bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-13-08: The DCIS Score - Potential for healthcare savings?
Authors: Young Rebekah , Gergelis Kimberly , Kalnicki Shalom , Fox Jana L 
Published: May 2015

Abstract
Introduction
The Oncotype Dx Recurrence Score for DCIS (DCIS Score) is a 12-gene assay derived from the original Oncotype DX test that evaluates recurrence risk among women with invasive carcinoma of the breast. The DCIS Score provides a local recurrence risk estimate at 10 years following lumpectomy for ductal carcinoma in situ (DCIS). Results can help guide decisions regarding adjuvant radiation (RT). Foregoing RT can be a source of significant healthcare savings. We investigated the actual healthcare dollar savings to-date in our patient population.
Methods
We evaluated patients in whom the DCIS Score was ordered (x) and calculated total cost of testing. Potential cost of RT was that of IMRT as reimbursed by Medicare for a hypofractionated (16 fraction) course, multiplied by x. Many of our large-breasted patients require IMRT to increase dose homogeneity and to limit dose to normal tissues. We also calculated potential cost with 3D conformal (3D-CRT). Total potential cost was the sum of testing and treatment costs, determined for each modality. The number of patients ultimately treated (y) was also multiplied by these costs. Total actual cost was the sum of test expenses and actual treatment costs. Savings was the difference between the total actual and total potential cost.
Results
From February, 2012 to May, 2014 the DCIS Score was performed in 38 patients (x= 38). Median age was 66 (40-85). Grade was low in 39%, intermediate in 45%, and high in 16%. 50% had necrosis present, and the median size of DCIS was 0.5cm (0.1 - 3.1cm). The total cost of testing was $4125 * 38 = $156,750. IMRT reimburses at approximately $23, 000 and 3D-CRT at approximately $11,000 per treatment. (Medicare reimbursement rates can vary among states.) The potential total cost of RT ranged from $418,000 - $874, 000; testing brought the total potential costs to $574, 750 - $1,030, 750. Upon receipt of the test results, 12 (y) patients ultimately underwent therapy. IMRT was given in 11 patients and 3D-CRT in 1, for a total treatment cost of $264, 000. Therefore, total actual expenditures were $420, 750. Savings amounted to (574, 750 – 420, 750) = $154, 000 to (1,030, 750– 420, 750) = $ 610, 000.
Conclusions
In the era of rising healthcare costs, it is imperative to examine instances of possible over-treatment. The DCIS Score has the potential to save not only healthcare dollars, but to spare patients radiation side effects, time lost from work, and transportation expenses. While there are costs associated with the assay, if ordered judiciously, these can be offset by the subsequent savings from eliminating treatment.
Citation Format: Rebekah Young, Kimberly Gergelis, Shalom Kalnicki, Jana L Fox. The DCIS Score - Potential for healthcare savings? [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 P6-13-08.
Abstract P6-17-02: Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions
Authors: Schem Christian , Tower Rob J , Kneissl Philipp , Rambow Anna C , Campbell Graeme M , Heilmann Thorsten , Trauzold Anna , Jonat Walter , Glüer Claus C , Schott Sarah , Tiwari Sanjay 
Published: May 2015

