bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-12-01: Survival of women with inflammatory breast cancer: A large population based study
Authors: Dawood S , Lei X , Dent R , Gupta S , Sirohi B , Cortes J , Cristofanilli M , Bucholz T , Gonzalez-Angulo AM 
Published: August 2014

Abstract
Background
The introduction of efficacious polychemotherapy regimens and targeted biologicals has contributed to significant improvements in survival of women with breast cancer. However, our group has previously reported that women with inflammatory breast cancer (IBC) continue to have worse outcome compared to those with non-inflammatory breast cancer. We undertook this population based study to see if there have been improvements in survival among women with stage III IBC, over time.
Methods
We searched the Surveillance, Epidemiology and End Results Registry to identify female patients diagnosed with stage III IBC between 1990 and 2010. Follow up cut off was December 31st 2010. Patients were defined as having IBC according to the AJCC 6th edition criteria. Patients were divided into 4 groups according to year of diagnosis: 1990-1995, 1996-2000, 2001-2005 and 2006-2010. Breast cancer specific survival (BCSS) was estimated using the Kaplan-Meier method and compared across groups using the log rank statistic. Cox models were then fitted to determine the association of year of diagnosis and BCSS after adjusting for patient and tumor characteristics.
Results
7,679 patients with IBC were identified of whom 1,084 patients (14.1%) were diagnosed between 1990-1995, 1,614 patients (21.0%) between 1996 -2000, 2,683 patients (34.9%) between 2001-2005 and 2,298 patients (29.9%) between 2006-2010. Median follow-up was 30 months. The 2-year BCSS for the whole cohort was 71%. 2-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990-1995, 1996-2000, 2001-2005 and 2006-2010 respectively (p&lt;0.0001). The absolute increase in 2-year BCSS over the immediately preceding time period were 5%, 5%, and 4%, respectively. Significant improvements in survival over time were also observed among patients younger and older than age 35 years. In a multivariable cox regression analysis increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risk of death from breast cancer (HR = 0.98, 95% CI: 0.97 – 0.99, P &lt; 0.0001).
Conclusion
There has been a significant improvement in survival of patients diagnosed with IBC over a two decade time span in this large population based study. This suggests that therapeutic strategies researched and evolved in the context of non inflammatory breast cancer have also had a positive impact in women with IBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-01.
Abstract P6-12-11: Celecoxib inhibits the growth of IBC tumors by suppressing the regulation of cancer stem-like cells by nodal
Authors: Reyes ME , Zhang D , Eckhardt B , Masuda H , Pirman DA , Reuben JM , Woodward W , Yang P , Hortobagyi GN , Wang X , Ueno NT 
Published: August 2014

Abstract
Background: Inflammatory breast cancer (IBC) is an aggressive type of breast cancer with no known molecular targets for treatment. Although erythema is commonly associated with IBC, the molecular mechanism of inflammation in the pathogenesis of IBC remains unknown. We have previously shown that EGFR is an emerging target in IBC (Zhang D. et al Clin Can Res 2009). As crosstalk between EGFR and COX-2 plays an important role in the inflammatory response in several cancers, including breast cancer, we hypothesized that COX-2 promotes the tumorigenesis and metastasis of IBC cells.
Methods: Using clinically derived IBC and non-IBC tumor samples, a Spearman's Rank correlation coefficient analysis was performed to analyze the expression levels of COX-2 and EGFR in IBC and non-IBC. The levels of COX-2 metabolites, prostaglandins (PGs) PGE2 and PGF2α, were measured in IBC and non-IBC cell lines by HPLC/MS method. Cell migration and invasion assays were performed using SUM149 and KPL-4 IBC cell lines treated with PGs or the COX-2 inhibitor, celecoxib. We evaluated the epithelial to mesenchymal transition (EMT)-like phenotype in 3D culture of SUM149 cells treated with celecoxib, and the stem-like population by mammosphere formation, and CD44+/CD24− and aldefluor+ population by FACS. We treated preclinical IBC xenograft mice with celecoxib and measured tumor growth, PGs levels, and the expression of EMT protein markers. Nodal, a stem cell regulator and potential biomarker for breast cancer progression, was evaluated in IBC cells following treatment with celecoxib and recombinant Nodal or transfection with Nodal cDNA.
Results: EGFR and COX-2 expression levels positively correlated within IBC, but not non-IBC tumors. Elevated levels of PGE2 and PGF2α were identified in multiple IBC cell lines suggesting that COX activity is elevated within IBC compared to non-IBC cells. PGs altered EMT protein markers and promoted cell migration and invasion, while Celecoxib inhibited EMT and migration and invasion in SUM149 and KPL-4 cells. Celecoxib treatment inhibited tumor growth in mice, and downregulated the expression of EMT protein markers, including Nodal. Celecoxib decreased the stem-like CD44+/CD24−, and aldefluor+ population and the formation of mammospheres. Exogenous Nodal mitigated the effects of celecoxib on cell migration and invasion and the stem-like population in SUM149 cells.
Conclusion: We conclude that activation of the COX-2 inflammatory signaling pathway is critical in the development and progression of IBC. This study provides a novel insight into how inflammation may regulate cancer stem cells via Nodal, and will guide future research into the development of stem cell targeted therapies for IBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-11.
Abstract P6-12-14: Histone deacetylase inhibitor suberoylanilide hydroxamic acid targets breast cancer stem cells and inhibits metastasis
Authors: Chu K , Green TL , Boley KM , Cristofanilli M , Robertson FM 
Published: August 2014

