bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors of Breast Cancer in Relation to Classical Histopathology.
Authors: Olsson H. , Ellberg C. 
Published: December 2010

Abstract
Background: Classical histopathological groups of breast cancer have recently been less studied in relation to etiological factors than the new more molecular oriented taxonomy such as luminal A,B, Her2-neu and basal type of breast cancer. In the present investigation we have related histopathology to breast cancer risk factors to shed light on the possibility that the classical taxonomy may have a biological meaning presently not fully recognized.Material and methods:In 1677 consecutive breast cancer patients the following risk factors were related to histopathology; parity, HRT use, breast cancer screening, vertical inheritance of breast cancer (possibly dominant), horizontal inheritance of breast cancer (possibly recessive), and germline mutation carrier status (BRCA1, BRCA2, CDKN2A, p53). Patients with mixed tumor types were excluded. All analyses were age adjusted and factors were simultaneously adjusted for.Results: A germline mutation was present in 1.5% of the cases. A relationship between medullary tumors and BRCA1 mutations was seen. Germline mutation carriers were in further analysis excluded. Among remaining cases a vertical family history was present in 23% and a horizontal one in 5% of the cases. A horizontal family history was significantly associated with tubular tumor type (OR=3.9, 1.4-10.4) and age, and non-significantly associated with tumor progesterone receptor content (OR=1.7, 0.8-4.0), and lobular tumor type (OR=1.4, 0.6-3.2). A vertical family history was significantly related to tumor multifocality (OR=2.3, 1.5-3.5), tumor bilaterality (OR=2.1, 1.4-3.0) and screening detection (OR=1.5, 1.1-2.1), while age and a tubuloductal tumor type (OR=0.5, 0.3-0.9) were significantly negatively related. Patients with ductal and mucinous tumors had significantly fewer children (OR=0.9, 0.8-0.99) and (OR=0.6, 0.4-0.8) respectively, while patients with comedocancer had significantly more children (OR=1.2, 1.1-1.4) .HRT use increased non significantly the risk for lobular breast cancer, while significantly being related to mixed lobular cases.Conclusion.These results demonstrate that classical histopathological groups are related to breast cancer risk factors and indeed may have a biological relationship to etiological factors.Especially factors related to parity, HRT use and family history seem to relate to different histopathological groups. Molecular signatures as well as classical histopathology should be used in future risk factor studies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6065.
Breast-Conserving Surgery Is Preferred Though Not Commonly Performed in an Urban Region of China.
Authors: Zhang G. , Lian R. , Yue R. , Wang G. , Liang X. , Gao J. 
Published: December 2010

Abstract
Introduction: Breast-conserving surgery (BCS) followed by radiation therapy has proven to be as effective as modified radical mastectomy, and has, therefore, been considered as the standard treatment for patients with localized breast cancer in Western societies. However, performance of BCS for the treatment of breast cancer in China is not as common as in Western countries. This study was to evaluate healthy women's attitudes towards BCS in an urban region of China.Method: Between February and March 2009, three hundred and fifty healthy women from three urban suburbs of Taiyuan city in Northern China were invited to complete a self-administered questionnaire. Participants' characteristics, including age, education, occupation, and attitudes towards breast cancer treatment options and involvement of treatment decisions, were collected and analyzed.Results: Three hundred and fifteen women returned the questionnaire. The response rate was 90%. The median age of the participants was 31.2 years old (range: 16 – 69 years old). Among them, 49.2% were married, 27.9% had received high levels of education, and 87.3%, 95.2% and 71.4% would like to know the disease status, to involve making treatment decisions, and to accept BCS, respectively, if they were diagnosed with breast cancer. Women aged above 45 years were more likely to choose BCS compared with those less than 45 years old (73.4% vs 61.5%, P = 0.08). There was no association between choices of surgical approaches and levels of education or occupation. As for breast cancer treatment information sources, 76.8% of the participants mentioned oncologists, followed by the internet (12.1%), friends, and media (10.8%). Almost all responders (93.3%) would like to attend hospitals specialized in cancer treatment if breast lumps were detected.Conclusion: Although only 7.1% of breast cancer patients attending a specialized tumor hospital in Taiyuan city underwent BCS, the current study indicate that most women in Northern China would prefer BCS to mastectomy if they were diagnosed with breast cancer. Therefore, further occupational training is warranted for oncologists in China so that optimal treatments for patients with breast cancer can be carried out.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6077.
A Phase I Pilot Study of the Oral mTOR Inhibitor RAD001 in Combination with Capecitabine for Metastatic Breast Cancer.
Authors: Chen C. , Chen M. , Imaoka R. , Svahn T. , Guardino A. 
Published: December 2010