Abstract
Patients with breast cancer bone metastases suffer significant morbity from skeletal-related events but an effective agent that inhibits bone resorption while maintaining bone formation has not been identified. In this study we tested the therapeutic efficacy of a novel drug, 5-FdU-ale, a conjugate between the anti-metabolite 5-FdU and the bisphosphonate alendronate, in a mouse model of breast cancer bone metastases. Administration of 5-FdU-ale in vitro induces cell cycle arrest similar to treatment with unconjugated 5-FdU. In vivo, mice harboring bone lesions treated with 5-FdU-ale showed a reduction in tumor size not observed with administration of either Alendronate or 5-FdU. Since osteolysis mediated release of growth factors from bone contribute to tumor growth, we show 5-FdU-ale treatment significantly reduces bone resorption, although uniquely, the inhibition of osteoclast activity is not mediated through inhibition of prenylation of small GTPases. Furthermore, and in contrast to Alendronate, there is no concomitant decrease in bone formation activity, as determined by serum osteocaclin levels. This finding is supported by micro-CT analyses which reveal significantly higher bone volume and histologically, pockets of tumor cells are observed largely confined to regions of marrow space between endochondral and trabecular bone. Taken together, we conclude that 5-FdU-ale has potent anti-tumor efficacy in osteolytic bone lesions mediated uniquely through bone formation activity of osteoblasts and inhibition of bone resorption. The study identifies the important role of osteoblast in not only preventing the osteolytic metastatic phenotype but as a means of harnessing the therapeutic potential of bone formation to treat osteolytic lesions.
Citation Format: Christian Schem, Rob J Tower, Philipp Kneissl, Anna C Rambow, Graeme M Campbell, Thorsten Heilmann, Anna Trauzold, Walter Jonat, Claus C Glüer, Sarah Schott, Sanjay Tiwari. Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions [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 P6-17-02.
Abstract PL-2: Patient Derived Xenografts - Pre-Clinical Models for Prevention and Treatment of Metastasis
Authors: Welm Alana L. 
Published: May 2015

Abstract
Twenty to thirty percent of breast cancer patients eventually develop metastasis despite receiving state-of-the-art therapies. Clearly, identifying better ways to eliminate micro-metastatic tumor cells is paramount to eradicating death from breast cancer. Unfortunately, history suggests that developing yet another drug to target yet another pathway involved in tumor progression will not cure breast cancer. We now know that every tumor is unique; each tumor is heterogenous; tumors hijack multiple, redundant pathways to survive and grow; dormant tumor cells are resistant to chemotherapy; and tumors evolve resistance under pressure of therapy.
To better understand the problem of metastasis, and to develop better treatments, we must utilize in vivo models of metastasis that best recapitulate heterogenous human breast cancers. We have generated a collection of orthotopic patient-derived breast tumor xenograft (PDX) models from all of the major breast cancer subtypes. We found remarkable fidelity between PDX models and bona fide breast tumors, including the ability to metastasize and to evolve under pressure of treatment. This presentation will highlight the strengths and pitfalls of PDX models of breast cancer and how they might be utilized to develop new strategies for treatment.
Citation Format: Alana L. Welm. Patient Derived Xenografts - Pre-Clinical Models for Prevention and Treatment of 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 PL-2.
Abstract S5-01: The Connecticut experiment: 4 years of screening women with dense breasts with bilateral ultrasound
Authors: Weigert Jean M 
Published: May 2015

