bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of Active Surveillance and Endocrine Therapy Alone for DCIS.
Authors: Meyerson A. , Joe B. , Wolverton D. , Lessing J. , Hwang E. 
Published: December 2010

Abstract
Objective: There are currently no nonsurgical options offered to patients with DCIS. The purpose of this study was to assess clinical outcome in a cohort of women declining surgery for pathologically proven ductal carcinoma in situ (DCIS) who have opted for endocrine therapy and clinical/radiographic follow-up.Methods: Between 2003 and 2008, 52 women with ER-positive DCIS enrolled in an IRB-approved single-arm study of 3 months of neoadjuvant enodocrine therapy. The study design included definitive surgical excision. However, 9 women withdrew from the parent study at completion of 3 months and declined surgery, opting instead for a plan of active surveillance, with the intent to proceed with conventional therapy in the event of disease progression or radiographic suspicion for invasive disease. All women were amenable for follow up every 6 months with diagnostic mammography and breast MRI, and wished to continue endocrine therapy, despite unproven benefit in this setting. Endocrine treatment consisted of tamoxifen for premenopausal women or an aromatase inhibitor for postmenopausal women. Each patient was informed of the current treatment guidelines for DCIS, as well as the increased future probability for invasive cancer in the absence of standard treatment for DCIS.Results: The median age of the cohort was 48 years (41-60 years) at enrollment. Of these, 5 women were premenopausal on Tamoxifen, and 4 were post menopausal (3 on letrozole and 1 on arimidex). At the time of analysis, median follow up was 23 months (range 9-66 months). During follow up, 4 patients proceeded with surgery either electively (1 patient) or due to changes at imaging (3 patients). Two of these patients had node-negative invasive breast carcinoma identified at surgery, measuring 6 mm and 4 mm. Five patients have elected to continue surveillance (median follow up 34 months; range 10-66 months), and have had either stable disease or continued regression based on both mammographic and MRI criteria. Four patients remain on endocrine therapy. The patient with longest follow up has had almost complete resolution of radiographic abnormalities at 6 years of surveillance.Conclusion: In this pilot cohort, two-thirds of women who continued endocrine therapy and surveillance for ER-positive DCIS had radiographically stable disease or regression with short-term follow up. Women who initially declined surgery elected to undergo excision in the face of radiographic progression. Active surveillance with endocrine therapy for ER-positive DCIS is feasible, and a well-informed patient cohort is essential to minimize risk. The impact of such an approach on long-term morbidity is unknown, but requires further investigation. Ongoing efforts to improve the detection of invasive cancer in women with DCIS are expected to facilitate such an approach.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 954.
Outcomes Following Accelerated Partial Breast Irradiation in ASTRO Consensus Statement Unsuitable Patients.
Authors: McHaffie D. , Patel R. , Das R. , Cannon G. 
Published: December 2010

Abstract
Purpose/Objective: There are limited data to guide patient selection for accelerated partial breast irradiation (APBI). In the recent ASTRO consensus statement, an unsuitable group was defined for whom APBI should only be offered in the context of a clinical trial. In this analysis, we reviewed the outcomes in this cohort of potentially higher risk patients.Materials/Methods: Between 2/2001 and 6/2006, a total of 322 consecutive patients were treated with HDR APBI at the University of Wisconsin. A total of 107 “unsuitable” patients were identified: 80 pts (74.7%) age &lt; 50, 19 pts (17.8%) node positive, 20 pts (18.7%) with LVSI, 3 pts (2.8%) with tumors &gt; 3 cm, and 2 pts (1.9%) with multifocal disease. 17 pts (15.9%) had multiple unsuitable features. In addition, 53 pts (49.5%) possessed “cautionary” features, including 19 pts (17.8%) ER negative and 10 pts (9.3%) with pure DCIS. The median age at diagnosis was 47 (range 25 – 84). All patients received 32 – 34 Gy in 8 - 10 bid fractions using multicatheter (93.5%) or Mammosite balloon (6.5%) HDR brachytherapy.Results: With a median follow-up of 60 months (range 1.1 - 97.8 months), there were 8 loco-regional recurrences (3 local only, 2 regional and 3 loco-regional and distant). Four of 5 patients without distant disease were successfully salvaged and had no evidence of disease at last follow-up. The 6 yr actuarial loco-regional control rate is 91.3% +/- 5.9%, with a latency to recurrence ranging from 10 – 41 months. The 6 yr disease free survival for the entire cohort is 89%, with a cause-specific survival and overall survival of 92.5% and 89%, respectively. There were no loco-regional recurrences observed among those with age &lt; 50 without other unsuitable (LVSI, node +, &gt; 3 cm, multifocality) or cautionary (ER -, EIC, tumor 2 – 3 cm, lobular histology, DCIS, &lt; 2 mm margins) features (n = 31). In comparison, the loco-regional recurrence rate is 12.3% for those deemed unsuitable by virtue of surgical and pathologic factors (p = .064). Loco-regional recurrences were observed in 2/19 node positive pts, 3/20 pts with LVSI, 1/2 pts with multifocal disease, 2/34 with age &lt; 50 alone and cautionary features, and 0/3 pts with tumors &gt; 3 cm.Conclusions: Currently, uncertainty exists regarding patient selection for APBI. Based upon the observed local recurrence rates in the current analysis and the well-established benefits of whole breast radiotherapy, we continue to encourage clinical trial participation among this cohort of patients, specifically RTOG 0412/NSABP B-39. Although not statistically significant, the absence of local failures among women &lt; 50 yrs without adverse histopathologic features suggests they may be appropriate candidates for APBI.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 955.
Breast Cancer Stem Cells and the Epithelial-Mesenchymal Transition.
Authors: Weinberg R. 
Published: December 2010