Abstract
Background:RAD001 is an oral inhibitor of mTOR, an intracellular protein kinase downstream of the PI3K/Akt signaling pathway. There is evidence to suggest that Akt promotes breast cancer resistance to cytotoxic treatment and thus targeting this pathway with RAD001 may increase the efficacy of standard chemotherapy. We combined RAD001 in a Phase I dose escalation study with Capecitabine (oral fluorpyrimidine), as treatment of metastatic breast cancer. This study evaluated the oral combination for tolerability and safety. Pharmacokinetics of RAD001 was examined in all dosing cohorts.Methods:This was a single center, Phase I trial. Eligible patients had stage IV breast cancer, have not received endocrine or chemotherapy for 3 weeks prior to initiation and not receiving concurrent endocrine therapy. Patients must not have received prior therapy with capecitabine or an mTOR inhibitor and up to 3 prior chemotherapy regimens were allowable. Pharmacokinetic data are collected weekly for first 2 cycles.All patients received capecitabine (825 mg PO BID) and RAD001 in 3 dose-escalation cohorts: 2.5 mg every other day (Cohort 1), 2.5 mg daily (Cohort 2) and 5 mg daily (cohort 3). The primary endpoint is to determine the DLT of RAD001 + capecitabine, secondary endpoints include tumor response. Treatment continues until disease progression or unacceptable toxicity. Efficacy assessed every 6 weeks for first 4 cycles, then every 9 weeks until end of the 1st year of treatment, then every 12 weeks after.Results: As of April 2009, 12 patients with a median age of 58 years (range 34-75) have been treated at 3 dose levels: 3 in the 1st cohort, 6 in the 2nd cohort and 3 in the 3rd cohort. Toxicities in cohort 1 were generally manageable and expected. They most commonly consisted of nausea, hand-foot syndrome and elevated LFTs. 2 patients in cohort 2 had a grade 3/4 neutropenia and responded to dose reduction. 1 patient had a grade 3/4 elevated lipid panel. Other adverse events (all grade 1/2) included leukopenia, neutropenia, anemia, hypoalbuminemia, elevated LFTs, nausea, hand-foot syndrome, fatigue, sensory neuropathy, and thrombocytopenia. Of the 9 evaluable patients, the clinical benefit rate (CR+PR+SD ≥ 24 weeks) in this heavily pretreated group is 44%. No patient had DLT during cycle 1. 3 patients remain on treatment. Enrollment to the 3rd cohort continues.Conclusion:The all-oral regimen of RAD001 with capecitabine is well tolerated. The maximal tolerated dose (MTD) after 3 dose escalations was not reached. The maximal dose of 5 mg per day of RAD001 was well tolerated. Final toxicity data and preliminary efficacy will be presented at the meeting.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6112.
3,3'-Diindolylmethane Inhibits Activation of Akt through Inhibition of Hepatocyte Growth Factor Receptor c-Met Signaling.
Authors: Hantz H. , Lee K. , Bjeldanes L. 
Published: December 2010

