bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of Stereotactic Radiosurgery in the Management of Brain Metastasis in Patients with HER2 Positive Metastatic Breast Cancer.
Authors: Raza S. , Narayana A. , Morsi A. , Parker E. , Rush S. , Golfinos J. , Novik Y. 
Published: December 2010

Abstract
Background:We present single institution experience on the effect of Her 2 status on results of Gamma knife radiosurgery (SRS) for brain metastases (BM) as to local control, pattern of relapse and survival.Material and Methods:From 2004 to 2008, 65 patients with metastatic breast cancer (MBC) were treated with GK-SRS at our center, 52 had documented Her 2 status. We performed analysis based on Her 2 status of the original tumor defined as positive by 3+ DAKO or FISH. SRS was delivered using cobalt leksell GKS to a median dose of 20Gy (range 16-20 Gy) at 50% isodose line. Responses were evaluated by gadolinium enhanced MRI. We analyzed the data as to: objective response (OR) defined as radiologic response or stable disease, and local progression –free survival (PFS) defined as freedom from progression of treated BM, appearance of new brain metastases and/or leptomeningeal progression, as well as overall survival (OS) measured from the time of SRS .ResultsTwenty-eight patients were identified as HER2 positive (Group A) and 24 patients were HER2 negative (Group B). Median time to develop BM in group A was 60 months (4 -240 months) versus 48 months (4-156) in group B. Median follow-up was 12 months (1-48) from the time of onset of BM. 66% patients in group A and 82% patients in group B have no more than 2 BM at the time of SRS.In group A, OR was 78.6% (22 pts)and 21.4%(6 pts) had progressive disease (PD) where as in group B the OR was 83% (20 pts) and 17%(4 pts) had PD. Median time to local recurrence of the treated lesion in group A was 13 months (95% CI 5.84 to 20.15) compared to 8 months (95%CI 6.75 to 9.25) in group B. Local PFS at 1 year for Group A vs. B was: control of the treated lesions 69% versus 41.2% respectively, p= 0.97 by log rank test; and development of new BM 67% compared to 86% (p=0.2).Out of all CNS relapses, almost a quarter of patients in both groups received second SRS whereas 25% patients in group A and 31% patients in group B received whole brain irradiation respectively. Interestingly, 28% (9 pts) failed as leptomeningeal disease following SRS, 7 of them with Her 2 positive tumors. Leptomeningeal relapses were seen both as only pattern of recurrence (4 pts) or associated with other types of CNS progression: local re-growth or new BM (5pts).ConclusionsSRS provides high rate of objective response and local control for BM from both Her 2 positive and Her 2 negative breast cancer. No statistically significant difference in local PFS was seen. More frequent pattern of relapse as leptomeningeal disease was seen in Her 2 positive after SRS. Evaluation of novel systemic targeted therapies in conjunction with local therapies is needed for effective management of BM from breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6152.
Predominance of Brain and Lung Metastases in Triple-Negative Breast Cancer Patients.
Authors: Gadiyaram V. , Kurian S. , Abraham J. , Hobbs G. , Vona-Davis L. , Vona-Davis L. 