Abstract
The acquisition of highly malignant traits by carcinoma cells is often associated with the activation of a transdifferentiation program termed the epithelial-mesenchymal transition (EMT). The EMT program is deployed in a variety of steps of embryonic morphogenesis, enabling the interconversion of epithelial and mesenchymal cell types. When both normal and neoplastic epithelial cells undergo an EMT, they acquire addition changes in addition to expressing characteristic mesenchymal cell markers. In particular, they acquire motility, an increased resistance to apoptosis and, in the case of carcinoma cells, invasiveness. The motility and invasiveness components associated with the EMT would appear to empower many types of cancer cells to metastasize. An interesting question is how the resulting disseminated cancer cells are able to spawn a macroscopic tumor mass at distant anatomical sites, since this clonal expansion would appear to require an ability to self-renew. Recently, we have examined the cellular products of an EMT. Contrary to our expectations, the resulting cells acquired many of the attributes of stem cells, including the expression of stem cell-associated cell-surface markers. Conversely, mammary epithelial cells that naturally express these markers also express greatly elevated levels of at least four pleiotropically acting transcription factors that have been found able to induce an EMT. More recent studies have confirmed that the product of an EMT in mouse mammary epithelial cells is a cell that has a greatly increased ability to generate an entire mammary ductal epithelial tree. Moreover, we find that cells with the attributes of stem cells exist naturally as minor subpopulations in cultured human mammary epithelial cells. These cells can differentiate spontaneously into non-stem cells and, conversely, the non-stem cells appear capable of dedifferentiating spontaneously into cells with progenitor or stem-cell phenotypes. Hence, the study of certain aspects of mammary epithelial cell biology, including the biology of mammary carcinoma stem cells, may be feasible with cultured cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr A1-1.
Membrane ER in Endocrine Resistance in the Lab and the Clinic: Should We Be Convinced?
Authors: Dowsett M. 
Published: December 2010

Abstract
There is clear evidence, including from our own lab, that in vitro some ER-alpha localises to the plasma membrane in MCF7 cells that acquire resistance to tamoxifen (TamR cells) in contrast to the nuclear localisation in wild-type cells. Immunoprecipitation shows co-localisation of ER and HER2 with immunohistochemical studies unequivocally demonstrating the latter being exclusively membrane bound. Similar membrane localisation of ER-alpha is demonstrable in BT474 cells which are highly HER2-amplified. Clinical samples prepared after formalin-fixation and paraffin-embedding however do not show specific membrane staining with a variety of anti-ER-alpha antibodies, irrespective of whether these tumours are HER2 positive or negative or whether they have acquired tamoxifen resitance, including a small number of samples where this resistance is associated with a gain of HER2 expression. We have found that formalin-fixation of TamR cells leads to loss of ER-alpha membrane staining and that this might be considered a potential explanation for the discrepancy. However, a more compelling explanation is seen in the absence of membrane staining when these cells are grown in 3D culture, despite their identical fixation to those in 2D culture. The clinical and biological response of breast cancer to estrogen deprivation correlates well with nuclear levels of ER. We are currently assessing whether unique gene expression patterns seen with estrogen dendramer conjugates (kindly provided by John and Benita Katzenellenbogen) that cannot enter the nucleus of MCF7 cells correlate with gene expression changes seen in ER-alpha positive breast carcinomas after estrogen deprivation. While there is strong evidence for membrane localisation of ER-alpha of some breast cancer cells in some culture conditions no convincing evidence has yet been gathered for its occurrence in human breast carcinomas.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr BS2-2.
Cancer Immunoediting: Immunologic Control and Sculpting of Cancer.
Authors: Schreiber R. 
Published: December 2010

