bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract S3-07: 16 year long-term follow-up of the IBIS-I breast cancer prevention trial
Authors: Cuzick Jack , Sestak Ivana , Cawthorn Simon , Hamed Hisham , Holli Kaija , Howell Anthony , Forbes John F 
Published: May 2015

Abstract
Background: Several randomised clinical trials have shown the benefit of tamoxifen in healthy women to reduce their risk of breast cancer. Here, we report the blinded median 16 year follow-up of the IBIS-I trial to update the long-term prevention of breast cancer with tamoxifen treatment.
Methods: 7154 pre- and postmenopausal women were randomised to receive daily 20mg tamoxifen (N=3579) or matching placebo (N=3575) for 5 years. The primary endpoint of this analysis was the occurrence of breast cancer (invasive and ductal carcinoma in situ (DCIS)). Secondary endpoints included overall mortality, other cancers, and breast cancer specific mortality. Cox proportional hazard models were used to assess occurrence of breast cancer and survival. All statistical tests were two-sided.
Results: After a median of 16.2 years (IQR 14.4 to 17.7) of follow-up, a total of 589 breast cancers have been reported (tamoxifen: 246 (6.9%) vs. placebo: 343 (9.6%)). Tamoxifen reduced the incidence of all breast cancer overall by 29% (HR=0.71 (0.60-0.83), P&lt;0.0001) (Figure 1). Invasive ER-positive (ER+) breast cancers were reduced by 35% (HR=0.65 (0.53-0.80), P&lt;0.0001) (Figure 1), but no effect was seen for invasive ER-negative (ER-) breast cancers (HR=1.06 (0.71-1.58), P=0.8). A non-significant 30% reduction in DCIS was seen with tamoxifen (36 vs. 51, HR=0.70 (0.46-1.07); P=0.1). The overall risk reduction was similar in years 0-10 (HR=0.71) and years 10-20 (HR=0.70). Similar effects were seen in pre- and postmenopausal women (HR 0.71 vs. 0.71). All-cause mortality was non-significantly increased in women randomised to tamoxifen (173 vs. 158, OR=1.10 (0.88-1.38), P=0.4). The excess in deaths with tamoxifen is smaller than in the 96 month update. No differences in breast cancer mortality was seen (24 tamoxifen vs. 27 placebo; OR=0.89 (0.49-1.60), P=0.7). A non-significant increase in other cancers than breast were reported by women on tamoxifen (350 vs. 315, OR=1.12 (0.95-1.32); P=0.2). Specifically more endometrial cancers (28 vs. 17), non-melanoma skin cancers (108 vs. 85), and lung cancer (32 vs. 20) were found in those randomised to tamoxifen.
Conclusion: This updated analysis of the IBIS-I trial confirms the significant reduction in breast cancer occurrence with tamoxifen in the post-treatment follow-up period. These results indicate tamoxifen has a long-term preventive effect on invasive ER+ breast cancer in both pre- and postmenopausal women.
Citation Format: Jack Cuzick, Ivana Sestak, Simon Cawthorn, Hisham Hamed, Kaija Holli, Anthony Howell, John F Forbes. 16 year long-term follow-up of the IBIS-I breast cancer prevention 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 S3-07.
Abstract SF1-2: Improving access to innovative anticancer medicines: a clinicians viewpoint
Authors: Schellens Jan H. M. 
Published: May 2015

