bluuebunny/crossref_metadata_2025_split huggingface dataset:
OT3-01-07: The BEACON Study (BrEAst Cancer Outcomes with NKTR-102): A Phase 3 Open-Label, Randomized, Multicenter Study of NKTR-102 Versus Treatment of Physician's Choice (TPC) in Patients (pts) with Locally Recurrent or Metastatic Breast Cancer (MBC) Previously Treated with an Anthracycline, a Taxane, and Capecitabine (ATC).
Authors: Awada A , Leung ACF , Zhao C , Hannah AL , Perez EA 
Published: June 2012

Abstract
Background
NKTR-102 is a next-generation topoisomerase I inhibitor-polymer conjugate with a markedly reduced Cmax and a continuous exposure profile compared to irinotecan. A phase 2 trial of single-agent NKTR-102 compared a dose of 145 mg/m2 every 2w or every 3w in 3rd-line MBC (Awada et al, ASCO 2011). Overall the ORR was 29% (including 3% CR) with the prior ATC subset demonstrating an ORR of 31%. Dosing every 3w was better tolerated; in this arm, median PFS equaled 5.3m and median OS equaled 13.1m.
Trial Design: NKTR-102 will be compared to TPC in an open-label, randomized, parallel, two arm multicenter Phase 3 pivotal study in pts with previously treated locally recurrent or metastatic breast cancer.
Key Entry Criteria: Adult females, with ECOG 0 or 1 with adequate liver, kidney and marrow function. All patients must have received prior therapy with an anthracycline (in neo/adjuvant or metastatic setting or both), a taxane (in neo/adjuvant or metastatic setting or both) and capecitabine (in neo/adjuvant or locally advanced/metastatic setting or both) unless not medically appropriate or explicitly contraindicated for the patient. All chemotherapy- and radiation-related toxicities must have resolved to ≤ Grade 1, except for stable sensory neuropathy ≤ Grade 2 and alopecia. Pts with brain metastases may be eligible, if stable for prior 4 weeks without steroids. Pts with Grade ≥ 2 pre-existing diarrhea or receiving chronic anti-diarrheal supportive care are not eligible.
Statistical Methods: The primary efficacy endpoint is OS. Secondary endpoints include ORR by RECIST v1.1 and PFS. Pts will be randomized 1:1 to NKTR-102 given IV at 145 mg/m2 over 90-min every 21 days or TPC. Patients randomized to TPC will receive single agent chemotherapy, limited to choice of one of the following 5 agents: eribulin, ixabepilone, vinorelbine, gemcitabine, or a taxane. The investigator must decide which agent will be given to the patient prior to randomization. Pts will be stratified by geographical region and disease characteristics.
Target Accrual: Approximately 840 patients (420 pts per treatment arm) will be randomized in order to obtain 615 deaths (alpha = 0.05; power 90% with one interim analysis scheduled when 50% of the deaths have occurred). PK sampling will be performed in a subset of pts and blood and/or tumor samples are planned for potential predictive markers of response and toxicity. Enrollment is expected to remain open until the end of 2013.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-07.
P1-01-03: The Cytotoxicity of Select Neutrophils in Cancer Patients and the Role of Chemokines in Inducing Neutrophil Cytotoxicity.
Authors: Comen E , Granot Z , Norton L , Benezra R 
Published: June 2012

Abstract
Background: Using murine mammary tumor models, recent research conducted by our laboratory at the Sloan-Kettering Institute indicates that select neutrophils are mobilized by a primary breast tumor and uniquely have the capacity to inhibit metastatic seeding in the lung (Granot Z et al. unpublished). We sought to evaluate the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with those from women without breast cancer and women with DCIS. In addition, we sought to determine whether the addition of select chemokines to neutrophils from a DCIS patient could induce cytotoxicity.
Methods: Neutrophils were purified from the blood of 21 newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 9 healthy female volunteers with no history of any cancer, and 3 patients with newly diagnosed DCIS. Cytotoxicity was evaluated by incubating isolated neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity, as a reflection of% cell kill, was measured using a Bio-Tek microplate luminescence reader. Neutrophils from a DCIS patient with low cytotoxicity were then co-cultured with various CC chemokines (CCl2, CCL3 and CCL5) or CXCL chemokines (CXCL1, CXCL12, and CXCL16) at 100ng/ml.
Results: Significant cytotoxicity was notably observed when MDA-MB-231 cells were co-cultured with neutrophils purified from patients with invasive tumors. Pre-operative breast cancer patients (n=21) had a cell kill range of 0–30% (mean = 12.1%), whereas healthy subjects (n=9) had a cell kill range of 0.2-8% (mean = 2.6%), p&lt;0.004. DCIS patients (N=3) had a cell kill range of 3–4% (mean = 2.7). The addition of select chemokines to neutrophils from a DCIS patient with low cytotoxicity (3.2%) resulted in significant increases in cytotoxicity. Table 1 indicates the relative cytotoxicity percentages from the addition of each chemokine.
Conclusions: To date, this preliminary work is the first to demonstrate the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with those from women without breast cancer. We further demonstrate the novel induction of neutrophil cytotoxicity by select chemokines. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils as well as the role of chemokines in neutrophil cytotoxicity.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-03.
P1-01-04: Immunological Effects of Bisphosphonates on gdT Cells in Breast Cancer.
Authors: Sugie T , Tanaka Y , Toi M , Minato N 
Published: June 2012