Abstract
Introduction: Inflammatory breast cancer (IBC) is a distinct and aggressive subtype of locally advance breast cancer associated with increased aldehyde dehydrogenase 1 (ALDH1) positive cancer stem cells (CSCs). IBC is associated with a poor survival rate (40% 5-year survival), with few therapeutic strategies identified that effectively blocked the growth and metastasis of IBC. Our previous in vitro studies revealed that the pan-histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) effectively targets self-renewal of IBC tumor cells.
Materials and Methods: The IBC cell line, SUM149 was tagged with the Luciferase gene (SUM149-LUC) and their in vivo growth in immune compromised mice tested in both orthotopic and metastatic settings.
Results: SUM149-LUC rapidly develop primary tumors and metastatic lesions at a variety of locations including lung, brain, bone, liver, reproductive organs and adrenal glands. SAHA effectively blocked growth of SUM149 primary tumors and inhibited metastasis, which was synergistic with the microtubule stabilizer, Paclitaxel. The therapeutic efficacy of SAHA was associated with a significant decrease in ALDH1+ CSCs populations.
Conclusions: Collectively, these results suggest that strategies of combining agents such as SAHA that target CSCs with Paclitaxel that targets the bulk of proliferating tumor cells warrant further investigation for their potential effectiveness in IBC patients, who have the lowest survival of breast cancer patients and have few therapeutic options.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-14.
Abstract P6-12-15: Preclinical testing of a novel platelet derived growth factor receptor alpha (PDGFRa) inhibitor in inflammatory breast cancer
Authors: Joglekar M , Van Laere S , Vermeulen P , Dirix L , Carter M , Rhamchandran A , van Golen KL 
Published: August 2014

Abstract
Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer and carries a guarded prognosis. IBC presents with a “lumpless” primary tumor, which rapidly infiltrates and forms tumor emboli within the dermal lymphatic vessels of the skin overlying the breast. It is clear from the recent research advancements that IBC is a unique entity, not only in its clinical presentation, disease progression and response to therapy but also in its molecular expression profile. Therefore, it is essential to carry out molecular expression studies in IBC compared to non-IBC as well as to pursue these differences to study their effects on IBC phenotype. Our laboratory has demonstrated that the platelet derived growth factor receptor alpha (PDGFRa) is significantly over expressed in IBC patient samples (between 15-36%) compared to non-IBC patient samples. Using multiple approaches we demonstrate the PDGFRα activation signature in IBC patient samples and cell lines. Our data demonstrates that PDGFRα is constitutively active and localized in the cytoplasm of IBC cells. Although the receptor is intracellular, PDGFRα signaling remains intact. Thus, PDGFRα is an attractive target for therapy. Here we show that a novel PDGFR inhibitor, crenolanib, which specifically targets active PDGFR, is able to significantly inhibit IBC tumor growth and progression. In nude mice, 200 mm3 orthotopic IBC tumors did not increase in size when the mice were treated with crenolanib. In contrast, mice treated with vehicle control demonstrated a 4-fold increase in tumor growth over the 2-week course of the experiment. In addition, by using a novel in vitro IBC emboli growth model, we demonstrate that crenolanib prevents IBC tumor emboli formation and acts to sensitize IBC cells to chemotherapeutic agents. We were able to achieve a similar level of IBC cell killing with a 10-fold lower dose of chemotherapeutic agents compared to the agents by themselves. Together, these data demonstrate that PDGFRα is a viable target in IBC patients and that crenolanib is a potent and effective therapeutic agent against IBC cells.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-15.
Abstract P6-12-16: Treatment with indol-3-carbinol (I3C) in a mice xenograft model of canine breast carcinoma alter hormone metabolism and produce liver metastases
Authors: Illera JC , Martin-Ruz AL , Caceres S , Diez L , Gonzalez-Gil A , Peña L 
Published: August 2014