Abstract
For most forms of cancer there is high unmet need. This is especially the case for advanced cancer. Improved understanding of mechanisms of unresponsiveness to currently available treatments and identification of novel drugable targets have boosted anticancer drug development, often leading to so-called breakthrough medicines, i.e. drugs that can dramatically improve cure rate and survival. The monoclonal antibodies (mAb) trastuzumab and rituximab and the tyrosine kinase inhibitor (TKI) imatinib, developed in the recent past, deserved this qualification. These drugs have not only changed the standard of practice, they also served as template for new drug development leading to EMA & FDA approval of &gt;30 novel mAbs and TKIs for cancer indications since the introduction of rituximab in 1998. However, this does not guarantee swift patient access to new medicines nor to equal access for all indicated patients. Also, some drugs with high anticancer potential in well defined cancer populations simply seem to be stuck in development. One of the examples of missed opportunities is the group of the PARP inhibitors (PARPi): first patient included in phase I was in the year 2005 and now almost a decade later there is still no availability worldwide for well characterized populations with BRCAm, including breast and ovarian cancer, of PARPi treatment. Clearly, there is room for improvement, for which there is a range of good opportunities: shorten time to registration, shorten time to reimbursement, improve patient selection, limit to well defined subsets and expand later, setup global biomarker networks, setup global well controlled access programs and lastly take more risk. These opportunities will be discussed and examples will be given.
Citation Format: Jan H. M. Schellens. Improving access to innovative anticancer medicines: a clinicians viewpoint [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 SF1-2.
Abstract A021: Loss-of-function screen for breast tumor initiating cells reveals PRC1 dependence
Authors: Chung Chi-Yeh , Gaspar-Maia Alexandre , Mullokandov Gavriel , Bosch-Gutierrez Almudena , Farias Eduardo , Brown Brian , Bernstein Emily 
Published: May 2015

Abstract
Breast tumor-initiating cells (BTICs) are a subset of cells within breast tumors thought to be more tumorigenic than non-BTICs and possess both self-renewal and differentiation potential. Gene expression and functional studies have demonstrated a correlation between BTICs and high-grade tumors, poor patient prognosis, and therapy resistance; however, the mechanisms underlying BTIC regulation remains poorly understood. Because epigenetic alterations play a key role in breast cancer progression and in stem cell regulation, we hypothesized that epigenetic factors mediate BTIC function. Using a mouse MMTV-Myc mammosphere (MS) culture system, which we showed to be enriched in BTICs by in vivo tumorigenicity assays and gene expression studies, we performed a pooled shRNA library screen coupled to next generation sequencing (NGS). Using a library of ~450 shRNAs targeting 60 epigenetic regulators, our screen identified multiple members of the Polycomb Repressive Complex 1 (PRC1) as top candidates, with shRNAs targeting PRC1 members significantly depleted in MS cells, but not in control bulk cells. This strongly suggests that PRC1 is required for MS/BTIC function. We have validated that knockdown of PRC1 members reduces MS formation and BTIC ‘markers’ in MMTV-Myc cells and human MDAMB-231Luc cells in vitro, and are currently performing in vivo tumorigenesis assays. Further, RNA-Seq and ChIP-Seq is underway to decipher the mechanisms by which PRC1 mediates BTIC regulation. In accordance with our screen, The Cancer Genome Atlas (TCGA) reports several members of PRC1 to be overexpressed in breast tumors, and we are further exploring the clinical relevance of PRC1 members in breast cancer patient samples.
Citation Format: Chi-Yeh Chung, Alexandre Gaspar-Maia, Gavriel Mullokandov, Almudena Bosch-Gutierrez, Eduardo Farias, Brian Brown, Emily Bernstein. Loss-of-function screen for breast tumor initiating cells reveals PRC1 dependence. [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 A021.
Abstract A027: Endothelial-like properties of triple-negative claudin-low breast cancer cells promote tumor-vascular interactions and tumor permeability
Authors: Harrell J. Chuck , Pfefferle Adam , Zalles Nicole , Prat Aleix , Fan Cheng , Khramtsov Andrey , Olopade Olufunmilayo , Troester Melissa , Dudley Andrew , Perou Charles 
Published: May 2015