Abstract
Cancer Immunoediting is the process by which the immune system controls and shapes cancer. We originally envisaged that cancer immunoediting would occur in three phases: Elimination (also known as cancer immunosurveillance, the host protective phase of the process), Equilibrium (the phase in which tumor cells that survive immune elimination remain under immunologic growth control resulting in a state of functional tumor dormancy) and Escape (the phase where clinically apparent tumors emerge because immune sculpting of the tumor cells has produced variants that display either reduced immunogenicity or enhanced immunosuppressive activity). Strong experimental data has now been obtained using mouse models of cancer to demonstrate the existence of each phase of the cancer immunoediting process and compelling clinical data suggests that a similar process may also occur during the evolution of certain types of human cancer. Our efforts now focus on elucidating the molecular and cellular mechanisms that underlie each phase of cancer immunoediting and identifying the critical checkpoints that regulate progression from one phase of the process to the next. This approach has led to the discovery of a new mouse cancer model that shows remarkable developmental, molecular and functional similarity to human estrogen receptor alpha positive (ERα+) luminal breast cancer. We have found that the cancers in our mice arise as a result of dysfunctional JAK-STAT pathway signaling and, interestingly, this observation has led to the discovery of a heretofore-unrecognized similar phenotype in a subset of human ERα+ luminal breast cancers. The therapeutic implications of our work will be discussed.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr BS3-1.
Epigenetic Therapy.
Authors: Issa J. 
Published: December 2010

Abstract
Epigenetic changes such as alterations in DNA methylation and histone modifications have been well described in various malignancies and are now recognized as targets of therapy (epigenetic therapy). The aim of epigenetic therapy is to reverse epigenetic changes and reactivate important genes thereby modifying the malignant phenotype and inducing clearance of the malignant clone by various mechanisms. Epigenetic modifying agents may also have mechanisms of anticancer action unrelated to gene reactivation. The hypomethylating drugs azacitidine and decitabine induce clinically meaningful remissions or improvements in 30-60% of patients with myeloid leukemias and prolong survival compared to standard approaches including chemotherapy. Both drugs been approved in the USA for the treatment of advanced and/or symptomatic MDS. Their clinical activity in other malignancies including breast cancer is poorly defined because published studies used drug doses and schedules of administration that are not optimal for epigenetic activation. New clinical trials are addressing their potential role in solid tumors. Histone deacetylase inhibitors belong to another class of epigenetic modifying agents. Clinically, they have impressive single agent activity in lymphoid malignancies, but have been disappointing so far in other cancers. However, they are synergistic with many cytotoxic or targeted agents, and their ultimate clinical role may well lay in combination studies. Current studies are focusing on identifying drugs that target additional epigenetic pathways such as the polycomb group proteins, as well as combinations of drugs to affect multiple epigenetic pathways simultaneously.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES4-3.
Clinical Trials 102: New Strategies in Targeted Therapy Clinical Trials.
Authors: Hilsenbeck S. , Piccart M. 
Published: December 2010

Abstract
The practice of clinical oncology is guided by randomized phase III clinical trials that are powered to detect average benefit of a therapeutic intervention when compared to standard treatment in large group of breast cancer patients. Although such “evidence-based” practice has moved clinical oncology from empiricism to scientific rigor, it is difficult for oncologists to apply these standards and predict whether a particular treatment will be effective for an individual patient. Recent advances in molecular profiling have begun to unravel the biological variations that underlie individual susceptibility, disease behavior, and response to therapy. Our improved understanding of the biological basis of breast cancer has coincided with the development of rationally designed “targeted therapies” that modulate specific oncogenic signaling pathways. The clinical development of trastuzumab, a monoclonal antibody against the HER2 receptor, illustrates how a targeted therapy that is associated with a well-defined predictive marker can produce dramatic gains in clinical effectiveness. In contrast, bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, has shown promising activity in advanced breast cancer, although its clinical development has been hindered by the lack of a clear predictive marker that can be used to guide therapy. In the future, the clinical testing of targeted therapies must be linked with biomarker discovery and validation at earlier stages of clinical development so that patients likely to benefit can be identified. In addition, the traditional approach of conducting early development trials in the second-line metastatic setting where relevant tissue for biomarker development is often not available, and where resistance may have developed, also hampers targeted therapy development. Neoadjuvant and "window of opportunity" studies coupled with biopsy of the primary tumor, offer possible solutions, and are being used more oftern. The Breast International Group (BIG) will launch a program of randomized phase II neo-adjuvant clinical trials (NeoBIG) to accelerate drug and biomarker development. These studies will integrate emerging technologies, such as genomics, proteomics, metabolomics, pharmacogenetics and functional imaging, to identify predictive markers of efficacy that can be validated in subsequent adjuvant registration trials.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES5-1.
Obesity, Insulin Resistance and Insulin.
Authors: Goodwin P. 
Published: December 2010