Abstract
Background: Human γδT cells play an important role in the first-line of defence. Accumulating data demonstrate that γδ T cells recognize nonpeptide antigens such as IPP and HMBPP and activated γδT cells have potent cytotoxic activity against tumor cells. Nitrogen-containing bisphosphonates like zoledronic acid inhibit farnesyl diphosphate synthetase, resulting in the accumulation of upstream metabolites such as IPP. Previous studies on the adoptive transfer of ex-vivo amplified γδ T cells demonstrated the safety and feasibility of γδT cell-based immunotherapy for metastatic cancer. According to ABCSG-12 clinical trial, zoldedoric acid improved DFS of patients with early-stage breast cancer under adjuvant endocrine therapy. Whereas a precise mechanism remained unclear, it is likely that γδT cells are involved in this anti-tumor effect in breast cancer.
Materials and Methods: Peripheral blood mononuclear cells derived from 63 (54 untreated non-metastatic and 9 metastatic) patients with breast cancer were examined for the baseline population of γδT cells and their proliferative responses to zoledronic acid in vitro. Tumor-infiltrating lymphocytes were isolated from 20 tumor biopsies and 2 pleural effusions. Peripheral blood γδT cells were stimulated with 5 μM zoledronic acid and cultured in the presence of 100 IU/ml IL-2 for 10 days. Amplified γδ T cells were analyzed for cytokine production and cytotoxic activity.
Results: The proportion of γδ (TCRVδ2 -bearing) T cells among peripheral blood CD3+ cells was 4.2 ± 5.0%. Although it was equivalent to the previously reported value of 4.3 ± 2.2% in healthy volunteers, 14% (9/63) of patients exhibited an increase in the number of peripheral blood γδT cells at baseline. The level of TCRVδ2 T cells with potent anti-tumor activity was significantly higher than that of TCRVδ1 T cells (4.2± 5.0% vs. 1.5 ± 1.8%, p&lt;0.001), whereas they were present in tumor-infiltrating cells at essentially the same levels (4.4± 9.6% vs. 3.7 ± 9.7%, p=0.434). Percentage of TCR Vδ2+ CD3+ cells among amplified γδ T cells in vitro and cytokine (IFN-γ and TNF-α) production by them were significantly proportional to the initial level of TCRVδ2+/CD3+ ratio in peripheral blood. Upon treatment with zoledronic acid, breast cancer cell lines became susceptible to γδ T cells.
Conclusions: γδ (TCR Vδ2-bearing) T cells increased in some patients with breast cancer and the TCRVδ2+/CD3+ ratio at baseline was correlated with the efficiency of proliferation and cytotoxic activity when treated with zoledronic acid. Zoledronic acid efficiently sensitized breast tumor cells to be lyzed by γδ T cells. The present results suggest that γδ T cells stimulated with zoledronic acid can be utilized for immunotherapy against breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-04.
P1-01-11: CD4+CD25highCD127low/− Regulatory T Cells Have Immunosuppressive Function in Patients with Breast Cancer.
Authors: Sakemura N , Nakatsugawa M , Ito H , Isaka H , Imi K , Tazaki E , Miyamoto K , Wada N , Imoto S , Nakatsura T 
Published: June 2012

Abstract
CD4+CD25highFoxp3+ regulatory T cells play a central role in self-tolerance and suppress antitumor immune response. Recent studies have shown that low levels of the IL-7 receptor (CD127) are expressed on CD4+CD25highFoxp3+ regulatory T cells surfaces and the expression of CD127 is inversely correlated with the suppressive function of CD4+CD25high regulatory T cells. We evaluated the frequency of CD4+CD25highCD127low/− T cells in peripheral blood lymphocytes of 72 breast cancer patients and 21 healthy volunteers. The expression of Foxp3 mRNA was inversely correlated with the CD127 expression and correlated with CD25 expression. The frequency of CD4+CD25highCD127low/− T cells in breast cancer patients was significantly higher than that of healthy volunteers (p=0.0045). CD4+CD25highCD127low/− T cells were increased in hormone receptor negative patients and HER2 positive patients, but no statistical significant was observed in stage progression. In addition, the frequency of CD4+CD25highCD127low/− T cells decreased after curative resection in breast cancer patients (p=0.005). CD4+CD25highCD127low/−T cells also suppress proliferation of autologous CD4+CD25− helper T cells and CD8+ cytotoxic T cells in CFSE-based cell proliferation assay. These findings suggest that CD4+CD25highCD127low/− T cells a useful marker for regulatory T cells in breast cancer. Circulative peripheral regulatory T cells may participate in immune tolerance to breast carcinoma.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-11.
P1-02-06: Silencing of IGF-1R Has Paradoxical Effects in Triple Negative Breast Cancer Phenotypes.
Authors: Taliaferro-Smith LD , Oberlick EM , Liu T , Eggers C , Kline ER , Nagaraju GPC , Marcus A , O'Regan R 
Published: June 2012