Abstract
The different intrinsic subtypes of human breast tumors vary in rate and location of metastatic dissemination. In this study, we aimed to determine if tumor-associated vascular properties could help to explain the differences observed in metastagenicity. We used endothelial and breast cancer cell line models to develop gene expression signatures that measured vascular quantity and vascular proliferation. We tested these signatures, amongst other published endothelial signatures, and found that the genomic programs that measured vascular quantity, vascular proliferation, and a VEGF/Hypoxia-signature were the most highly expressed in claudin-low and basal-like tumors. We then tested the vascular signatures on five human breast cancer datasets (n&gt;3,000) and identified two vascular signatures that added prognostic information to intrinsic subtype classification. Next, microvessel density (MVD) scores were obtained from a set of 70 tumors which were also subjected to gene expression profiling. Interestingly, several of the vascular signatures added metastasis-predicting information in addition to MVD (p&lt;0.05). Similar to the tumor data, claudin-low cell lines also expressed high levels of vascular gene signatures as compared to luminal cell lines. Interestingly, pure claudin-low cell lines, and subsets of claudin-low-like cells within established basal-like cell cancer cell lines, exhibited endothelial-like morphology when culture on Matrigel. In vivo xenografts of claudin-low tumors, but not luminal tumors, extensively perfused injected contrast agent through paracellular spaces and non-vascular tumor-lined channels. Taken together, the endothelial-like characteristics of the cancer cells, combined with both the amount and the physiologic state of the vasculature, contribute to breast cancer metastatic progression. We hypothesize that the genetic signatures we have identified highlight patients that should respond most favorably to anti-vascular agents.
Citation Format: J. Chuck Harrell, Adam Pfefferle, Nicole Zalles, Aleix Prat, Cheng Fan, Andrey Khramtsov, Olufunmilayo Olopade, Melissa Troester, Andrew Dudley, Charles Perou. Endothelial-like properties of triple-negative claudin-low breast cancer cells promote tumor-vascular interactions and tumor permeability. [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 A027.
Abstract A040: Id-1 increases mammary basal stem cell activity and tumorigenesis by activating the Wnt/c-Myc pathway
Authors: Shin Dong-Hui , Lee Jeong-Yeon , Jang Ki-Seok , Min Kyueng-Whan , Jang Si-Hyong , Oh Seung Hyun , Kong Gu 
Published: May 2015

Abstract
Inhibitor of differentiation/DNA binding (Id)-1 is a crucial regulator of mammary development and breast cancer progression. Here, we demonstrate that Id-1 induces mammary tumorigenesis by increasing normal and malignant mammary stem cell (MaSC) activities. MaSC expansion and increased self-renewal and in vivo regenerative capacity of MaSCs were observed in the mammary glands of MMTV-Id-1 transgenic mice. Id-1 maintains the MaSC-enriched basal cells, but not the luminal cell lineage, in the mammary glands. Furthermore, Id-1 induces ductal hyperplasia and mammary tumors with high expression of basal markers in MMTV-Id-1 transgenic mice. It also increases breast cancer stem cell populations and activity in human breast cancer lines. In experiments with mouse primary mammary epithelial cells and human cancer cells, the effects of Id-1 on normal and cancer stem cell activity were shown to be mediated by the Wnt/c-Myc pathway. Collectively, these findings indicate that Id-1 regulates mammary basal stem cells by activating the Wnt/c-Myc pathway, thereby contributing to basal marker-positive breast tumor development.
Citation Format: Dong-Hui Shin, Jeong-Yeon Lee, Ki-Seok Jang, Kyueng-Whan Min, Si-Hyong Jang, Seung Hyun Oh, Gu Kong. Id-1 increases mammary basal stem cell activity and tumorigenesis by activating the Wnt/c-Myc pathway. [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 A040.
Abstract A076: Deficiency of Fes tyrosine kinase expression correlates with delayed mammary tumor onset in a HER2/Neu overexpressing transgenic mouse model
Authors: Zhang Connie Shengnan , Greer Peter A. 
Published: May 2015

