer. It has been also reported to be associated with venous thrombosis in short-term studies on advanced metastatic breast cancer patients.
Methods: We assessed whether an early CTC detection (CellSearch®), before the start of the first line chemotherapy, impacts Thrombosis-Free Interval during the whole course of metastatic breast cancer. Electronic medical files of all patients included in the large prospective IC 2006-04 CTC detection study (NCT00898014, Pierga et al, Ann Oncol 2012) and treated at Institut Curie (Paris, France) were manually and automatically searched for thrombosis events in the course of their metastatic breast cancer. Superficial venous thromboses were not taken into account.Thrombosis-Free Interval (TFI) was defined as the first event occuring between venous or arterial thrombosis.
Results: In the 142 patients studied, with a median follow-up of 64 months [25-81 months], venous (deep venous thrombosis, pulmonary embolism, catheter thrombosis and portal vein thrombosis) and arterial thrombosis occurred in 21.8% and 4.2% of patients, respectively. Twenty-four (30%) of the 80 patients with ≥1 CTC/7.5ml of blood before the start of first line chemotherapy experienced at least one thrombotic events in the course of their disease, while only 10 (16%) of the 62 CTC-negative patients experienced a similar event (p=0.06). Baseline positive CTC was associated with a higher risk of experiencing a venous or arterial thrombosis (TFI: HR=2.6 [1.2-5.5], p=0.009). The median TFI was 64 months in CTC-positive patients and not reached in CTC-negative patients. Among the other patients characteristics tested at baseline, Performance Status (PS=1 vs PS=0: HR=0.85 [0.4-1.9], p=NS; PS=2 or 3 vs PS=0: HR=3.7 [1.5-8.7], p=0.003) and LDH levels at baseline (LDH&gt;UNL vs LDH&lt;UNL HR=2.4 [1.2-4.9], p=0.012) were also associated with TFI.
Conclusions: Metastatic breast cancer patients with ≥1 CTC before the start of chemotherapy are at higher risk of venous thrombosis; the clinical relevance of thrombo-prophylaxis should be investigated in this population.
Citation Format: Beinse G, Berger F, Cottu PH, Dujaric M-E, Kriegel I, Guilhaume M-N, Dieras V, Beuzeboc P, Pierga J-Y, Bidard F-C. Initial circulating tumor cell count and venous thrombosis-free interval in the course of metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-08.
Abstract P2-03-06: Dysregulation of miR-34a-SIRT1 axis reduced breast cancer stemness
Authors: Xiao GG , Ma W , Mao J , Li L 
Published: May 2016

Abstract
Recent studies show that enforced expression of miR-34a results in elimination of cancer stem cells (CSCs) in many malignant tumors. Sirtuin-1 (SIRT1) being confirmed as a direct target of miR-34a was reported to be involved in regulation of growth and survival of leukemia stem cells (LSCs). In this study, we aim to understand regulatory mechanism of miR-34a -SIRT1 axis in breast cancer stem cells (BCSCs). Lower endogenous level of miR-34a and higher level of Sirtuin1 (SIRT1) gene were identified in CD44+/CD24- BCSCs than breast cancer cells. Either ectopic expression of miR-34a or silenced SIRT1 in MCF-7 cells inhibited cellular proliferation, and led to cell apoptosis. Overexpression of miR-34a also suppressed expression of ALDH1, BMI1 and Nanog, and decreased capacity of mammosphere formation significantly.. Studies in vivo showed that stable expression of miR-34a reduced tumor burden significantly in nude mice xenografts. Taken together, our results showed that miR-34a inhibit the proliferative potential of BCSCs in vitro and in vivo, at least partially through downregulating SIRT1. miR-34a-SIRT1 axis may play an important role in self-renewal and stemness maintenance of BCSCs. This study may provide a novel BCSCs specific therapeutic strategy to improve breast cancer treatments.
Citation Format: Xiao GG, Ma W, Mao J, Li L. Dysregulation of miR-34a-SIRT1 axis reduced breast cancer stemness. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-03-06.