Abstract
Indol-3-carbinol (I3C) is a chemical component found mainly in the cruciferous family lants (i.e. broccoli, cabbage, cauliflower, etc.). I3C is considered a potential anticancer agent that is naturally present in the diet and could prevents the development of certain tumors, activating tumor suppressor genes, genes involved in apoptosis and detoxifying genes. It has been observed in vitro that suppresses cell proliferation and induces apoptosis in some breast cancers. I3C is also estrogen receptor (ER) and androgen receptor (AR)Antagonist. Therefore, studies using I3C in breast cancer animal models for its action as a preventive or therapeutic substance have started. There are no data on the influence of I3C in human and/or spontaneous or experimental canine inflammatory breast cancers, that has shown to have distinct pathogenic mechanisms. The aim of this study was to analyze the effect of I3C administration at a comparable dose used as preventive in humans in a xenograft model of canine inflammatory carcinoma established in SCID mice. Eighteen mice were used as controls and 13 mice were treated with I3C dose 150 mg/kg/day. Tumor cell proliferation was decreased in the I3C-treated xenografts (lower Ki-67 index, p &lt;0.001), but neoplasms were more frequently ulcerated (p = 0.028), and mice had a higher number of emboli in dermis (p = 0.012) (characteristic of inflammatory breast carcinoma) and liver metastases (p = 0.05). In the treated group the presence of a subpopulation of neoplastic lipid-rich cells was characteristic (p = 0.001) togetehr with a higher content of intratumor androgens (p = 0.02) and serum steroid hormone (p &lt;0 05). These results indicate that treatment with I3C, as administered, is not suitable for inflammatory breast carcinoma.
This study was funded by the research project of the Ministry of Science and Innovation SAF2009-10572.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-16.
Abstract PD2-5: Low carbohydrate dietary intervention improves insulin, hormonal levels and inflammatory markers in early stage, postmenopausal breast cancer survivors
Authors: Krie AK , Bohlen KN , Hu Y , Ageton C , Demuth H , Norfolk D , Kittelsrud J , Thomes R , Fahrendorf A , Muth J , Rojas-Espaillat LA , Davies GE 
Published: August 2014

Abstract
Background: Obesity has been associated with decreased disease free survival and overall survival in postmenopausal breast cancer survivors. Proposed mechanisms for this finding include elevated estradiol levels, hyperinsulinemia, and increased inflammatory mediators. This feasibility study evaluated whether a low carbohydrate, calorie restricted dietary intervention could achieve weight loss and measurable metabolic changes in a group of obese postmenopausal breast cancer survivors.
Methods: Twenty-three early stage estrogen receptor positive breast cancer survivors were enrolled on a low carbohydrate, calorie-restricted dietary intervention. At time of enrollment the patient had to be deemed postmenopausal and have a BMI &gt;28. Patients were not allowed to have an underlying inflammatory condition or be receiving treatment for diabetes. The mean age was 57 years old (42-68) with a mean weight of 220 lbs (171-300) and mean BMI of 37 (28-48.5). All subjects had completed surgery and adjuvant chemotherapy. The majority of patients were on endocrine therapy with 61% on an AI and 35% on tamoxifen. The dietary intervention utilized 0.5g protein/pound (actual body weight), less than 40 grams of carbohydrates and 800-1200 calories per day. The program provided weekly coaching, meal replacement protein products and nutritional supplements. Subjects were medically monitored with brief physical exams and labs done every 2 weeks for the first 12 weeks, then monthly thereafter. Subjects were seen by a health coach every week. The average weight loss period spanned 23 weeks (7-59 weeks) due to the variance in weight loss goals aimed at a BMI ≤28.
Results: The mean weight loss was 19.9% of total body weight, the equivalent of 43.7 pounds. Total body fat lost was 6.86%. Weight loss averaged 5.4 pounds in week one and 2.14 pounds per week in weeks 2-19.
Statistically significant declines in the total estrogen level (p = 0.0345), estrone (p = 0.0296), and estradiol serum levels (p = 0.0296) were demonstrated. A rapid decline in fasting insulin level was seen with a 23% decline by Week 3 (p = 0.0959), 26% by Week 7 (p = 0.0139), and 42% by Week 19 (p = 0.0071). A statistically significant improvement in the CRP level compared to baseline was also demonstrated with a 40% decrease at Week 19 (p = 0.0272).
Conclusions: Our results support that a low carbohydrate dietary intervention can be used to successfully achieve weight loss and improve metabolic parameters. This feasibility study provides additional support for larger trials evaluating the role of carbohydrate restriction in breast cancer survivors.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD2-5.
Abstract PD2-7: Vigorous exercise across the lifespan and reduced risk of estrogen receptor negative breast cancer in African American women
Authors: Adams-Campbell LL , Palmer JR , Bethea T , Kipping-Ruane K , Rosenberg L 
Published: August 2014