Abstract
Fes (a.k.a. Fps) is a cytoplasmic protein tyrosine kinase that is highly expressed in breast epithelial cells during lactation, as well as in vascular endothelial and myeloid cells. Retrovirally encoded oncogenic alleles of Fes are associated with tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established.
Using an orthotopic mouse mammary engraftment model, we previously found that Fes deficiency correlated with reduction in engrafted tumor growth rates, lung metastasis, and circulating tumor cells. Reduced vascularity and fewer infiltrating macrophages suggested the tumor microenvironment of Fes-deficient mice was less supportive of tumor growth and metastasis. In co-culture with tumor cells, Fes-deficiency in macrophages correlated with a reduced ability to promote tumor cell invasive behavior. These results suggested a tumor promoting role of Fes kinase in breast cancer through roles in cells of the tumor microenvironment.
In a transgenic mouse model of breast cancer driven by an activated HER2/Neu allele expressed in the mammary epithelium, we observed delayed tumor onset in Fes-deficient mice compared to wild-type mice. However, there was no difference in tumor growth rates.
Taken together, these observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages, or by delaying breast tumor onset in women with HER2 overexpression.
Note:This abstract was not presented at the conference.
Citation Format: Connie Shengnan Zhang, Peter A. Greer. Deficiency of Fes tyrosine kinase expression correlates with delayed mammary tumor onset in a HER2/Neu overexpressing transgenic mouse model. [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 A076.
Abstract A113: Chronic stress promotes lymph node metastasis through beta-adrenergic regulation of lymphangiogenesis
Authors: Le Caroline P. , Pimentel Matthew A. , Kim Corina , Nowell Cameron J. , Karnezis Tara , Chai Ming G. , Herald Marco , Stacker Steven A. , Sloan Erica K. 
Published: May 2015

Abstract
Lymphangiogenesis drives breast cancer metastasis to lymph nodes. However, the physiological pathways that regulate lymphangiogenesis and lymph node metastasis are yet to be defined. We have previously shown that chronic stress increased metastasis of primary tumour cells to lymph nodes via beta-adrenergic receptor signaling. Consistent with a critical role for beta-adrenergic signaling in cancer progression, recent clinical studies found that blockade of beta-adrenergic activation protected women with triple negative breast cancer from distant metastasis.
To investigate if the beta-adrenergic pathway promotes metastasis by impacting lymphangiogenesis, we explored the effect of restraint stress or pharmacological activation of beta-adrenergic pathways in an orthotopic xenograft model of triple negative breast cancer. To physiologically activate beta-adrenergic signaling, mice were subjected to 2 hours of daily restraint for 7 days prior to tumor cell inoculation and 14 days thereafter. Serial bioluminescence imaging revealed chronic stress reduced time to lymph node metastasis and increased tumor cell load in draining lymph nodes. Stress increased the expression of lymphangiogenic factor VEGF-C and its receptor Vefgr-3 and increased lymphangiogenesis within primary tumors. Pharmacological activation of beta-adrenergic signaling with isoproterenol similarly increased lymphangiogenesis and metastasis.
Prostaglandin-mediated dilation of lymphatic collector vessels was recently linked to increased breast cancer metastasis. We found stress increased expression of COX-2, the rate limiting enzyme in prostaglandin production, and increased dilation of lymphatic vessels that link primary tumors to draining lymph nodes. Treatment with COX-2 inhibitor celecoxib reversed stress-induced lymph vessel dilation and similarly blocked stress-enhanced lymph node metastasis and tumor lymphangiogenesis.
Together, these data show that beta-adrenergic receptor signalling may be an important effector pathway of stress-enhanced lymphangiogenesis and LN metastasis and that beta-blockade of lymphangiogenesis may be an important mechanism in protecting women with breast cancer from the adverse effects of stress biology.
Citation Format: Caroline P. Le, Matthew A. Pimentel, Corina Kim, Cameron J. Nowell, Tara Karnezis, Ming G. Chai, Marco Herald, Steven A. Stacker, Erica K. Sloan. Chronic stress promotes lymph node metastasis through beta-adrenergic regulation of lymphangiogenesis. [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 A113.
Abstract A118: The mTORC2 component Rictor directs branching morphogenesis and survival in the mammary epithelium
Authors: Morrison Meghan M. , Hicks Donna , Cook Rebecca S. , Brantley-Sieders Dana M. 
Published: May 2015