Abstract P2-04-03: SUMO wrestles breast cancer: SUMO posttranslational modification directs breast cancer cell epigenome
Authors: Bawa-Khalfe T , Kumar S , Lin F-M 
Published: May 2016

Abstract
Epigenetic reprogramming allows breast cancer (BCa) cells to bypass normal growth checkpoints and acquire an aggressive morphology. Function of critical epigenetic proteins is directed by small ubiquitin-like modifiers (SUMO) posttranslational modification (PTM). Components of the SUMO system are dysregulated in BCa. Our objective is to delineate how changes to SUMO-PTM affect epigenetic programs that coordinate BCa pathology. We report that chromatin-bound SUMO protease SENP7L is upregulated in metastatic tamoxifen-resistant (TamR) and triple-negative BCa. SENP7L facilitates chromatin remodeling that potentiates the growth and invasiveness of these BCa subtypes. SENP7L interacts with and deSUMOylates heterochromatin protein 1 alpha (HP1-alpha/CBX5) to mediates these responses. Canonical models suggest that HP1-alpha reads the histone mark to localize predominantly at constitutive heterochromatin. Our studies challenge the old paradigm as we show that SUMOylated HP1-alpha is enriched outside heterochromatin at euchromatin, including E2F-responsive and mesenchymal gene loci. Recruitment of SUMOylated HP1-alpha supports de novo heterochromatin formation at these loci. However, SUMOylated HP1-alpha is lost in aggressive BCa due to SENP7L induction. Consistently, SENP7L upregulation prompts chromatin de-condensation and gene transcription. Nuclei acid and chemical targeting of SENP7L reduces self-renewal/differentiation properties of TamR mammospheres as well as tumor volume and secondary tumor formation of TamR cells. Hence, SENP7L inhibitors can serve as promising tools to modulate epigenetic abnormalities in TamR BCa.
Citation Format: Bawa-Khalfe T, Kumar S, Lin F-M. SUMO wrestles breast cancer: SUMO posttranslational modification directs breast cancer cell epigenome. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-04-03.
Abstract P2-05-05: Expression profiling of in vivo DCIS progression models identified BCL9 as a molecular driver of invasive progression
Authors: Behbod F , Elsarraj H , Hong Y , Valdez K , Chien J , Godwin A , Fields T 
Published: May 2016

Abstract
Introduction: There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. At present, it is not clear why some DCIS remain non-invasive for decades while others become invasive. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of DCIS patients. To identify factors that promote DCIS invasion, we have profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using two in vivo models, MIND (mouse-intraductal) and DCIS/IDC tandem lesions. These studies led to the identification of B cell lymphoma-9 as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated β-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However its role in breast cancer progression had not been recognized.
Methods: Microarray and RNA sequencing were utilized to characterize the sequential and temporal changes in mRNA expression during DCIS invasive transition. BCL9 shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, EMT and canonical Wnt signaling. Immunofluorescence of 28 patient DCIS samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. TCGA data was analyzed to assess the status of BCL9 gene alterations in 959 human breast cancers.
Results: Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: ER and PR negative, high nuclear grade, and high HER2. In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of epithelial-mesenchymal transition (EMT). Analysis of the TCGA data showed BCL9 gene to be altered in 26% of breast cancers. This is a significant alteration when compared to ERBB2 (19%) and ESR1 (8%). A significantly higher proportion of basal like invasive breast cancers showed BCL9 amplification.
Conclusion: BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.
Citation Format: Behbod F, Elsarraj H, Hong Y, Valdez K, Chien J, Godwin A, Fields T. Expression profiling of in vivo DCIS progression models identified BCL9 as a molecular driver of invasive progression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-05.