Abstract
Background. Recreational exercise has been associated with a reduced risk of breast cancer, but evidence regarding breast cancer among African American women and about breast cancer subtypes is sparse.
Methods. We assessed lifetime vigorous exercise (average of high school, age 21, age 30, and baseline) in the Black Women's Health Study in relation to the incidence of invasive breast cancer overall (n = 1,377), estrogen receptor-positive (ER+) breast cancer (n = 556), estrogen receptor-negative (ER-) breast cancer (n = 327), and triple negative breast cancer (TN) (n = 103); analyses were based on 275,188 person years of follow-up of 44,704 African American women who were aged 30 or more at entry to the study. Cox proportional hazards models estimated incidence rate ratios (IRR) and 95% confidence intervals (CI), controlling for breast cancer risk factors.
Results. For ER- breast cancer, the IRRs for 1-2.2 hours/week, 2.3-2.9 hours/week, and 3+ hours/week relative to &lt;1 hour/week were 0.76 (95% CI 0.52-1.11), 0.78 (95% CI 0.52-1.17) and 0.53 (95% CI 0.31-0.90), respectively; the p value for trend was 0.058. The inverse association was apparent only among postmenopausal women. There was also an inverse association, although nonsignificant, of exercise with the incidence of TN breast cancer. Vigorous exercise was not associated with a reduction in ER+ breast cancer risk.
Conclusion. These results indicate that physical activity may protect against the development of ER- breast cancer in African American women. The association, if confirmed, is of great public health importance given the high mortality associated with this subtype and its higher incidence in African American women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD2-7.
Abstract PD4-5: Longitudinal massively parallel sequencing analysis of circulating cell-free tumor DNA: A feasibility study
Authors: De Mattos-Arruda L , Cortes J , Saura C , Nuciforo P , Bidard F-C , Won HH , Weigelt B , Berger M , Seoane J , Reis-Filho JS 
Published: August 2014

Abstract
Background: Plasma-derived cell-free tumor DNA (ctDNA) has been shown to constitute a potential surrogate for tumor DNA obtained from tissue biopsies. We posit that the genetic data obtained from massively parallel sequencing analysis of ctDNA may be more informative than analysis of single tumor tissue biopsies, and would, therefore, constitute a tool to identify the presence of potentially actionable driver somatic genomic alterations, and monitor changes in the genetic landscape during the course of therapy.
Methods: Our index case is a patient with an estrogen receptor (ER)+/ HER2 -, highly proliferative, grade 2, mixed ductal/lobular breast cancer and synchronous bone and liver metastases at diagnosis. DNA extracted from archival tumor material and plasma, and from peripheral blood leukocytes was subjected to targeted massively parallel sequencing using a platform comprising 280 cancer genes known to harbor actionable mutations. Multiple plasma samples were collected during the fourth line of treatment with an AKT inhibitor.
Results: Average read depths of &gt;100x were obtained from the archival primary tumor sample and between 200x and 900x from the ctDNA samples. Sixteen somatic non-synonymous mutations were detected at high frequencies in all plasma samples, of which 11 (CDKN2A, AKT1, TP53, CDH1, TSC1, NF1, JAK3, ESR1, MML3, EPHB1, PIK3C2G) were also detected in &gt;5% of alleles obtained from the primary tumor sample. Importantly, allelic frequencies of approximately 50% for missense mutations of AKT1(p.E17K) and ESR1(p.E380Q) were detected in the plasma ctDNA, providing strong evidence to suggest that most of the cell-free plasma DNA obtained from this patient was tumor-derived. The allelic frequency of ESR1 in the tumor sample was &lt;5%, whereas for AKT1 it was 80%. In ctDNA samples, there was enrichment for mutant ESR1 alleles as compared to the primary.
The mutant allelic frequencies identified in ctDNA samples were reduced following the targeted therapy administered, which mirrored the pharmacodynamic response as assessed by PET-CT. Subsequently, the mutant allelic frequencies were increased again at the time of progression. Single agent treatment with an AKT inhibitor provided benefit in terms of long-lasting biochemical and radiologic responses (stable disease: 8 months) as shown by CA15.3 levels and radiologic assessment (RECIST 1.1), respectively.
Conclusions: Targeted capture massively parallel sequencing of plasma-derived ctDNA represents a potential tool to uncover and monitor tumor somatic alterations during the course of targeted therapy. The clinical and therapeutic impact of actionable mutations in luminal/ER+ breast cancers warrants further investigation.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD4-5.
Abstract PD5-8: Phase I clinical trial of neoadjuvant BIBF1120 plus weekly paclitaxel (P) in early HER-2 negative breast cancer. CNIO-BR-01-2010/GEICAM 2010-10 study
Authors: Quintela-Fandino M , Urruticoechea A , Guerra J , Gil M , González-Martin A , Marquez R , Hernandez-Agudo E , Rodríguez-Martin C , Gil M , Bratos R , Escudero MJ , Colomer R 
Published: August 2014