Abstract
Background: 3,3'-Diindolylmethane (DIM), the major acid condensation product of indole-3-carbinol, is a promising anticancer compound that is bioavailable, non-toxic, and easily obtainable. Although DIM has strong anticancer activity against breast cancer cells in vitro and in vivo, the exact mechanism for this activity is not known. We and others have found that DIM inhibits activation of the Akt pathway in breast cancer cells. Akt is a serine threonine protein kinase involved in many important cellular functions including proliferation and cell survival. Akt is active when phosphorylated at serine-473 and threonine-308. In breast cancer cells, Akt can be activated by various stimuli, including signaling from growth factor receptors like the hepatocyte growth factor (HGF) receptor c-Met, which is often overexpressed in breast cancer. In this project, we show that c-Met is an upstream point of inhibition of the Akt pathway by DIM.Materials and Methods: When MDA-MB-231 breast cancer cells reached 70-80% confluency, we serum-starved them by reducing the fetal bovine serum concentration in the media from 10% to 1% for 20 hours and then treated with DIM or the vehicle control DMSO for 4 hours or the indicated time. When using recombinant growth factors to activate Akt or c-Met, we incubated cells in medium containing no fetal bovine serum and added the growth factors for 10 minutes after incubation with DIM. To analyze protein expression and protein phosphorylation we performed Western blotting. To analyze c-Met kinase activity we used a commercially available kit.Results: DIM does not inhibit activation of Akt downstream of either epidermal growth factor or insulin-like growth factor-1. However, DIM does inhibit Akt activation downstream of HGF and of fetal bovine serum. DIM inhibits tyrosine phosphorylation of c-Met at Y1349 and Y1234/1235. DIM does not affect total c-Met protein or mRNA levels and does not directly inhibit c-Met kinase activity.Discussion: While we have determined that DIM inhibits c-Met phosphorlyation, and therefore HGF signaling, the mechanism of this inhibition requires further study. We hypothesize that DIM induces serine phosphorylation of c-Met, since c-Met can be inhibited by reactive oxygen species (ROS)-induced phosphorylation of serine-985 by protein kinase C (PKC), and DIM increases ROS levels in cells.Components of the Akt pathway are frequent targets for mutations in breast cancer and c-Met and its ligand HGF are associated with lower survival and increased risk of distant metastases in breast cancer. This project represents an important step in determining the mechanism of action for DIM, a promising phytochemical for the treatment of breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6117.
The Role of microRNA Genes in Breast Cancer Progression and Metastasis.
Authors: Johnstone C. , Lucas E. , Kusdra L. , Goga A. , Anderson R. 
Published: December 2010

Abstract
MicroRNAs influence tumor progression and metastasis via action as metastasis promoting genes (for example mir-373 and mir-520) or metastasis suppressor genes (for example mir-335). To identify additional microRNAs capable of driving breast cancer metastasis in vivo, we employed a functional genomics screen using the '4T1' syngeneic (Balb/c) mouse model of breast cancer progression. Approximately 400 microRNA sequences were subcloned into the pMSCV_puro retroviral expression vector and the resultant microRNA expression library transduced into fluorescent non-metastatic 67NR-pMSCV_mCherry and mildy-metastatic 66cl4-pMSCV_mCherry cells and selected with puromycin. The transduced cell lines were then implanted into the mammary fat pads of 20 syngeneic Balb/c mice per cell line. Following establishment of primary tumors, the primary tumors and secondary organs (lung, liver, spine, femurs), including any overt metastatic deposits, were dissected under a fluorescent stereomicroscope and the microRNA inserts amplified from the integrated retroviral genome by PCR.In an alternative approach, we have studied two populations of MDA-MB-231 human breast cancer cells that exhibit different behavior in vitro and in vivo to elucidate processes involved in cellular invasion and metastasis. A late-passage MDA-MB-231 (231variant) population formed invasive clusters when embedded in Matrigel, whereas early-passage (P3) MDA-MB-231 (231) cells did not. Moreover, 231v cells were more motile than 231 cells and showed enhanced tumorigenicity when grown as subcutaneous xenografts in nude mice, whereas proliferation and apoptotic response were indistinguishable between the two lines in vitro. Molecular characterization of the two cell populations cultured in 3D by array-based gene expression profiling revealed elevated expression of NF kappa B target genes in 231v cells (IL1A, IL1B, IL6, PTX3, NR4A2, HMOX1, FLIP). MicroRNA array analysis of 3D cultures also revealed marked induction (approximately 8-fold) of the related NF kappa B target microRNAs, mir-146a and mir-146b (Figure 1). Further evaluation of a panel of human breast cancer cell lines revealed that mir-146a and mir-146b were dramatically elevated in metastatic human breast cancer cell lines that display both epithelial-to-mesenchymal transition and high NF kappa B activity (MDA-MB-231, Hs578T, MDA-MB-436), compared to non-metastatic lines. Experiments to elucidate the function of mir-146a and mir-146b during breast cancer progression are underway. Figure 1: TaqMan qPCR analysis of mir-146a and mir-146b expression in 231 and 231v cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6142.
The Secretory Small GTPase Rab27B Regulates Invasive Tumor Growth and Metastasis through Extracellular Heat Shock Protein 90α.
Authors: Hendrix A. , Maynard D. , Pauwels P. , Braems G. , Denys H. , Van den Broecke R. , Van Belle S. , Cocquyt V. , Bracke M. , Seabra M. , Gahl W. , De Wever O. , Westbroek W. 
Published: December 2010