Published: December 2010

Abstract
Background: Patients with triple-negative breast cancer have an increased likelihood of recurrence compared to other types of breast cancer, however, little is known about their pattern of metastatic spread. Our object was to evaluate the metastatic patterns of women diagnosed with triple-negative breast cancer compared to other subtypes. Methods: We studied a cohort of 572 white patients diagnosed with invasive breast cancer at West Virginia University Hospital between 1999 and 2004. Hospital registry, charts, and pathology records provided clinical data including tumor receptor status and biopsy-proven metastatic spread to bone, brain, liver and lung. Breast cancers that were negative for estrogen, progesterone, and HER2neu, otherwise known as triple-negative were compared with HER2neu-postive and HER2neu-negative (endocrine receptor positive) disease. Body mass index was calculated and a value of ≥30 considered indicative of obesity. Specimens of primary carcinoma were available for analysis of Ki67 mitotic index and expression of p53. Results: 134/572 (23.4%) had triple-negative breast cancer, while the frequencies were 108/572 (18.9%) and 330/572 (57.7%) in HER2neu-positive and HER2neu-negative (endocrine receptor positive) groups. Women with triple-negative disease were more likely to have brain-metastasizing breast cancer; 10.5% versus 4.6% for HER2neu-positive and 3.3% for HER2neu-negative (P&lt;0.05). They were also more likely to have metastasis to the lung; 10.5% versus 2.8% for HER2neu-positive and 7.0% for HER2neu-negative (P&lt;0.05). Triple-negative breast cancer patients who developed brain and lung metastases were younger &lt;50 years and significantly more obese (P=0.0236). High Ki67 labeling index and p53 expression were associated with more advanced disease indicating an aggressive phenotype for this group.Patterns of metastasis in breast cancer subtypesSite of metastasisTriple-negativeHER2-positiveHER2-negativeP valueBone20/134 (14.9)7/108 (6.5)38/330 (11.5)0.1037Brain14/134 (10.5)5/108 (4.6)11/330 (3.3)0.0136*Liver11/134 (8.2)4/108 (3.7)22/330 (6.7)0.3261Lung14/134 (10.5)3/108 (2.8)23/330 (6.9)0.0507*Other5/134 (3.7)3/108 (2.8)3/330 (0.91)0.1093 Conclusion: The excess risk of brain and lung metastasis in women with triple-negative breast cancers versus other subtypes needs further validation. The unique biology of triple-negative tumors may explain this pattern of metastatic spread.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6159.
Fatty Acid Synthase (FASN) as a Therapeutic Target for Breast Cancer Metastasis.
Authors: Gonzalez-Guerrico A. , Lupu R. 
Published: December 2010

Abstract
Numerous solid tumors confirm increased expression of FASN. FASN expression is upregulated in early steps of breast cancer, such as DCIS, and is associated with poor clinical outcome in more advanced disease. The objective of this study is to evaluate FASN inhibition as a prevention of breast cancer progression and as an effective treatment of metastasis. We utilized the model the MCF10CA1 series of cell lines, which complete the spectrum of breast cancer progression ranging from non-transformed breast epithelial cells to metastatic breast cancer cells. These metastatic cell lines are CA1A and CA1D cells (short for MCF10A-CA1A and MCF10A-CA1D), which metastasize to the lung following a tail vein injection. Interestingly, we determine that with the progression of breast cancer in these model series the level of FASN was correlated with the evolution to a more aggressive phenotype. The CA1A and CA1D cells expressed the highest levels of FASN. To determine whether FASN plays a role in the aggressiveness of these cells we introduced a specific FASN silencing RNA into CA1A and CA1D cells and isolated stable cell lines in which FASN expression was significantly reduced. Stable expression of a FASN shRNA completely abrogated the anchorage-independent growth ability of the metastatic cells and furthermore these cells reverted from EMT to MET (Mesenchymal Epithelial Transition) as demonstrated by a Matrigel 3Dimentional (3D) assay and the immunofluorescence staining of E-Cadherin in matrigel. These results emphasize the potential of FASN as a therapeutic target and as a key modulator of breast cancer progression and metastasis.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6160.
Hammerhead Ribozyme Suppresses the Expression of MLN64 and Affects the Function of Breast Cancer Cells In Vitro.
Authors: Cai W. , Cai W. , Ye L. , Mansel R. , Jiang W. 
