bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-12-01: Characterizing the clinical presentation of individuals with pathogenic variants in a breast/ovarian cancer gene panel
Authors: Vaccari Erica , Yackowski Lauren , Hussong Melanie , Murphy Patricia , Cremona Maria L , Booker Jessica , Hruska Kathleen 
Published: May 2015

Abstract
Background: Hereditary breast and ovarian cancer (HBOC) is a common indication for referral to cancer genetic counselors. Next generation sequencing panels allow for the efficient evaluation of many genes associated with increased risk of these cancers. The purpose of this study is to compare clinical histories of those with pathogenic variants in high risk versus low/moderate risk genes in order to determine which patients might benefit from more extensive testing by a panel approach.
Methods: We queried the results of patients tested at GeneDx for a panel of 21 genes causing increased breast and/or ovarian cancer risk. Data regarding personal and family history of cancer provided on the test requisition forms were analyzed and classified according NCCN guidelines for testing criteria for HBOC syndrome.
Results: Of 1709 individuals referred for testing, 146 (8.5%) tested positive for a pathogenic variant. Of these, 33% percent were found to carry a pathogenic BRCA1/2 variant while 67% tested positive for a pathogenic variant in a gene other than BRCA1/2 (CHEK2: 17%; ATM: 12%; PALB2: 10%; BRIP1: 7%; BARD1: 3%; PTEN: 3%; each of FANCC, MSH2, MSH6, NBN, PMS2, RAD51C, RAD51D: 2%; MLH1: 1%). Eighty-six percent of these individuals were affected with cancer. In the probands with a pathogenic BRCA1/2 variant, 66% were diagnosed with breast cancer and 22% with ovarian cancer compared to the probands with a pathogenic variant in a gene other than BRCA1/2 of whom 84% had a history of breast cancer and 17% had ovarian cancer. The highest number of breast cancer diagnoses were found, in decreasing order, in association with pathogenic variants in BRCA1 (20), CHEK2 (20), ATM (17), PALB2 (14), BRCA2 (13), and BRIP1 (12). The greatest number of ovarian cancers were identified, in decreasing order, in association with pathogenic variants in BRCA2 (8), BRCA1 (3), CHEK2 (3), and ATM (3). Furthermore, all of the individuals with pathogenic variants met NCCN guidelines for HBOC.
Conclusion: A high yield of pathogenic variants were found in genes other than BRCA1/2. Data analysis also shows that individuals with a pathogenic variant in genes other than BRCA1/2 did not have a notably less severe clinical history than those pathogenic variants in BRCA1/2. As all individuals tested meet NCCN guidelines for HBOC testing, panel testing should be considered in this population.
Citation Format: Erica Vaccari, Lauren Yackowski, Melanie Hussong, Patricia Murphy, Maria L Cremona, Jessica Booker, Kathleen Hruska. Characterizing the clinical presentation of individuals with pathogenic variants in a breast/ovarian cancer gene panel [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-01.
Abstract P4-15-17: A novel targeted engineered toxin body for treatment of HER2 positive breast cancer
Authors: Willert Erin K , Rajagopalan Sangeetha , Robinson Garrett L , Brieschke Brigitte , Erdman Jennifer , Null William , Higgins Jack P 
Published: May 2015

Abstract
The HER2 receptor is overexpressed in 20-30% of breast cancers. HER2 overexpression in breast cancer has been successfully targeted by both antibody and antibody-drug conjugate (ADC) approaches. The recently approved trastuzumab-emtansine (T-DM1, Kadcyla) ADC has shown promising clinical results in patients refractory to trastuzumab (Herceptin). Because DM1 is a chemotherapeutic and refractory breast cancer patients have typically progressed through several rounds of chemotherapy, we are developing a new targeted therapy approach utilizing a novel mechanism of action. MT-2H74 is an engineered toxin body comprised of the trastuzumab single chain variable fragment (scFv) and a modified ribosome-inactivating protein derived from Shiga-like toxin 1 A (SLT-1A). We have proprietarily modified SLT-1A for reduced immunogenic potential and increased stability. MT-2H74 selectively binds HER2-expressing breast cancer cells, and exerts a potent HER2-specific cytotoxic effect on several tested cell lines. MT-2H74 demonstrates effective cell kill at picomolar concentrations on cell lines expressing high levels of HER2 and is not cytotoxic to HER2 negative control cell lines. Multi-drug resistance transporter 1 (MDR1) has been reported to confer resistance to chemotherapeutic and ADC treatments, such as direct T-DM1 cell kill; however, MT-2H74 displays cytotoxic activity against HER2 transfected NCI/ADR-RES cells known to express MDR1. Murine models are under investigation to determine therapeutic efficacy in vivo. MT-2H74 is a promising HER2-targeted therapeutic agent against breast carcinomas with a unique mechanism of action and is currently under further development.
Citation Format: Erin K Willert, Sangeetha Rajagopalan, Garrett L Robinson, Brigitte Brieschke, Jennifer Erdman, William Null, Jack P Higgins. A novel targeted engineered toxin body for treatment of HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-17.
Abstract P5-04-12: Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in breast tumors
Authors: Freimark Bruce , Gong Jian , Nguyen Van , Yin Shen , Archer Rich , Hutchins Jeff 
Published: May 2015

