bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A45: Autocrine and paracrine IL-6 and IL-8 drive osteosarcoma metastasis
Authors: Roberts Ryan D. , Bid Hemant K. , Phelps Doris , Hendrickson Brett W. , Cam Hakan , Houghton Peter J. 
Published: May 2015

Abstract
For patients with most types of solid tumors, metastases drive the morbidity and mortality of their disease. For patients with osteosarcoma this is particularly true, with metastases that occur almost exclusively within the lung. We set out to identify the factors that facilitate growth of osteosarcoma specifically within the lung environment. To do this, we identified a set of candidate genes and tested them for reliably enriched levels of expression in metastatic lesions relative to primary tumors in the same patients. IL-6 and IL-8 are among the most reliably enriched genes in the metastatic lesions. Osteosarcoma cell lines that express high-levels of IL-6 and IL-8 not only respond to these signals in an autocrine manner, but form lung metastases much more readily than cell lines with low IL-6 and IL-8 expression in mouse xenograft models. IL-6 and IL-8 drive chemokinesis, directional migration, and invasive activity in osteosarcoma cells independent of the degree to which they express these cytokines. Blocking IL-6 and IL-8 signals reduces the metastatic efficiency of osteosarcoma cells. These data suggest that IL-6 and IL-8 play a central role in the mechanisms that account for lung tropism in osteosarcoma and provide attractive targets for therapies intended to prevent metastasis in order to improve outcomes in patients with osteosarcoma.
Citation Format: Ryan D. Roberts, Hemant K. Bid, Doris Phelps, Brett W. Hendrickson, Hakan Cam, Peter J. Houghton. Autocrine and paracrine IL-6 and IL-8 drive osteosarcoma metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A45.
Abstract B78: Targeting the translational apparatus in MYCN-driven medulloblastoma
Authors: Meyerowitz Justin G. , Gustafson W. Clay , Nekritz Erin , Swartling Fredrik , Shokat Kevan M. , Ruggero Davide , Weiss William A. 
Published: May 2015

Abstract
Amplification of MYCN is associated with high-risk SHH-driven and group 4 medulloblastoma, while mis-expression and amplification of MYC is associated with aggressive group 3 tumors. The biology of these tumors, particularly the group 3/4 tumors, is poorly understood, with no effective targeted therapies. We have recently developed a model of group 4 medulloblastoma in which high levels of mutationally-stabilized MYCN protein drive oncogenesis. We have shown in other tumor types that modulation of the translational apparatus downstream of the mammalian target of rapamycin (mTOR) is required for MYC-driven oncogenesis and that there is a synergistic relationship between MYC and the mTOR axis to promote tumor formation. mTOR signals through two primary outputs, rpS6 kinase (S6K) and the translation initiation factor eIF4E. A new class of clinical mTOR active site inhibitors disrupts signaling through both effectors, whereas the allosteric binder rapamycin disrupts only S6K. We describe genetic and therapeutic studies aimed at distinguishing the effects of S6K and eIF4E in both tumor formation and in therapy. These mechanistically distinct activities have enormous therapeutic implications, as in our medulloblastoma model, active site inhibitors of mTOR, but not rapamycin, demonstrate efficacy. Taken together, this supports the idea that signaling through S6K is dispensable, whereas eIF4E is required for MYC-driven oncogenesis.
Citation Format: Justin G. Meyerowitz, W. Clay Gustafson, Erin Nekritz, Fredrik Swartling, Kevan M. Shokat, Davide Ruggero, William A. Weiss. Targeting the translational apparatus in MYCN-driven medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B78.
Abstract PR04: Novel somatic and germline mutations in intracranial germ cell tumors
Authors: Wang Linghua , Yamaguchi Shigeru , Terashima Keita , Burstein Mathew D. , Nakamura Hideo , Susuki Tomonari , Nishikawa Ryo , Natsume Atsushi , Terasaka Shunsuke , Ng Ho Keung , Adesina Adekunle , Gibbs Richard , Wheeler David , Lau Ching 
Published: May 2015