Abstract
The intracellular serine/threonine kinase mTOR functions in two distinct complexes that integrate many cellular cues to regulate diverse processes in development and disease. Raptor-dependent mTOR Complex-1 (mTORC1) mediates cell growth and metabolism, whereas the less well-studied Rictor-dependent mTOR Complex-2 (mTORC2) promotes cell survival and cytoskeletal organization. Previous studies link mTORC1 to malignant transformation of mammary epithelial cells (MECs). The role of mTOR and the relative contributions of mTORC1 versus mTORC2 in postnatal mammary morphogenesis, however, remain unclear. We report that mTORC2 ablation via Rictor loss impaired branching morphogenesis, MEC survival, MEC migration, and mTORC2-mediated signaling through Akt and Rac1-GTPase in vivo and ex vivo. Constitutively active Rac1 (CA-Rac1) rescued branching, invasion, and survival of mTORC2-impaired MECs, but CA-Akt did not. These effects were recapitulated by rapamycin treatment. Surprisingly, genetic mTORC1 disruption via Raptor gene targeting did not affect ascinar mammary morphogenesis in organoids or in vivo, but did cause decreased signaling through the mTORC1 effector ribosomal protein S6 and transiently slowed cellular proliferation. These data demonstrate the distinct, non-overlapping properties of mTORC1 and mTORC2 during post-natal mammary development, roles which may be preserved in breast cancers.
Citation Format: Meghan M. Morrison, Donna Hicks, Rebecca S. Cook, Dana M. Brantley-Sieders. The mTORC2 component Rictor directs branching morphogenesis and survival in the mammary epithelium. [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 A118.
Abstract A130: Progesterone expands a hormone-dependent progenitor population in luminal breast cancers
Authors: Fan Huaping , Horwitz Kathryn B. 
Published: May 2015

Abstract
More women die of Luminal, hormone-dependent, breast cancers than any other types. These tumors are estrogen (ER) and progesterone (PR) receptor-positive. Luminal cancers can recur many years after diagnosis, and when they do, they are just as deadly as rapidly-recurrent Basal cancers. Cytokeratin 5 (CK5) is a marker of triple negative Basal breast cancers. We have models in which Luminal breast cancer cells grown as xenografts in ovx'd mice or as 3D colonies in hormone-free or estrogen (E)-containing media are ER+PR+CK5–. However, if E is supplemented with progesterone (P), an ER–PR–CK5+ Basal-like subpopulation expands; we term these cells “Luminobasal”. Detailed IHC shows heterogeneity within the E+P-induced Luminobasal population, with rare cells that are ER+PR+CK5+; hence “Double Positive”. Similar “Double Positive” cells can be detected in clinical Luminal tumor samples stained for PR and CK5. Luminal cells in E+P colonies were FACS-sorted into CK5+ and CK5– subpopulations. RNA was extracted and subjected to gene expression profiling. The gene list was analyzed for cell surface markers unique to the CK5+ cells that might be useful for live-cell FACS sorting. Several were tested, and one marker is of considerable interest. FACS analysis shows that these Double Positive cells are rare (0.12%) in E, but increase to 6.63% under E+P. The cells are confirmed PR+CK5+ by IHC. Importantly, these PR+CK5+ cells form mammospheres indicating their self-renewal capacity. In the absence of hormones, the cells within the mammospheres differentiate into the heterogenous subpopulations that characterize Luminal disease, including PR+CK5–, PR–CK5+ and PR+CK5+ cells. Studies of hormone dependence and tumor-forming potential are ongoing. We speculate that Double Positive cells are progenitors of Luminal tumor-cell heterogeneity.
Citation Format: Huaping Fan, Kathryn B. Horwitz. Progesterone expands a hormone-dependent progenitor population in luminal breast cancers. [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 A130.