Abstract
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells. PS exposure becomes enhanced in response to chemotherapy, irradiation, and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs), immature dendritic cells, and M2-like macrophages as well as the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumor cells and their secreted microparticles triggers an Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses the immunosuppressive PS meditated checkpoint, thereby enhancing anti-tumor immunity. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using breast tumors in immune competent mice, we demonstrate PS targeting antibodies enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies in the presence and absence of conventional chemotharapy. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.
Citation Format: Bruce Freimark, Jian Gong, Van Nguyen, Shen Yin, Rich Archer, Jeff Hutchins. Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in breast tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-12.
Abstract P5-05-11: Growth hormone receptor silencing sensitizes triple negative breast cancer cells to chemotherapy
Authors: Arumugam Arunkumar , Subramani Ramadevi , Nandy Sushmita , Lopez-Valdez Rebecca , Lakshmanaswamy Rajkumar 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer, which, accounts for approximately, 15% of breast cancers diagnosed in women. TNBCs lack expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor type 2 (HER2). So, there are no targeted therapies available for TNBCs and chemotherapy is the main choice for the treatment. Although the tumors respond initially, large numbers of patients develop recurrence due to chemoresistance. Growth hormone receptor (GHR) is a class I cytokine receptor, which plays vital role in the development of chemoresistance. Studies have shown that silencing of GHR sensitizes breast cancer cells to chemotherapeutic drugs. In this study we investigated the impact of GHR silencing in TNBC cells and further analyzed the possible mechanisms associated with GHR silencing induced sensitization. GHR was silenced using small interfering RNAs in metastatic breast cancer cells MDA MB 231 and MDA MB 468. Molecular analyses were performed to determine apoptosis, cytotoxicity, colony formation, invasion and migration in GHR knockdown cells. Silencing of GHR induced cytotoxicity and apoptosis in TNBC cells. Migratory and invasive potentials were drastically reduced in GHR silenced cells. Moreover, epithelial to mesenchymal transition markers were significantly down regulated by GHR siRNA treatment. GHR targeting significantly increased the efficiency of docetaxel against TNBC cells. Inhibition of GHR also inhibited the expression of BCRP, which is frequently associated with the development of chemoresistance in breast cancer. Further, treatment with GH induced the overexpression of drug transporter proteins involved in chemoresistance. Inhibition of GHR in breast cancer cells reverted the expression of these proteins and sensitized the cells to docetaxel. These findings support the hypothesis that targeting GHR could have a potential new therapeutic approach to overcome chemoresistance in TNBCs.
Citation Format: Arunkumar Arumugam, Ramadevi Subramani, Sushmita Nandy, Rebecca Lopez-Valdez, Rajkumar Lakshmanaswamy. Growth hormone receptor silencing sensitizes triple negative breast cancer cells to chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-05-11.
Abstract P5-05-13: Obesity confers chemotherapy resistance in triple negative breast cancer cells
Authors: Lehrmann Victoria R , Bowers Laura W , Brenner Andrew J , deGraffenried Linda A 
Published: May 2015