Abstract
There is growing acceptance that overweight and obesity are associated with poor outcomes in early stage breast cancer. This effect has been reported in pre-and postmenopausal women, regardless of hormone receptor status. Postulated mechanisms have included presentation of cancer at a more advanced stage, underdosing of chemotherapy and higher levels of endogenous estrogens in overweight and obese women. Recent research has provided strong evidence that insulin may play a key role in mediating these prognostic effects. Overweight and obesity are associated with insulin resistance (and resulting hyperinsulinemia) in both the general population and in breast cancer patients; both insulin resistance and high insulin levels have been associated with increased risk of breast cancer recurrence or death, independent of traditional prognostic factors. Breast cancer cells commonly overexpress insulin receptors (frequently a fetal form of the receptor that may hybridize with the IGF-1 receptor), providing a biologic basis for a prognostic effect of insulin. These receptors are not downregulated by circulating insulin; as a result, cancer cell growth may be stimulated by high circulating insulin levels, leading to poor prognosis. Preclinical work provides strong evidence for a mitogenic role of insulin in breast cancer. Taken together, these observations have led to the development of lifestyle interventions targeting insulin and/or insulin resistance in breast cancer patients. Interventions include weight loss (which reduces insulin levels in the general population) and physical activity (which has been shown to reduce insulin in breast cancer patients). Randomized trials of weight loss are ongoing and planned. One completed trial (Women's Intervention Nutrition Study, J Natl Cancer Inst 2006;98:1767-1776) reported improved relapse free survival in breast cancer patients randomized to a reduced fat diet (that was associated with significant weight loss). Effects were greatest in hormone receptor negative breast cancer. Recent interest has focused on the use of metformin, a biguanide commonly used to treat type 2 diabetes. Metformin reduces insulin resistance and lowers insulin levels in many populations, including early stage breast cancer patients. In addition to this indirect (insulin lowering) effect, metformin may also exert direct anti-tumor effects via mTOR inhibition. Studies using metformin in the neoadjuvant setting in breast cancer are ongoing. The effect of metformin on breast cancer outcomes (with embedded correlative studies that will examine direct and indirect effects of the drug) will be examined in NCIC MA.32, a randomized trial of metformin versus placebo involving 3582 women with early breast cancer that will be activated in early 2010. Together, these lifestyle and pharmacologic studies will provide important information on the effect of modification of a key host factor (obesity with associated hyperinsulinemia) on breast cancer outcomes.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr MS2-1.
The Development of PI3K Pathway Modulators for Cancer.
Authors: Sellers W. 
Published: December 2010

Abstract
The phosphoinositide-3 kinase pathway is a key oncogenic pathway in breast cancer where direct mutation of PIK3CA, loss-of-function of PTEN and amplification of HER2 all result in constitutive pathway activation. The pathway, under physiologic control, integrates extracellular growth factors signals with nutrient and other environmental conditions such as hypoxia to enact directed changes in cell proliferation, survival, migration and the regulation of key metabolic pathways such as glucose homeostasis. In cancer the constitutive activation of the pathway leads to the untoward induction of proliferation and cell survival. In addition, pathway function is likely required for hypoxia-mediated induction of angiogenesis. These observations/discoveries have motivated and set the stage for the development of therapeutic molecules targeting key pathway components. The progression of allosteric mTOR inhibitors, catalytic mTOR inhibitors, dual mTOR/PI3K inhibitors and selective PI3K inhibitors in the clinic heralds the opportunity to answer critical questions regarding the role of this pathway in breast cancer. The data emerging from the pre-clinical and clinical development of a series of distinct pathway inhibitors targeting mTOR and PI3K will be discussed with a focus on understanding pathway dependence pre-clinically and in humans.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr P2-1.