Abstract
OBJECTIVE: To determine if the addition of screening breast ultrasound in women with mammographically normal but dense breasts has increased breast cancer detection over the 4 years since the legislation was first enacted in 2009.
METHODS: The study utilized a retrospective chart review. Data collected included: (1) total number of screening mammograms; (2) total number of dense breast screening ultrasounds; (3) screening ultrasound Breast Imaging Reporting Data System (BI-RADS) code results; (4) biopsy results; and (5) demographic data on women with malignant biopsies. Data was obtained from included sites from October 2009 through December 2013.
FINDINGS: Data was collected from 2 Radiology practices with a total of 5 sites.
In year 1, 30670 mammograms and 2706 screening ultrasounds were performed. In year 2, 32050 mammograms and 3351 ultrasounds; in year 3, 32230 mammograms and 4128 ultrasounds and in year 4, 27937 mammograms and 3331 ultrasounds were performed.
In year 1, 151 ultrasounds were BIRADS 4 or 5 with 11 cancers detected. The PPV was 7.1%; the detection rate was 4/1000 and 22% of eligible women had the study (assuming 40% of women have dense breasts). In year 2, 180 ultrasounds were BIRADs 4 and 5 with 11 cancers detected. The PPV was 6.1% and the cancer detection rate was 3.2/1000 with 26% of eligible women having the study. In year 3 148 ultrasounds were BIRAD 4 and 5 with 13 cancers detected. The PPV was 8.1% and the cancer detection rate was 3.2/1000 with 32% of eligible women having the study. In year 4, 53 ultrasounds were BIRAD 4 and 5 with 11 cancers. The PPV was 17.2% with the cancer detection rate of 3.3/1000 and 28% of eligible women having the study.
Four Years of Screening Breast Ultrasound Data Year 1Year 2Year 3Year 4Screening Mammograms30670320503223027937Breast Ultrasounds for Dense Breasts2706335141283331BIRAD 4 and 5 Ultrasounds15118017853Cancers11111311PPV7.16.18.117.2Number Cancers per 1000 Screened4.03.23.23.3% Eligible Screened22.126.132.028.3
CONCLUSIONS: Based on the data collected from these sites, screening breast ultrasound in women with dense breast parenchyma detects mammographically occult malignancy. Over the 4 years studied, the PPV improved from 7% to 17.2% indicating that the selection of lesions biopsied was more accurate with fewer false positives. The rate of detection in the first year was 4.0/1000 and then remained stable at 3.2/1000 in the three subsequent years. Of concern, the number of eligible women who elect to have the additional test remains low at about 30% which is due to several factors including education and cost.
Citation Format: Jean M Weigert. The Connecticut experiment: 4 years of screening women with dense breasts with bilateral ultrasound [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 S5-01.
Abstract A059: Context-dependent regulation of breast cancer metastasis by E-cadherin and p120-catenin
Authors: Schackmann Ron CJ , Klarenbeek Sjoerd , Amersfoort Miranda van , Jonkers Jos , Diest Paul van , Derksen Patrick 
Published: May 2015

Abstract
While it is well established that mutational inactivation of E-cadherin is a causal event in the development and progression of invasive breast cancer, still little is known about how this event controls the metastatic process.
Using conditional E-cadherin knockout mouse models of human invasive lobular carcinoma (ILC), we recently demonstrated that p120-catenin (p120) translocates to the cytosol upon E-cadherin inactivation. Here, it acts as an oncogene by regulating Rock-dependent control of tumor growth and metastasis through binding and inhibition of the Rho antagonist Mrip. Furthermore, new evidence indicates that p120 shuttles to the nucleus where it relieves Kaiso-dependent transcriptional repression of Wnt11, leading to autocrine activation of RhoA.
Conversely, since p120 controls E-cadherin stability and turnover, we also addressed the hypothesis that p120 may function as a tumor suppressor in breast cancer. In contrast to E-cadherin loss and the development of metastatic ILC, we show that somatic inactivation of p120 results in the formation of stromal-dense tumors resembling human metaplastic carcinoma that metastasize to lungs and lymph nodes. Mechanistically, we demonstrate that acquisition of metastatic potential was acquired through relieve of E-cadherin-dependent repression of growth factor receptor (GFR) function, leading to hyper-activation of GFR signaling and subsequent anchorage independence.
In summary, our data show that p120 can act as an oncogene or metastasis suppressor, depending on context and timing of junctional inactivation. Furthermore, our experiments indicate that targeted intervention strategies using Rock inhibitors may be applicable for the treatment of ILC. Based on our findings we also anticipate that patients suffering from E-cadherin or p120 negative breast cancer will benefit from clinically established inhibitors targeting GFR/PI3K/AKT/FOXO pathways in the absence of GFR or PIK3CA activating mutations.
Citation Format: Ron CJ Schackmann, Sjoerd Klarenbeek, Miranda van Amersfoort, Jos Jonkers, Paul van Diest, Patrick Derksen. Context-dependent regulation of breast cancer metastasis by E-cadherin and p120-catenin. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A059.
Abstract A062: Sensitizing low BIM expressing breast cancers to targeted therapies
Authors: Faber Anthony C. , Vora Sadhna , Engelman Jeffrey A. 
Published: May 2015