Published: December 2010

Abstract
Background: The MLN64 gene, which is localized in q12-q21 of the human chromosome 17, encodes a novel transmembrane protein that shares homology with the cholesterol binding domain (START domain) of the steroidogenic acute regulatory protein. The function of MLN64, initially reported in the metastatic lymph nodes, remains unclear, but has been indicated to probably regulate cholesterol transport. MLN64 is highly expressed in certain breast carcinomas, often co-amplified with erbB-2, and thus may contribute to the development and progression of breast tumours. The present study investigated the molecular and cellular impact of MLN64 on the functions of breast cancer cells.Methods: An anti-human MLN64 hammerhead ribozyme transgene was constructed using the mammalian expression vector pEF6/V5-His TOPO, and transfected into breast cancer cells MDA MB 231 and MCF-7 by electroporation. Expression of MLN64 mRNA and protein was determined using RT-PCR and Western blotting respectively. Cell growth, invasiveness, adhesion, motility and migration assays were used to assess, in vitro, the impact of MLN64 knockdown on the cells. In addition, expression of MLN64 was evaluated in a cohort of breast tumours, at protein and message levels.Result: Loss of MLN64 in MCF-7 cells resulted in a significant reduction of cellular growth (growth index for MCF-7ΔMLN64 being 0.87±0.07, P&lt;0.01 vs wild type control (MCF-7WT 1.13±0.06) and transfection control (MCF-7pEF 1.27±0.05). Interestingly, the same change in cell growth was not seen with MDA-MB-231 cells, in that MDA-MB-231ΔMLN64 didn't exhibit a significant effect on the cell growth comparing with corresponding WT and PEF controls. In matrix adhesion assay, MDA-MB-231ΔMLN64 cells showed a significant increase in adhesion (86±14), compared with MDA-MB-231WT and MDA-MB-231pEF (61 ±20 and 45±27, respectively, P&lt;0.01). In MCF-7 cell line, no significant differences were observed between the knockdown mutants and the wild types and pEF type. Breast cancer tissues showed a higher levels of MLN64 transcript than normal tissues (median (IQR) 1.08 (0.19-4.7) copies vs 0.5 (0.18-1.3) copies. Furthermore, ER positive tumours had significantly higher levels of MLN64 transcript (2.86(0.53-11.9) copies) than ER negative tumours (0.59 (0.15-2.68) copies), p=0.0012.Conclusion: In this first report on the functions of MLN64 in breast cancer cell lines, we have shown that MLN64 levels are correlated with the growth and adhesion of breast cancer cells in vitro. It is suggested that MLN64 has a direct influence on the aggressiveness of breast cancer cells and may play a role in progression and metastasis of breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6163.
Lympho-Vascular Invasion by Detecting D2-40 Was the Potent Prognostic Predictor in Breast Cancer Patients.
Authors: Woo S. , Ryu W. , Lee J. , Kim H. , Kim C. , Son G. , Lee E. , Lee J. , Bae J. 
Published: December 2010

Abstract
(Introduction) Distant metastasis and recurrence are the major factors of prognosis in breast cancer patients. Both of lymphovascular invasion (LVI) and blood vascular invasion (BVI) are known to be the important route for metastasis to regional lymph nodes and systemic metastasis. Despite the importance of vascular invasion as a prognostic factor, the application of vascular invasion as a histopathologic criterion is controversial. The aims of this study were to distinguish between LVI and BVI for the role of prognosis and recurrence in breast cancer patients by using an endothelial subtype specific immunohitochemical stain (podoplanin, D2-40 and CD31)Methods) Sections from 80 paraffin-embedded archival specimens of invasive breast cancer were stained for expression of podoplanin, D2-40, and CD31. The results of immunohistochemical staining were correlated with clinicopathologic features, such as tumor size, the status of lymph node metastases, estrogen receptor status, progesterone receptor status and HER2 expression, and recurrence. The patients with ductal carcinoma in situ and stage 4 breast cancer were excluded.Results) A significant correlation was found in the higher expression of D2-40, and lymph node metastasis. (P=0.02) We found a significant correlation between the expression of D2-40 and the recurrence of breast cancer. (P=0.04) However, there was no significant correlation between BVI and recurrence. A poorer disease free survival was shown in the higher expression of D2-40. (P&lt;0.01) In multivariate analysis, the higher expression of D2-40 revealed a significant association with decreased disease-free survival.Conclusion) The higher expression of D2-40 was the more prognostic predictor than blood vascular invasion in breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6171.
A Single Nucleotide Polymorphism in Steroid Receptor Coactivator-1 Diminishes the Coactivation of ERα.