Abstract
Introduction: Obesity is associated with a more aggressive breast cancer and a worse outcome following chemotherapy treatment. Triple negative breast cancer is a highly aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and human epidermal growth factor-2 (HER2) receptors. This subtype has also been correlated with a worse prognosis. This study aims to investigate the impact of obesity on triple negative breast cancer cells’ response to chemotherapy treatment and elucidate potential therapeutic options to improve response.
Methods: Sera was collected from breast cancer patients at the Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio (UTHSCSA) and pooled according to body mass index (BMI) category (Control:18.5 to 24.9 kg/m2; Obese:≥30 kg/m2). MDA-MB-231 cells, a triple negative breast cancer cell line, were grown in serum-free media supplemented with 2% obese or control patient sera to create an in vitro model of obesity. The effects of docetaxel, a chemotherapeutic agent, on cell viability in the presence of obese versus control sera were examined by MTT. Modulation of B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and mammalian target of rapamycin (mTOR) were evaluated as possible mechanisms for obesity-induced chemotherapy resistance.
Results: The obese sera significantly reduced sensitivity of the MDA-MB-231 cells to docetaxel. In fact, there was no variance in the viability level of cells grown in obese patient sera for 96 hours with and without docetaxel treatment. The mechanism for resistance does not appear to involve Bcl-2 or COX-2, previously implicated in docetaxel resistance. Intriguingly, suppression of mTOR did provide significant benefit, in agreement with our previous in vivo studies investigating obesity and aromatase inhibitor (AI) response. The role of the mTOR pathway in modulating therapeutic response is still being investigated.
Conclusion: Exposure to obesity-associated circulating factors confers chemotherapy resistance in triple negative breast cancer cells. Further research will be conducted to determine the mechanism by which obesity promotes chemotherapy resistance and whether modulation of the mTOR pathway will provide significant benefit.
Citation Format: Victoria R Lehrmann, Laura W Bowers, Andrew J Brenner, Linda A deGraffenried. Obesity confers chemotherapy resistance in triple negative breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-05-13.
Abstract P5-15-12: Clinico-biological characteristics of patients surviving more than two years with metastatic breast cancer (MBC): Results of a transversal national multicentric survey
Authors: Loirat Delphine , Tlemsani Camille , Arrondeau Jennifer , Bellesoeur Audrey , Le Tourneau Christophe , Rousseau Benoit 
Published: May 2015

Abstract
Introduction:
MBC cancer patients may have prolonged survival, and MBC cancers can be considered as a chronic disease. The main goal of the present study was to describe the clinico-biological features of patients surviving more than two years with MBC.
Method: During 4 months, we conducted a national multicentric survey about patients aged ≥ 18 in metastatic setting (all solid tumors) for more than 24 months. Clinico-biological data from 200 patients were collected in 39 French centers. Preliminary results of MBC patients (N=88, 87 women/one man) are presented.
Results: Most of them were ductal carcinoma (88%), expressing hormonal receptor HR (77%). 43% of tumors overexpressed HER2 (HER2+ tumors: 43%; Triple negative tumors: 6%). Median age at MBC diagnosis was 53 years [29-85]. 18% had metastatic disease at diagnosis and 82 % were localized with a disease-free survival of 65 months [4-312]. Median time of MBC disease was 4,5 years [2-20]. At the time of MBC diagnosis, 64% of patients were not single; 55% were working while 30% were retired. At data collection, 89% of non-single patients were not separated, and 43 % of working patients at diagnosis were still working.
Mean number of treatment lines in advanced disease was 4.7 [1-13]. 89% of MBC patients received at least one chemotherapy, 68% hormonotherapy, 70% targeted therapy and 38% had been included in at least one clinical trial. 97% of patients had a local treatment of their primary tumor. Concerning metastasis, 23% had a surgical treatment and 40% radiotherapy treatment. 80% of patients remain with PS of 0 or 1. Only 9% of patients were followed by a palliative care team, 24% by a psychologist and 23% by a nutritionist.
Conclusion: Our preliminary results of suggest that an important proportion of MBC cancer patients who live more than 2 years are young, have been treated with chemotherapy, hormonal and targeted therapy, have participated to clinical trials and still have good performance status. No change in marital status was observed. Half of working patients at MBC diagnosis continue to work. Few of them received palliative care. This study may help to better describe long-term survivors with MBC, and socio-medical burden as cancer became a chronic disease.
Citation Format: Delphine Loirat, Camille Tlemsani, Jennifer Arrondeau, Audrey Bellesoeur, Christophe Le Tourneau, Benoit Rousseau. Clinico-biological characteristics of patients surviving more than two years with metastatic breast cancer (MBC): Results of a transversal national multicentric survey [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-12.
Abstract P6-02-05: Systemic statin treatment and intra-tumoral lipid metabolism - report from a window-of-opportunity breast cancer trial
Authors: Feldt Maria , Menard Julien , Belting Mattias , Borgquist Signe 
Published: May 2015