Abstract
HER2 amplification is found in up to 20% of breast cancers and PIK3CA mutations occur in up to 30%. These cancers are susceptible to targeted therapies directed against oncogenic HER2 and PI3K. Emerging evidence from clinical trials has revealed a surprising heterogeneity in response to targeted therapies, for example within HER2 positive breast cancer patients, the efficacy of HER2 inhibitors has varied. We have previously shown in breast cancer cell lines and a small cohort of HER2 positive breast cancer patients that low levels of the pro-apoptotic BIM can confer intrinsic resistance to HER2 inhibitors, by repressing the apoptotic response following treatment. Here in, we investigated the ability of a BCL-2/Bcl-XL inhibitor to enhance the apoptotic response specifically in low BIM HER2 amplified and PIK3CA mutant breast cancers with intrinsic resistance to targeted therapies, by freeing up BIM from BCL-2:BIM and BCL-xL:BIM complexes. We found that in these cancers, the addition of BCL-2/BCL-xL inhibitors synergized with HER2 inhibitors and PI3K inhibitors to induce apoptosis, and to similar levels induced by targeted therapy alone in the high BIM expressing breast cancers. Biochemical analysis revealed that PI3K inhibition downregulated MCL-1 in PIK3CA mutants, which leads to a further increase in the amount of free BIM, further “maximizing” the otherwise low levels of cellular BIM in these cells. These results translated to tumor regressions in mouse xenografts treated with the combination, similar to what was seen with single-agent PI3K inhibitor in a high BIM expressing PIK3CA mutant breast cancer xenograft model. Thus, combining a BCL-2/BCL-xL inhibitor with the appropriate targeted therapy may overcome intrinsic resistance caused by low BIM expression in HER2 amplified and PIK3CA mutant breast cancer.
Citation Format: Anthony C. Faber, Sadhna Vora, Jeffrey A. Engelman. Sensitizing low BIM expressing breast cancers to targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A062.
Abstract A067: Targeting p21-activated kinases in breast cancer
Authors: Hoeflich Klaus , Ong Christy , Lyle Karen , Jubb Adrian , Zhou Wei , Harris Adrian , Belvin Marcia , Friedman Lori , Koeppen Hartmut , Rudolph Joachim , Staben Steven 
Published: May 2015

Abstract
Luminal breast cancer is the most commonly diagnosed cancer worldwide and mechanisms of innate and acquired resistance are not yet well understood. P21-activated kinases (PAKs) are members of the STE20 family of serine/threonine kinases that lie downstream of receptor tyrosine kinases and Rho family GTPases. PAKs regulate many cellular processes that are commonly perturbed in cancer, including migration, polarization and proliferation, and are therapeutic targets of interest. PAK1 is also overexpressed in several cancers and we recently showed that focal genomic amplification of PAK1 occurs in ~8% of luminal breast cancer (Proc Natl Acad Sci 2011; 108:7177). PAK1 amplification has also been associated with poor patient outcome and PAK1 is a putative mediator of resistance to anti-estrogen therapy (Nature 2012; 486:346). The aim of this study was to further characterize PAK family kinases in breast adenocarcinoma. Luminal breast cancer cells with PAK1 focal amplification rapidly underwent apoptosis following inhibition of this kinase. To identify potential mechanisms of acquired resistance we have derived PAK1-resistant cell lines and begun characterizing via genomic and proteomics approaches. Furthermore, in contrast to the role of PAK1 in luminal breast cancer, elevated expression of PAK4 was associated with poor outcome in basal-like breast cancer. We developed a novel small molecule inhibitor with high potency and selectivity of group II PAKs to delineate the role of PAK4 signaling in basal breast cancer. Together, our results provide evidence for dysregulation of PAK1 and PAK4 in differing subtypes of breast cancer and roles in for these kinases in cellular survival, proliferation and migration in this tumor indication.
Citation Format: Klaus Hoeflich, Christy Ong, Karen Lyle, Adrian Jubb, Wei Zhou, Adrian Harris, Marcia Belvin, Lori Friedman, Hartmut Koeppen, Joachim Rudolph, Steven Staben. Targeting p21-activated kinases in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A067.
Abstract A083: Neutrophils promote metastasis of invasive lobular carcinoma
Authors: Coffelt Seth B. , Doornebal Chris W. , Kersten Kelly , Ciampricotti Metamia , Hau Cheei-Sing , Vrijland Kim , Weiden Jorieke , Jonkers Jos , Visser. Karin E. de 
Published: May 2015