Authors: Hartmaier R. , Hartmaier R. , Hartmaier R. , Richter A. , Richter A. , Richter A. , McGuire S. , McGuire S. , Wang J. , Lee A. , Lee A. , Lee A. , Osborne C. , Osborne C. , O'Malley B. , Brown P. , Brown P. , Brown P. , Xu J. , Skaar T. , Skaar T. , Philips S. , Philips S. , Rae J. , Rae J. , Azzouz F. , Azzouz F. , Li L. , Li L. , Henry N. , Henry N. , Nguyen A. , Nguyen A. , Stearns V. , Stearns V. , Hayes D. , Hayes D. , Flockhart D. , Flockhart D. , Oesterreich S. , Oesterreich S. , Oesterreich S. , Oesterreich S. 
Published: December 2010

Abstract
Estrogen signaling is critical in the progression of a large fraction of breast cancers as well as in the maintenance of bone mineral density. Generally speaking, Tamoxifen, a selective estrogen receptor modulator (SERM), blocks estrogen signaling in the breast by acting as an antagonist at the same time as promoting estrogen signaling in the bone by acting as an agonist. This tissue specific action characteristic of SERMs is thought to be maintained by the balance of levels and/or activities of estrogen receptor (ER) coregulators. Because of this critical role, single nucleotide polymorphisms (SNPs) in ER coregulators could have a dramatic effect on tamoxifen action.Previous studies have implicated steroid receptor coactivator-1 (SRC-1) as a critical coregulator for the mixed antagonist-agonist specificity of tamoxifen. By using an ERE-Tk-Luciferase transient transfection assay, we have shown that a SNP causing the amino acid change P1272S in SRC-1 dramatically reduces its ability to coactivate ERα.To assess the impact of this SNP on tamoxifen action in breast cancer we decided to genotype the SRC-1 P1272S SNP in a breast tumor DNA bank. This bank was generated from archived tumors from individuals either exclusively receiving adjuvant tamoxifen or not receiving any adjuvant therapy following surgical resection. Currently, the bank is composed of 1000 samples divided equally among the two groups. Genotyping for the SRC-1 P1272S SNP is currently underway.Since SRC-1 has also been shown to be important in proper maintenance of bone mineral density (BMD) and in the agonist action of tamoxifen in certain tissues, we also assessed the impact of the P1272S SNP in bone following tamoxifen therapy. We genotyped breast cancer patients exclusively receiving tamoxifen therapy (i.e. no chemotherapy, no radiation) who had lumbar (n=113) and/or hip (n=108) BMD scans before and after 12 months of tamoxifen therapy. We observed a significant association between the SNP and bone loss; women harboring the P1272S SNP lost 6.4% of their lumbar BMD, while women with the WT version lost only 1.3% of their lumbar BMD.These findings illustrate the critical role of SRC-1 in tamoxifen action in bone, and potentially other hormone responsive tissues. Studies are ongoing to decipher the mechanism for decreased coactivation activity of the SNP, and also to extend the clinical association studies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 66.
Changes in the Dynamic Relationship between ER and HER2 in Paired Breast Cancer (BC) Biopsies from Patients (Pts) with Recurrent Tamoxifen-Resistant Breast Cancer.
Authors: Leary A. , Drury S. , Drury S. , Detre S. , Martin L. , Dowsett M. , Dowsett M. , Johnston S. 