Abstract
Background: Vesicle exocytosis, controlled by secretory GTPases such as Rab27B, delivers critical pro-invasive factors into the tumor microenvironment. The biological role and expression status of Rab27B in breast cancer was unknown.Methods: Rab27B was studied in human breast cancer cells (MCF-7, T47D, ZR75.1) using GFP-fusion constructs, including Rab27A and Rab27B point mutants defective in GTP-binding or geranylgeranylation. In cell culture, cell-cycle progression was evaluated by flow cytometry and Western blotting, invasion was assessed using Matrigel and collagen type I substrates. Orthotopic tumor growth, local invasion and metastasis were analyzed in mouse xenograft models. Mass spectrometry was performed to identify Rab27B-secreted pro-invasive factors. Rab27B levels in clinical breast cancer were analyzed by quantitative reverse transcription-polymerase chain reaction (n=20) and immunohistochemistry (n=60). Statistical tests were two-sided.Results: Rab27B-upregulation promoted G1/S phase cell cycle transition, F-actin reorganization and invasion in cell culture, and invasive tumor growth and peritoneal metastasis in a xenograft mouse model (at 10 weeks, survival of MCF-7 GFP vs GFP-Rab27B injected mice was 100% vs 62.5%, P=0.0307). Proteomic analysis of purified Rab27B-secretory vesicles and the secretome of Rab27B-expressing breast cancer cells identified heat shock protein (HSP)90α as key pro-invasive factor. HSP90α secretion occurred in a Rab27B-dependent manner and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. In clinical samples, upregulation of endogenous Rab27B mRNA and protein correlated with lymph node metastasis (P=0.0002) and differentiation grade (P=0.0014) in estrogen receptor (ER)-positive human breast tumors.Conclusions: Rab27B, a new prognostic marker for ER-positive breast cancer, regulates invasive growth and metastasis.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6144.
Programmed Cell Death 4 (PDCD4), a Novel Inhibitor of Leptin-Induced Breast Cancer Cell Invasion.
Authors: Gonzalez-Villasana V. , Gonzalez-Villasana V. , Nieves-Alicea R. , McMurtry V. , Tari A. , Gutierrez-Puente Y. 
Published: December 2010

Abstract
Obesity is known to increase the risk of breast tumor development in post menopausal women. Leptin, an adipokine produced in high levels in obese individuals, has been found in breast tumors and been linked with increased incidence of breast cancer metastasis. Breast cancer metastasis is directly associated with breast cancer cell invasion. Previously we demonstrated that leptin increases breast cancer cell invasion. Here we determined whether PDCD4, a novel tumor suppressor, could block leptin-induced breast cancer cell invasion. In MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4), leptin failed to induce invasion, in contrast to the parental MCF-7 cells, indicating that PDCD4 blocks leptin-induced breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Pretreatment of MCF-7/PDCD4 cells with TIMP-2 siRNA allowed leptin to induce the invasion of MCF-7/PDCD4 cells, thus indicating that knocking down TIMP-2 expression reversed the anti-invasive effects of PDCD4. The levels of phospho-ERK and phospho-STAT3 were higher in MCF-7/PDCD4 cells treated with leptin and TIMP-2 siRNA than in MCF-7/PDCD4 cells treated with leptin and non-silencing control siRNA. Yet the levels of phospho-JNK were similar in leptin-treated MCF-7/PDCD4 cells transfected with TIMP-2 siRNA or non-silencing control siRNA. Here we report the novel findings that PDCD4 increases TIMP-2 expression to block leptin-induced breast cancer cell invasion by suppressing ERK and STAT3 activities. Metastasis is the primary cause of breast cancer mortality. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity-related breast tumor progression and prolong patients' lives.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6153.
Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC→T) with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC→TH) with Docetaxel, Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast Cancer Patients: BCIRG 006 Study.
Authors: Slamon D. , Eiermann W. , Robert N. , Pienkowski T. , Martin M. , Rolski J. , Chan A. , Mackey J. , Liu M. , Pinter T. , Valero V. , Falkson C. , Fornander T. , Shiftan T. , Olsen S. , Buyse M. , Kiskartalyi T. , Landreau V. , Wilson V. , Press M. , Crown J. ,   on Behalf of BCIRG006 Investigators
Published: December 2010