Abstract
The multistep process of metastasis is highly dependent on the intrinsic mutations that accumulate in cancer cells. However, recent experimental evidence has shown that these mutations are not sufficient to facilitate metastatic disease. Cues from the tumor microenvironment are also required. In order to understand how systemic changes might affect metastasis formation, we profiled the cellular and molecular alterations in various organs of K14cre;EcdF/F;p53F/F mammary tumor-bearing mice – a model of invasive lobular breast cancer. Among all immune cells, increased neutrophil accumulation was the most pronounced. To test the functional importance of neutrophils in the metastatic process, we utilized our recently described model of spontaneous metastasis. This model is based on the transplantation of K14cre;EcdF/F;p53F/F tumor pieces into wild-type recipient mice, and subsequent surgical removal of the primary tumor, permitting us to investigate neutrophil function in both the neoadjuvant and adjuvant settings. Interestingly, mice treated with neutrophil-depleting antibodies in the neoadjuvant setting displayed a profound reduction in pulmonary metastasis, whereas metastases in the adjuvant group were equivalent to controls. These data indicate that neutrophils play a prominent role during the very early stages of the metastatic cascade. Our preliminary data suggest that these tumor-educated neutrophils can suppress the activation of T cells, as one mechanism by which they may promote metastasis. In addition, cytokine analysis of K14cre;EcdF/F;p53F/F mammary tumors demonstrated an increase in the IL17 pathway when compared to wild-type mammary glands. Subsets of T cells are known producers of IL17 and this pathway regulates neutrophil expansion indirectly. In accordance with this, K14cre;EcdF/F;p53F/F mice lacking the adaptive immune system displayed reduced IL17 levels and reduced circulating neutrophils. Current efforts are underway to determine whether T cells play a role in the pro-metastatic function of neutrophils. Together, these findings indicate that neutrophils are crucial for the establishment of breast cancer metastasis.
Citation Format: Seth B. Coffelt, Chris W. Doornebal, Kelly Kersten, Metamia Ciampricotti, Cheei-Sing Hau, Kim Vrijland, Jorieke Weiden, Jos Jonkers, Karin E. de Visser. Neutrophils promote metastasis of invasive lobular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A083.
Abstract A092: Molecular mechanisms of early metastatic dissemination in breast cancer
Authors: Hosseini Hedayatollah , Nanduri Lahiri Kanth , Ehrl Carolin , Maneck Matthias , Husemann Yves , Klein Christoph A. 
Published: May 2015

Abstract
Accumulating evidence indicates that tumor cells spread to distant sites much earlier than previously thought. The analysis of the BALB-neuT transgenic mouse model of breast cancer revealed that the relative number of disseminating cancer cells is highest at early stages of tumorigenesis. To unravel the mechanisms of early dissemination we performed a stage-dependent analysis of gene expression patterns in BALB-neuT mice. At the stage of atypical hyperplasia (ADH) gene expression profiles differed substantially from advanced tumors and lung metastases. We identified an ADH-specific gene expression signature and found that among the several hundred differentially expressed genes, many of them are regulated by sex hormones. We investigated whether this expression pattern might be linked to the propensity to disseminate. For this we established a surrogate signature for the ADH-specific pattern comprising five genes and tracked the regulating role of hormones in vitro or in vivo. Our results indicate that sex hormones act indirectly on mammary stem and progenitor cells to induce dissemination and metastasis and that hormone nuclear receptors are down-regulated in advanced tumors. Thereby, large tumors become less capable of disseminating metastatic cells.
Citation Format: Hedayatollah Hosseini, Lahiri Kanth Nanduri, Carolin Ehrl, Matthias Maneck, Yves Husemann, Christoph A. Klein. Molecular mechanisms of early metastatic dissemination in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A092.