Published: December 2010

Abstract
Background: Paired biopsies at diagnosis and relapse on tamoxifen (TAM) provide information regarding adaptive changes associated with endocrine resistance. We previously reported that conversion to a HER2+ phenotype occurs infrequently1, however modest increases in HER2 may be relevant in the context of TAM resistance. Also while TAM resistance in general is associated with a fall in mean ER and PgR levels, this masks changes in individual pts.Aim: To determine whether a subset of HER2 negative BC demonstrated modest increases in HER2 by IHC and FISH, and if so whether this correlated with changes in ER and PgR expression in individual pts.Methods: Triplicate TMAs were constructed of paired primary and recurrent tumor samples from pts relapsing after adjuvant TAM. TMAs were stained for ER and HER2, whole sections for PgR. HER2 amplification was assessed by FISH.Results: Paired samples from primary and TAM-resistant recurrences were available on 53 ER+ and/or PgR+ pts. 10% had a HER2+ primary (IHC3+ and FISH+). 19% (10/53) showed increasing HER2 in the relapsed tumor (0 to 1+ in 5 pts, 1+ to 2+ in 2 pts and 0/1+ to 3+ in 3 pts). The 3 pts converting to 3+ also became FISH+. 71% (38/53) had stable or decreasing HER2. DFI was 50.3 months in the subset with stable or decreasing HER2, 40.2 in the subset with increasing HER2, and 35.2 in the HER2+ subset (p=NS). We next compared changes in ER and PgR in the 3 subsets. Among pts with stable or decreasing HER2 (N=38), there was a significant decrease in mean H-scores for both ER (p=0.001) and PgR (p=0.002) at relapse (Fig 1); the majority recurred with reduced ER (76%) or PgR levels (84%). In contrast, among pts with increasing HER2, there was no change in mean ER or PgR levels (Fig 2A); however when considering changes in individual pts, there was a balanced split between tumors relapsing with up- vs. down-regulation in ER/PgR (Fig 2B,C). In the HER2 positive subset, 100% of the pts relapsed with suppressed ER and PgR.Conclusion: In an updated series of TAM-resistant pts, we show that while conversions to HER2 3+/FISH+ remain rare (5%), modest increases in HER2 are more frequent (19%). TAM resistance in general is associated with decreasing ER and PgR. However, among pts with adaptive increases in HER2, TAM resistance is associated with either down- or up-regulation in ER expression and function. This is consistent with data from acquired endocrine resistance models we previously reported2,3.1Gutierrez et al, JCO 20052Pancholi et al, ERC 2008,3 Martin et al, JBC 2003
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 704.
A Randomised Controlled Trial of Forward-Planned Intensity Modulated Radiotherapy (IMRT) for Early Breast Cancer: Interim Results at 2 Years Follow-Up.
Authors: Coles C. , Barnett G. , Wilkinson J. , Moody A. , Wilson C. , Twyman N. , Hoole A. , Burnet N. , Wishart G. 
Published: December 2010

Abstract
Background: This large single centre trial was designed to investigate whether correction of dose inhomogeneities using IMRT reduces late toxicity and improves quality of life in patients with early breast cancer. We report interim results at 2 years follow-up.Materials and Methods: Standard tangential breast radiotherapy plans of 1145 trial patients were assessed for dose inhomogeneity as defined by ICRU recommendations. Patients with inhomogeneous plans were randomised to either IMRT or standard radiotherapy. Patients with homogenous plans were treated with standard radiotherapy, but were followed up within the trial as per randomised patients. The primary endpoint of the trial was photographic assessment of breast shrinkage. Secondary endpoints included photographic assessment of final cosmesis, clinical assessment of toxicity, and patient-reported symptoms and quality of life. All endpoints were scored using validated assessment methods. Data were collected on potential confounding factors which included: age at randomisation, smoking history, body mass index, co-morbidity such as diabetes mellitus, cardiovascular and peripheral vascular disease, use of hormones and/or chemotherapy, treated breast volume, and presence or absence of breast boost.Results: 330/1145 (29%) of patients had adequate dosimetry with standard 2D radiotherapy and were not randomised. In the 815 randomised patients, dosimetry was significantly improved in the interventional (IMRT) arm compared to the control. Currently, data from 632 randoimsed patients who have reached 2 years of follow up have been analysed. This interim analysis demonstrates that the incidence of telangiectasia in the control arm was significantly greater than in the interventional group (P = 0.024). Pre-radiotherapy surgical cosmesis significantly affected photographic assessment of final cosmesis, and clinical assessment of breast shrinkage and induration (P &lt; 0.0001). In randomised patients who had good surgical cosmesis, there was a significant difference improvement in final cosmesis with the use of IMRT (P = 0.038). The quality of life data has not been analysed at this stage.Discussion: This trial shows that the use of forward-planned IMRT can significantly improve dose homogeneity, and suggests that this translates into improvements in late toxicity at only 2 years from completion of radiotherapy. Surgical cosmesis appears to be a very important determinant of overall final cosmesis after 2 years of follow-up, and may mask any beneficial effects of IMRT at this early stage. It is highly likely that these trial patients will have not expressed their final level of toxicity at 2 years post-radiotherapy, and re-analysis is planned at 5 years from completion of radiotherapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 71.