Abstract P2-05-08: p53 deficiency enhances metastatic potential of triple negative breast cancer by promoting growth in primary and metastatic sites
Authors: Powell E , Shao J , Mistry N , Yuan Y , Tieu T , Decker K , Chen H-C , Cai S , Do K-A , Heffernan TP , Edwards J , Piwnica-Worms D , Piwnica-Worms H 
Published: May 2016

Abstract
TP53 is one of the most commonly mutated genes in human cancer. Mutation or loss of TP53 can occur during the early stages of oncogenesis or as a later event as tumors progress to more aggressive forms. We used a patient-derived xenograft (PDX) model of triple negative breast cancer (TNBC) to investigate how p53 deficiency contributes to metastasis. The PDX line was generated by engrafting the primary breast tumor of a patient with TP53 wild-type metastatic TNBC into the humanized mammary fat pad of NOD/SCID mice. Isogenic lines differing only in TP53 status were generated from this model by silencing p53. Here we demonstrate that the p53-proficient and -deficient tumors metastasized from the mouse mammary gland and colonized the lung, liver, bone, brain, and lymph nodes with similar frequency. p53-deficient tumors grew faster in both the primary and metastatic sites as a result of increased mitosis and decreased apoptosis. Circulating tumor cells (CTCs) are currently being evaluated in p53-proficient and –deficient PDX models. Gene expression profiling identified candidate genes with potential clinical relevance that may be responsible for increased tumor growth upon p53 loss in late stage tumors.
This model is also being used to identify genes that promote breast cancer metastasis. To enrich for metastasis, metastatic subpopulations of tumor cells were isolated from lungs and serially passaged in vivo. This serial passaging enriched for metastasis to multiple secondary sites. A transcriptional signature of putative metastasis genes was generated and is being functionalized with high throughput screening in vivo.
Citation Format: Powell E, Shao J, Mistry N, Yuan Y, Tieu T, Decker K, Chen H-C, Cai S, Do K-A, Heffernan TP, Edwards J, Piwnica-Worms D, Piwnica-Worms H. p53 deficiency enhances metastatic potential of triple negative breast cancer by promoting growth in primary and metastatic sites. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-08.
Abstract P2-05-13: A novel mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene that predicts survival of breast cancer patients
Authors: Bii VM , Rae DT , Trobridge GD 
Published: May 2016

Abstract
Breast cancer (BC) is a heterogeneous disease and the second leading cause of malignancy among women in the U.S.. Metastasis of the primary tumor results in poor prognosis and increased mortality and the molecular mechanisms by which metastatic tumors occur are not well understood. Identifying the genes that drive the metastatic process could provide targets for improved therapy and biomarkers to improve outcomes for BC patients. Here, we utilized a replication-incompetent gammaretroviral vector (γRV) to perform a forward insertional mutagenesis screen to identify genes involved in BC metastasis. In this approach, BC cells mutagenized with a γRV were xenotransplanted into the mammary fat pad of immunodeficient mice, and primary tumors and metastases were allowed to develop. Metastatic lesions were collected and analyzed for proviral integration sites to identify vector integration sites and nearby candidate metastasis genes. The γRV has a bacterial origin of replication and kanamycin resistance gene that allows for rescue in bacteria and rapid identification of vector integration sites. Using this approach, we identified the previously described metastasis gene WWTR1, and several other novel candidate metastasis genes including SHARPIN. SHARPIN was then independently validated as a BC metastasis gene in vivo using RNAi. Analysis of patient data showed that SHARPIN expression predicts metastasis-free survival after adjuvant chemotherapy (p &lt; 0.005, Concordance Index = 55.3, Risk Groups Hazard Ratio = 1.87). Our replication-incompetent γRV approach is efficient and has broad potential to identify genes involved in oncogenic processes for BC and other cancers.
Keywords
Insertional mutagenesis screen, Gammaretroviral vector (γRV), Metastasis, Inducible shRNA, Prognostic biomarker.
Citation Format: Bii VM, Rae DT, Trobridge GD. A novel mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene that predicts survival of breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-13.