Abstract
Background:
In recent years, attention has been drawn to the plasma cholesterol lowering drugs statins (HMGCR-inhibitors) due to their exertion of pleiotropic intratumoral effects such as induction of apoptosis and inhibition of proliferation, generating a possible utility in cancer prevention and treatment. However, the molecular mechanisms are complex and remain largely undefined. The aim of this study was to assess the statin induced changes of the intra-tumoral levels of cholesterol, to gain enhanced understanding of the role of the mevalonate pathway in cancer lipid metabolism.
Methods:
The study was designed as a window-of-opportunity trial, where 50 patients with primary invasive breast cancer were included, and treated with 80 mg of atorvastatin/day for two weeks, between the time of diagnosis and surgery. From frozen tumor tissue samples pre- and post atorvastatin treatment, lipids have been extracted, and the cholesterol levels have been measured using a cholesterol quantification assay. In vitro experiments on MCF7-cells treated with atorvastatin was used for optimization and comparison on the cellular level.
Results:
42 patients completed all study parts, and assessment of the cholesterol levels in the paired frozen tumor tissue was achievable in 14 pairs. Following atorvastatin treatment, the intra-tumoral levels of total cholesterol was significantly increased (P=0.035), with an increase in 11 of the pairs, and decrease in 3 pairs. Similar findings were observed in the in vitro experiments, demonstrating increased levels of total cholesterol and storage in lipid droplets in the cells treated with atorvastatin.
Conclusions:
We have earlier reported statin-induced anti-proliferative effects in breast cancer. This study shows a statin-induced increase in the intra-tumoral cholesterol levels, which may however rely on the increased cholesterol storage in lipid droplets, a phenomenon observed in the in vitro experiments with MCF7 cells treated with atorvastatin. Our results suggest that the anti-proliferative effects exerted by statins reluctantly reduce cell metabolism and consequently increase the storage of e.g. lipids.
Citation Format: Maria Feldt, Julien Menard, Mattias Belting, Signe Borgquist. Systemic statin treatment and intra-tumoral lipid metabolism - report from a window-of-opportunity breast cancer trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-02-05.
Abstract P6-02-09: Structure-activity relationship of ruthenium (Ru) complexes to inhibit breast cancer growth and metastasis
Authors: Iida Joji , Prazo Marc L , Lu Yifeng , Bell-Loncella Elisabeth T , Shriver Craig D 
Published: May 2015

Abstract
Previous studies demonstrated that transition metal complexes inhibit cancer cell growth. We have examined a series of ruthenium (Ru (II)) complexes for their ability to inhibit growth of breast cancer cells. Among three complexes with the general formula [Ru(η6-p-cym)(N-N)Cl]+ tested for their abilities to inhibit MDA-MB-231 cell growth, the complex with o-phenalyenediamine (o-pda) as the bidentate nitrogen donor (N-N) ligand, [Ru(η6-p-cym)(o-pda)Cl]+, showed significant inhibitory activity in both a concentration- and a time-dependent manners. Although [Ru(η6-p-cym)(o-pda)Cl]+ inhibited growth of various human cancer types such as MCF-7 (breast), SK-Br3 (breast), B-cell lymphoma (Raji), osteosarcoma (HT1080), and melanoma (Bowes) cells, two TN breast cancer cells, HCC1806 and HCC38, were resistant to this treatment, suggesting cell-type specific functions of [Ru(η6-p-cym)(o-pda)Cl]+ for inhibiting cell growth. When MDA-MB-231 cells were treated with [Ru(η6-p-cym)(o-pda)Cl]+, both cleavage of caspase-3 and release of HMGB-1 into conditioned medium increased in a concentration dependent manner, suggesting [Ru(η6-p-cym)(o-pda)Cl]+ induced both apoptosis and necrosis processes. Importantly, [Ru(η6-p-cym)(o-pda)Cl]+ synergistically inhibited MDA-MB-231 cell growth with cyclophosphamide but not doxorubicin and paclitaxel. These results suggest that [Ru(η6-p-cym)(o-pda)Cl]+ is a potent tumor growth inhibitor per se and enhances tumoricidal activity of chemotherapeutic agents such as cyclophosphamide. Thus, Ru (II) complexes are promising anti-cancer drugs which could be used alone and/or in combination with chemotherapeutic agents for breast cancer patients. The opinion and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense.
Citation Format: Joji Iida, Marc L Prazo, Yifeng Lu, Elisabeth T Bell-Loncella, Craig D Shriver. Structure-activity relationship of ruthenium (Ru) complexes to inhibit breast cancer growth and metastasis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-02-09.