Abstract
Intracranial germ cell tumors (IGCTs) are rare and biologically diversified tumors affecting mainly male adolescents with the highest incidence in Japan and other Asian countries2. They are divided into two main groups, pure germinoma and nongerminomatous GCTs (NGGCTs). About 10% of germinomas and most NGGCTs remain refractory to multimodality therapy. Little is currently known about IGCTs except for KIT mutation/overexpression, which is observed in ∼25% of pure germinomas and is rarely seen in NGGCTs. As yet, there are no clues for the puzzle of onset during puberty, geographic and gender discrepancy in incidence of IGCTs. Here we report the analysis of 62 cases by whole-exome sequencing, deep-targeted sequencing and SNP array. The KIT/RAS pathway was frequently mutated in pure germinomas and mixed GCTs with germinoma components. In contrast, NGGCTs appear to have a paucity of clinically actionable mutations. We identified novel recurrent somatic mutations in KIT and 8 additional genes in KIT/RAS pathway that have not been previously associated with IGCTs: downstream mediators of KIT including KRAS, NRAS, MTOR, AKT1 and its negative regulator CBL (11%). We showed frequent focal amplification at AKT1 locus (19%), leading to AKT1 overexpression. Moreover, we identified loss-of-function mutations in BCORL1 (10%), a transcriptional corepressor and tumor suppressor. Furthermore, we report for the first time, significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor, among Japanese IGCT patients. Our data suggested a strong association of JMJD1C variants and the risk of developing of IGCTs (odds ratio=3.57). This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potential promising targets for development of novel therapeutics.
This abstract is also presented as Poster A14.
Citation Format: Linghua Wang, Shigeru Yamaguchi, Keita Terashima, Mathew D. Burstein, Hideo Nakamura, Tomonari Susuki, Ryo Nishikawa, Atsushi Natsume, Shunsuke Terasaka, Ho Keung Ng, Adekunle Adesina, Richard Gibbs, David Wheeler, Ching Lau. Novel somatic and germline mutations in intracranial germ cell tumors. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR04.
Abstract BS2-1: Collective invasion in breast cancer is led by specialized cancer cells with basal gene expression
Authors: Ewald Andrew J 
Published: May 2015

Abstract
Metastasis is the major driver of mortality and morbidity from breast cancer. Unfortunately, there are very few therapies that are effective in the metastatic setting. The overall hypothesis guiding our work is that a deeper biological understanding of the cellular and molecular mechanisms driving metastatic progression would facilitate the development of novel therapeutic concepts. A major barrier to achieving this goal is that the essential cellular steps occur deep within the body over a period of months to years.
To overcome this barrier, we developed a novel organoid invasion assay that enables us to prospectively identify the most invasive cells within primary breast tumors. We initially explanted organoids from advanced tumors derived from the MMTV-PyMT transgenic mouse model of luminal B breast cancer. Surprisingly, we discovered that the cells that lead invasion into the extracellular matrix express basal epithelial genes, such as keratin-14, p63, and P-cadherin, both in 3D culture and in vivo. We next demonstrated that the cells leading invasion in mouse models of Her2 overexpressing (MMTV-Neu) and basal breast cancer (C3(1)-Tag) also expressed basal epithelial markers. We then adapted our organoid invasion assay to study primary human breast tumors in real-time and found that keratin-14+ cells lead collective invasion across diverse molecular subtypes of breast cancer, both in 3D culture and in vivo. With these correlations firmly established, we returned to the MMTV-PyMT mouse model to dissect the mechanisms underlying collective invasion. Using a keratin-14 reporter line we revealed that the basal invasion program can be induced in luminal phenotype cancer cells and that these newly keratin-14+ cells can lead collective invasion. We then identified shRNA constructs to knockdown keratin-14 and demonstrated that it is required for collective invasion in 3D culture and in vivo.
Our current work focuses on using next generation sequencing to identify targetable genes required for the invasive process and using in vivo lineage analysis to study the relationship between collective invasion and distant metastasis.
Citation Format: Andrew J Ewald. Collective invasion in breast cancer is led by specialized cancer cells with basal gene expression [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 BS2-1.
Abstract ES2-3: Management of metastatic HER2 positive disease: optimizing current therapies and an overview of new agents in development
Authors: Krop Ian 
Published: May 2015