Abstract P2-05-15: NOS2&COX2 activation of TLR4 & EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation
Authors: Glynn S , Garrrido-Cuesta P , Wink D , Ridnour L , Ambs S , Keane M , Walsh E , Callagy G 
Published: May 2016

Abstract
Background
We seek to further elucidate mechanisms by which inflammatory mediators promote estrogen receptor (ER)-negative breast cancer progression and poor survival. We previously reported association between inducible nitric oxide synthase (NOS2) and poor outcome in ER-negative tumours. In tumours aberrant NOS2 induction facilitates tissue remodelling and stimulates neovascularisation. Also involved in inflammation and wound healing is cyclooxygenase-2 (COX2). We demonstrated that COX2 is associated with Akt activation and poor outcome in ER-negative tumours. We hypothesise that co-expression COX2 with NOS2 in ER-negative tumours amplifies effects of NOS2 on poor outcome, via EGFR and TLR4 signalling loop activation, and polarization of the tumour immune-compartment to pro-tumorigenic M2 phenotype.
Methodology
We determined the association of NOS2 and COX2 co-expression on breast cancer specific survival in ER-negative and triple negative breast tumours (N=102), via immunohistochemistry and cox regression statistical analysis. To explore the mechanism of NOS2 induction of COX2 through transactivation of EGFR, NO donors in combination with EGFR inhibitors were used to determine if NO exposure results in amplified EGFR and PGE2 pro-survival and pro-metastatic signalling in triple negative breast cancer cell lines. Finally, we explored the ability of NO to modify the ability of triple negative breast cancer secretome to induce polarisation of macrophages to a pro-tumorigenic M2 phenotype.
Results
Co-expression of NOS2 and COX2 in triple negative breast cancer results in poor outcome, via activation of pro-survival signalling and modification of the immune compartment to a pro-tumorigenic M2 associated phenotype. NO induces activation of growth factor signalling pathways and secretion of M2 promoting cytokines that induce THP1 macrophage polarization to an M2 phenotype.
Citation Format: Glynn S, Garrrido-Cuesta P, Wink D, Ridnour L, Ambs S, Keane M, Walsh E, Callagy G. NOS2&COX2 activation of TLR4 & EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-15.
Abstract P2-05-21: The AKT-mTOR pathway as a potential organ-specific drug target signature of hepatic metastases from breast cancer
Authors: Pierobon M , Wong S , Reeder A , Anthony SP , Robert NJ , Northfelt DW , Jahanzeb M , Vocila L , Wulfkuhle J , Dunetz B , Aldrich J , Byron S , Craig D , Liotta L , Petricoin EF , Carpten J 
Published: May 2016

Abstract
Background: The identification of organ-specific targetable signatures may help design more effective treatment for patients with metastatic breast cancer (MBC). We took a multi-OMIC approach to assess whether the AKT-mTOR pathway is globally activated during metastatic progression or whether it represents an organ-specific target.
Methods: Snap frozen biopsies from 25 MBC patients enrolled in a prospective phase II trial were used. Sites of metastasis were classified as liver (n=8) and others (n=17), the latter including cutaneous, lung, lymph nodes, and intra-abdominal lesions. Signaling analysis of the 25 cases was performed using Reverse Phase Protein Microarray (RPPA) coupled with Laser Capture Microdissection. Activation of the AKT-mTOR pathway was quantified as phosphorylation of AKT (S473) and the mTOR target p70S6 (T389). Matched exome (WES) and RNASeq data were available for 17 of 25 patients, five with liver metastases. Sequencing data was processed using an in-house developed pipeline to identify somatic events including coding mutations, copy number alterations, gene fusions, and differential expression. Activation of the AKT-mTOR pathway and sequencing data were compared between hepatic and non-hepatic lesions using an integrated RPPA and genomic approach.
Results: Among liver metastases, AKT was activated in 4 of the 8 (50.0%) patients, while 6 of the 8 cases (75.0%) showed activation of p70S6. Sequencing data revealed mutation of PIK3CA in 4 of the 5 liver metastases (80.0%). Three of the PIK3CA mutated specimens with catalytic domain mutations (codons 1023 and 147) demonstrated co-activation of AKT and p70S6, while the fourth case, containing a helical domain mutation (E542K), had activation of p70S6 only. The PIK3CA wild-type liver metastasis demonstrated low activation of AKT and p70S6. For non-hepatic metastases AKT was activated in 2 of the 17 cases (11.8%) and p70S6 in 5 of the 17 patients (29.4%).