Abstract
Background: Evaluation of the long-term benefit of biologically-based regimens of trastuzumab in the early breast cancer population, and optimization of trastuzumab integration to maximize efficacy and minimize cardiac toxicity.Material and Methods: We randomized HER2-positive (FISH+) breast cancer patients with axillary lymph node positive or high risk negative, to either standard AC (60/600 mg/m2 q3wk x4) followed by T (100 mg/m2 q3wk x 4) or two trastuzumab-containing regimens; AC followed by T with trastuzumab x 1 year or TCarbo (75 mg/m2/AUC6 q3wk x 6) with trastuzumab x 1 year. Patients were prospectively stratified by number of positive nodes (0, 1-3 vs 4+) and hormone receptor status. Patients with ER and/or PR positive (HR+) tumors received hormone-directed therapy for 5 yrs after chemotherapy. The primary endpoint was disease-free survival (DFS) with 80% power (0.05 significance level) to detect an absolute difference of 7%. Secondary endpoints include overall survival (OS) and safety, including cardiac toxicity (symptomatic events and asymptomatic LVEF decline). The first two protocol-specified analyses for this study were performed at 300 and 450 disease-related events. We now report the results of the third protocol-specified analysis conducted after 650 events, expected by end of June 2009.Results: A total of 3222 patients (1072 in AC-T, 1076 in AC-TH and 1074 in TCH) were recruited between April 2001 and March 2004. Baseline characteristics of the study population will be included. Cox analysis of DFS and OS (unadjusted and adjusted for nodal status) and cardiac toxicity data will be presented for the three treatment arms.Discussion: The results of this trial help define the role of trastuzumab in the breast cancer HER2-positive adjuvant setting, as well as the risks/benefits of adjuvant trastuzumab within the context of overall safety including cardiac toxicity. This latter objective is of particular importance given that many of these women may be cured of their disease in the adjuvant setting.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 62.
Do the ASCO/CAP 2007 HER2 Testing Guidelines Improve Prediction of Benefit to Adjuvant Trastuzumab?: Data from North Central Cancer Treatment Group N9831 Adjuvant Trial.
Authors: Perez E. , Reinholz M. , Dueck A. , Tenner K. , Davidson N. , Gralow J. , Harris L. , Kutteh L. , Jenkins R. , Chen B. 
Published: December 2010

Abstract
Background: In 2007, the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) recommended new guidelines to define HER2 positivity by immunohistochemistry (3+ IHC: uniform intense membrane staining of &gt;30% of invasive tumor cells) or fluorescent in situ hybridization (FISH+: HER2/CEP17 ratio &gt;2.2). The original criteria used for enrollment in the pivotal N9831 trial conducted from 2000-2005 were IHC&gt;10% (3+) or FISH ≥2.0.Purpose: To investigate the impact of the ASCO/CAP guidelines on patient (pt) eligibility and disease free survival (DFS) compared to the originally used FDA-approved definitions.Patients/Methods: This analysis included 2268 patients from the HER2+ N9831 adjuvant trastuzumab phase III trial. IHC was centrally performed at the Mayo Clinic using the DAKO HercepTest™ and was re-analyzed to determine the percent of tumor cells with 0, 1+, 2+, and 3+ staining intensities. DFS was compared between pts randomized to standard chemotherapy +/- concurrent trastuzumab (Arms A and C of the trial) within IHC/FISH subgroups using Cox proportional hazards regression stratified by hormone receptor and nodal status.Results: Based on 2268 pts, 83 pts (3.7%) were 3+ by FDA-approved guidelines but not 3+ by the ASCO/CAP guidelines. Among these pts, 77% (64/83) were FISH amplified centrally by ASCO/CAP guidelines. Only 1.5% (34/2268) of pts eligible under FDA-approved definitions from N9831 in this sample set would not meet the ASCO/CAP guidelines. In 1441 patients randomized to standard chemotherapy +/- concurrent trastuzumab, the exploratory DFS hazard ratio (HR) associated with trastuzumab in IHC/FISH subgroups were as follows: ASCO/CAP HER2+ HR=0.59 (95% CI: 0.47-0.75; p&lt;0.001); FDA-approved HER2+ HR=0.60 (95% CI: 0.47-0.75; p&lt;0.001); ASCO/CAP HER2 normal(not positive) HR=0.74 (95% CI: 0.35-1.57; p=0.43); and FDA-approved HER2 normal HR=0.53 (95% CI: 0.22-1.26; p=0.15).Conclusions: A small percentage (1.5%) of N9831 patients did not meet ASCO/CAP 2007 guidelines when applied retrospectively. Trastuzumab effect appeared similar for HER2+ patients regardless of ASCO/CAP or FDA-approved guidelines. Additional DFS analyses by IHC/FISH subgroups will be presented. We gratefully acknowledge support from the Breast Cancer Research Foundation, Genentech, and NIH CA25224 for this study.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 701.