Abstract
Amplification of the HER2/neu gene occurs in approximately 20% of invasive breast cancers and is associated with aggressive clinical behavior. The development of HER2-targeted therapies, including trastuzumab, lapatinib, pertuzumab and trastuzumab emtansine (T-DM1) has revolutionized the treatment of this disease, leading to dramatic improvements in clinical outcomes. Given these improvements, the goals in treating patients with advanced HER2-positive breast cancer are to both extend survival as well as to minimize toxicities of therapy. In patients with newly diagnosed metastatic breast cancer, pertuzumab, in combination with trastuzumab and docetaxel, markedly improves survival and only mildly increases toxicity compared to trastuzumab and docetaxel. Pertuzumab, trastuzumab, and a taxane should thus be considered the standard of care for most patients in the first line setting. In the second line setting, the antibody-drug conjugate T-DM1is the standard of care as it is associated with longer survival and less toxicity than capecitabine and lapatinib. In 3rd and later lines of therapy, continuation of HER2-directed therapy is important, but there are no definitive data that a particular regimen (e.g. trastuzumab + chemotherapy, lapatinib + chemotherapy, trastuzumab + lapatinib) is superior in this setting. Thus decisions regarding choice of therapy should be guided by patients' preferences regarding toxicity profiles and route of administration.
Although HER2-directed therapy has improved outcomes, resistance to these agents eventually develops in almost all patients. CNS metastases represent one increasingly common manifestation of treatment resistance in HER2-positive cancers. Understanding mechanisms of resistance and development of novel agents to overcome this resistance is critical. A multitude of agents designed to overcome resistance are currently being evaluated in the clinic including PI3-kinase inhibitors, more potent tyrosine kinase inhibitors, new antibody-drug conjugates, and novel immunotherapies. In addition, studies evaluating the genomic alterations present in metastatic HER2-positive cancer tissue are beginning to provide clues as to the mechanisms of resistance present in treatment refractory disease. It is possible that with continued improvements in therapies and a better understanding of molecular resistance mechanisms, mortality associated with metastatic HER2-positive breast cancer can be largely eliminated.
Citation Format: Ian Krop. Management of metastatic HER2 positive disease: optimizing current therapies and an overview of new agents in development [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 ES2-3.
Abstract OT3-1-06: A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (HER2)-positive breast cancer
Authors: Trudeau Maureen E , Winer Eric , Steinberg Joyce L , Liosatos Maggie , Poondru Srinivasu , Dydo Michael , Zhou Yun , Westphal Michael , Peterson Amy C , Gradishar William 
Published: May 2015

Abstract
Background
Androgen receptor (AR) expression is observed in ∼60% of patients (pts) with HER2+ breast cancer1. In vitro, ENZA inhibits proliferation of AR+/HER2+ cell lines and enhances the activity of trastuzumab. ENZA also inhibits proliferation of trastuzumab resistant HER2 positive cells2.
Methods
Any amount of AR expression (local or central) is allowed, submission of tissue is mandatory. Patients must have measurable disease per RECIST 1.1, and have received 1 to 4 prior lines of anti-HER2 therapy in the advanced / metastatic setting. Brain imaging is required to exclude patients with CNS metastases. Pts with a seizure history are excluded.
Women with metastatic or locally advanced HER2+, AR+, and ER-/PgR- breast cancer will receive daily ENZA (160 mg) continuously and trastuzumab (6 mg/kg) administered every 21 days, until disease progression (NCT02091960). The primary endpoint (EP) is clinical benefit rate (CBR) where benefit is defined as complete or partial response (CR or PR) or stable disease (SD) ≥24 weeks according to RECIST 1.1 criteria. Additional EPs include safety and tolerability, and the relationship between AR expression and ENZA activity. If the CBR is ≥3 in 21 evaluable pts, the sample size will increase to 66 pts.
The primary EP will be analyzed in pts with centrally confirmed AR expression (≥10% nuclear staining by IHC), who have received at least one dose of ENZA, and have ≥1 post-baseline tumor assessment. The null hypothesis (H0), that the true CBR is 10%, will be tested against a 1-sided alternative. This Simon’s two-stage design yields 90% power when the true response rate is 25% with a 1-sided type 1 error rate of 5%. Enrollment is expected to continue through 2016.
References:
1. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol. 2011;24(7):924-31.
2. J. Richer, AACR Advances in Breast Cancer, San Diego, CA, October 2013.
Citation Format: Maureen E Trudeau, Eric Winer, Joyce L Steinberg, Maggie Liosatos, Srinivasu Poondru, Michael Dydo, Yun Zhou, Michael Westphal, Amy C Peterson, William Gradishar. A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (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 OT3-1-06.
Abstract P1-02-11: Role of FDG-PET/CT in prediction of underestimation of invasive breast cancer in cases of ductal carcinoma in situ diagnosed at needle biopsy
Authors: Shigematsu Hideo , Kadoya Takayuki , Yoshimura Noriko , Kajitani Keiko , Emi Akiko , Masumoto Noriko , Haruta Rumi , Kataoka Tsuyoshi , Okada Morihito 
Published: May 2015