Discussion: Although these results need further validation, activation of the AKT-mTOR pathway appears to be a hepatic specific signature in MBC and could be used for the selection of targeted agents for hepatic lesions.
Citation Format: Pierobon M, Wong S, Reeder A, Anthony SP, Robert NJ, Northfelt DW, Jahanzeb M, Vocila L, Wulfkuhle J, Dunetz B, Aldrich J, Byron S, Craig D, Liotta L, Petricoin EF, Carpten J. The AKT-mTOR pathway as a potential organ-specific drug target signature of hepatic metastases from breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-21.
Abstract P2-08-06: Usefulness of the pre-treatment neutrophil-to-lymphocyte ratio in predicting first-line progression free-survival in triple-negative breast cancer patients
Authors: Fontanella C , Fanotto V , Gerratana L , Bonotto M , Cinausero M , Bozza C , Iacono D , Russo S , Andreetta C , Minisini AM , Moroso S , Mansutti M , Fasola G , Puglisi F 
Published: May 2016

Abstract
Background: The neutrophil-to-lymphocyte ratio (NLR) is an independent predictor of poor prognosis inunselected breast cancer patients with NLR &gt;3.3. Moreover, pre-treatment NLR has been associated with disease-free and overal survival (OS) in patients with early triple-negative breast cancer (TNBC). We aimed to determine whether the NLR is predictive of progression-free survival (PFS) in metastatic TNBC.
Methods: We reviewed the records of 48 TNBC patients who received at least one administration of first-line (1°L) chemotherapy for advanced disease from October 2004 to April 2014. The NLR (absolute neutrophil count/absolute lymphocyte count) was calculated from the full blood count routinely performed immediately before the initiation of first-line treatment. The association between categorical variables was calculated by X2 test. PFS (from start of 1°L treatment to disease progression or death) and OS (from start of 1°L treatment to death) were estimated using Kaplan Meier method. Multivariable Cox regression was used to determine the independent prognostic significances of the NLR (co-variables stage at diagnosis, histology, and tumor grade).
Results: NLR was not associated with stage at diagnosis (p=0.214), histology (p=0.597), or tumor grade (p=0.775). After a median follow-up of 10.9 months (range 1.3-54.9), 88.6% of TNBC patients with NLR≤3.3 versus 0.0% of patients with NLR&gt;3.3 had a 1°L PFS&gt;3 months (p&lt;0.001). Similarly, 62.9% of TNBC patients with NLR≤3.3 versus 30.8% of patients with NLR&gt;3.3 had an OS&gt;10 months (p=0.047). Metastatic TNBC patients with NLR≤3.3 had a longer median 1°L PFS (5.2 months) and median OS (13.5 months) compared with patients with NLR&gt;3.3 (1°L PFS 2.1 months, p&lt;0.001; OS 7.7 months, p=0.018). In multivariable analysis, NLR&gt;3.3 is associated with a shorter PFS (hazard ratio [HR] 22.4; 95% confidence interval [CI] 6.7-75.1, p&lt;0.001) and higher risk of death (HR 3.2, 95%CI 1.4-7.4, p=0.005).
Conclusion: Our study showed that pre-treatment NLR is associated with 1°L PFS and OS in patients with metastatic TNBC. However, further investigation in larger series of metastatic TNBC is warranted.
Citation Format: Fontanella C, Fanotto V, Gerratana L, Bonotto M, Cinausero M, Bozza C, Iacono D, Russo S, Andreetta C, Minisini AM, Moroso S, Mansutti M, Fasola G, Puglisi F. Usefulness of the pre-treatment neutrophil-to-lymphocyte ratio in predicting first-line progression free-survival in triple-negative breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-06.