Abstract
Background: BIBF1120 has shown promising preclinical efficacy in breast cancer, and weekly paclitaxel (P) is a standard of care in BC. We designed a phase I/II trial of BIBF 1120 plus weekly P in early breast cancer, and report here the phase I part of the trial. The recommended dose has been determined and, additionally, efficacy has been assessed.
Methods: Eligible patients had pathologically confirmed HER2 negative stage II or IIIA untreated breast cancer. BIBF1120 and P were administered at the following dose levels (DL): DL1: BIBF1120 150 mg bid p.o. days 1-21 plus P 80 mg/ m2 iv on days 1, 8 and 15 q21 days; DL2: BIBF1120 200 mg bid p.o. days 1-21 plus P same dose as level 1, q21 days. On the P-infusion day, the morning BIBF1120 dose was skipped to avoid potential PK interactions. A 3+3 escalation scheme with common dose-limiting toxicity (DLT) definitions was adopted. Four three-week cycles of BIBF1120 plus P followed by 4 AC cycles were administered. Surgery was planned 4-5 weeks after the last AC dose. We report the phase I part results of the phase I/II trial.
Results: 9 patients have been evaluated for toxicity (6 patients in DL1 and 3 in DL2). Median age was 47.6 years (38.1-66.7) and 8 patients (89%) were premenopausal; median tumour size was 3.0 cm (2.7-6.5), 6 patients (66.7%) had stage II disease and 3 patients (33.3%) stage III. Seven cases (78%) were hormone-receptor (HR) positive and 2 (22%) negative. Two patients had DLT at DL2: ALT grade 3 (one patient); and ALT grade 4, AST grade 3 and GGT grade 3 (one patient). One case was reduced to DL1 and one withdrew consent after 7 days of treatment. Main related toxicities during treatment: DL1 GGT grade 2 (16.7%), hypertension grade 2 (50%), DL2 ALT grade 3 (33.3%), AST grade 3 (33.3%), bilirubin grade 2 (33.3%), GGT grade 2/3 (100%). Toxicities observed at DL2 were reversible by withholding BIBF1120 administration. Eight patients were evaluable for efficacy after surgery and have been assessed for pathological response: 2/2 (100%) HR(-) and 2/6 (33%) HR(+) patients, for a total of 4/8 (50%) patients, pCR defined as Miller&Payne score scale of 5. Three of these received DL1 and 1 DL2. A total of 6 patients (75%) underwent conservative surgery.
Conclusions: Concomitant administration in early stage HER-2 negative breast cancer of BIBF1120 plus P at DL1 was manageable and had mild toxicity, showing remarkable efficacy specially in triple-negative breast cancer. BIBF1120 150 mg bid plus weekly P 80mg/m2 is the recommended dose for the ongoing phase II part of study CNIO-BR-01-2012/GEICAM 2010-10 with an enrolment target of 130 patients, of which 81 have been already recruited.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-8.