Abstract
Background: The aim of this study was to evaluate the significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for predicting the underestimation of invasive breast cancer in cases of ductal carcinoma in situ (DCIS) at needle biopsy.
Patients and Methods: Of 83 consecutive cases with diagnoses of DCIS at primary needle biopsy who underwent curative surgery between 2010 and 2013, the association between the maximum standardized uptake value (SUVmax) on FDG-PET/CT before excision and the underestimation of invasive breast cancer was examined.
Results: There were 29 (34.9%) cases diagnosed to have invasive breast cancer at excision. Receiver operating characteristics (ROC) curve analysis showed the cutoff value of SUVmax to predict underestimation of invasive breast cancer was 1.6. The rates of underestimation were 61.5% for patients with a tumor of SUVmax &gt; 1.6 and 11.4% for patients with a tumor SUV max ≤ 1.6 (p &lt;0.001). High value of SUVmax was significantly associated with symptomatic presentation (p &lt; 0.001), palpability (p &lt; 0.001), mass formation (p = 0.013), high Breast Imaging Reporting and Data System category (p = 0.011) and core needle biopsy (p = 0.007). In multivariate analysis, high SUVmax was only significant predictive factor of underestimation of invasive breast cancer (HR 11.7, 95% CI 3.70-37.0, p &lt; 0.001).
Association between each preoperative variable and underestimation of invasive component in multivariate analysis in cases of DCIS diagnosed at needle biopsyVariables HR (95% CI)P valuePresentationsymptomatic vs. screening detected1.64 (0.43-6.22)0.47Palpableyes vs. no1.54 (0.36-6.69)0.58Lesion size&lt; 2cm vs. ≥ 2cm1.23 (0.34-4.40)0.76Mass formationyes vs. no1.28 (0.36-4.44)0.7BI RADS category5 vs. 3, 42.92 (0.80-10.7)0.11Biopsy devicemammotome biopsy vs. CNB2.16 (0..64-7.30)0.21Nuclear gradehigh vs. not highhigh vs. not high 2.24 (0.51-9.78)0.29SUVmaxhigher vs. lower11.7 (3.70-37.0)&lt; 0.001BI RADS, Breast Imaging Reporting and Data System; DCIS, ductal carcinoma in situ; IBC, invasive breast cancer; SUVmax, maximum standardized uptake value
Conclusion: SUVmax on FDG-PET/CT is useful for predicting the underestimation of invasive breast cancer in cases of DCIS at needle biopsy.
Citation Format: Hideo Shigematsu, Takayuki Kadoya, Noriko Yoshimura, Keiko Kajitani, Akiko Emi, Noriko Masumoto, Rumi Haruta, Tsuyoshi Kataoka, Morihito Okada. Role of FDG-PET/CT in prediction of underestimation of invasive breast cancer in cases of ductal carcinoma in situ diagnosed at needle biopsy [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 P1-02-11.
Abstract P1-03-03: Experience in the community oncology practice with a 25-gene hereditary cancer panel
Authors: Diab Sami , Rodriguez Patricia , Leininger Anna , Clark Lisa , Janicek Mike F , Smith Ellen B , Sandbach John , Saam Jennifer , Langer Lucy 
Published: May 2015

Abstract
Introduction:
The identification of patients with an inherited cancer syndrome is becoming increasingly relevant in the treatment and prevention of cancer. Testing with a panel of genes provides the opportunity to rapidly identify or rule out deleterious mutations in several genes simultaneously and, thus, has the potential to streamline the testing process and more efficiently and accurately provide results. We report on the experience of panel-based testing in the community oncology setting.
Objectives:
To evaluate the performance of a 25-gene hereditary cancer test in the community oncology setting and describe the patient characteristics and test findings.
Methods:
We retrospectively evaluated the 25-gene panel testing data obtained between September 2013 and February 2014 in 6 large community oncology practices. The gene panel was based on next generation sequencing and rearrangement analysis of 25 genes with cancer risk data: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, CDKN2A, CDK4, PALB2, CHEK2, SMAD4, BMPR1A, STK11, TP53, CDH1, PTEN, ATM, NBN, BARD1, BRIP1, RAD51C, and RAD51D. Personal and family history was obtained by health care provider report on test requisition forms.
Results:
The panel test was performed on 359 individuals during the time period. 69.9% of these patients had a phx of at least one of the eight panel cancers: breast, ovarian, colorectal, endometrium, pancreas, melanoma, prostate, and/or stomach. cancer diagnosis. 97.8% of the patients tested met the 2013 NCCN guideline criteria for HBOC, 2012 NCCN guideline criteria for Lynch Syndrome, or both. 37 pathogenic mutations were found in 34 distinct patients. The variant rate in this population was 35.4%. Mutations were identified in 16 different genes, and only 20 of the 37 mutations (54.1%) were found to be in the 6 genes included in HBOC and Lynch Syndrome testing (BRCA1, BRCA2, MSH6, MLH1, MSH2, PMS2).
Conclusion:
The 25-gene hereditary cancer panel increased the identification of deleterious mutations which would otherwise not have been detected. The variant rate in this setting is similar to the rate reported previously in both community and academic centers where panel testing is used. Use of a hereditary cancer panel in the community oncology practice may improve detection rates and provide an opportunity for enhanced cancer management.
Citation Format: Sami Diab, Patricia Rodriguez, Anna Leininger, Lisa Clark, Mike F Janicek, Ellen B Smith, John Sandbach, Jennifer Saam, Lucy Langer. Experience in the community oncology practice with a 25-gene hereditary cancer 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 P1-03-03.