Abstract
Background: Triple negative (TN) breast cancers are a heterogeneous group of breast cancers with a poor prognosis in part due to a lack of effective targeted agents. Insulin-like growth factor-1 receptor (IGF-1R) has been shown to play a role in breast cancer cell proliferation, adhesion, invasion, and migration and is overexpressed in more than a third of TN breast tumors. We hypothesized that IGF-1R could be a therapeutic target for a subset of TN breast cancers. Methods: We evaluated the effects of IGF-1R silencing on the metastatic properties of TN breast cancer cells by knock down in two morphologically distinct TN breast cancer cell lines using shRNA lentiviral techniques. Reverse-transcription polymerase chain reaction (RT-PCR) and immunoblotting were used to detect mRNA and protein expression levels, respectively, of IGF-1R signaling molecules. Anchorage-dependent growth and Matrigel chamber assays were performed to assess the effects of IGF-1R silencing on colony formation and invasion of TN breast cancer cells, respectively; wound-healing and spheroid migration were also performed to assess the effects of IGF-1R inhibition on TN breast cancer cell motility. Results: Stably transfected mesenchymal MDA-MB-231 TN cells showed effective downregulation of IGF-1R protein expression, which resulted in mesenchymal-to-epithelial transition (MET), confirmed by upregulation of the epithelial marker E-cadherin and downregulation of the mesenchymal marker vimentin. Importantly, this MET resulted in reduced colony formation (p&lt;0.0042) and cell motility and dramatically reduced invasion (p&lt;0.0001). Conversely, silencing of IGF-1R in epithelial MDA-MB-468 TN cells induced epithelial-to-mesenchymal transition (EMT), confirmed by downregulation of E-cadherin and upregulation of vimentin expression, with resultant increased colony formation (p&lt;0.006), cell motility, and invasion (p&lt;0.0001). Conclusion: Collectively, these results demonstrate a paradoxical effect of targeting IGF-1R in TN breast cancers of mesenchymal and epithelial origin. Targeting IGF-1R in TN breast cancers with a mesenchymal phenotype decreases invasion and metastatic potential. In contrast, targeting IGF-1R in TN breast cancers with an epithelial phenotype could have potentially detrimental effects. Our data suggest that IGF-1R inhibition should be explored as a therapeutic modality in TN breast cancers with a mesenchymal phenotype.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-06.
P1-02-07: Epithelial-Mesenchymal Transition Correlated with Serum Cytokine Profiling in Breast Cancer Patients.
Authors: Giordano A , Cohen EN , Anfossi S , Gao H , Lee B-N , Mego M , Sanda T , Valero V , Alvarez RH , Cristofanilli M , De Placido S , Hortobagyi GN , Woodward W , Ueno NT , Reuben JM 
Published: June 2012

Abstract
Background: Inflammation contributes to the increased invasiveness and poor prognosis in breast cancer (BC) patients. Specifically, the expression of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and interleukin-1 (IL-1) have all been linked to increased invasiveness and poor prognosis. Interestingly, the increased invasiveness was associated with an increase in the acquisition of markers of epithelial-mesenchymal transition (EMT). Therefore, we determined whether the levels of circulating proinflammatory cytokines (IL-1, IL-6, TNFα) and antiinflammatory cytokines (IL10) were correlated with the induction of EMT transcription factors (TFs), Snail1, Zeb1, Twist1, in breast cancer patients.
Materials and Methods: From two laboratory-based ongoing studies at the MD Anderson Cancer Center, 41 BC patients were assessed for EMT-TFs in circulating CD45-ve cells (EMT-CTCs) and for serum proinflammatory cytokines before starting any treatment. 32 of 41 patients assessed for EMT had metastatic BC. EMT-CTCs were detected by qRT-PCR for the EMT-TFs Snail1, Zeb1 and Twist1 (Mego 2011; PMID 21387303) and serum cytokines were measured by Luminex bead array assay (MILLIPLEX™ MAP Human Cytokine/Chemokine Panel). Cytokine serum concentrations were compared with the median cytokine levels of healthy donors (HD). We examined the association of serum cytokines above the median HD levels and the presence of EMT-CTCs by non-parametric Mann-Whitney test with a statistical significance for p&lt;.05.
Results: Of the 41 patients assessed for both serum cytokines and EMT-CTCs, 14 (34%) were positive for at least one EMT-TF, including 3 of 9 (33%) patients with no-metastatic BC and 11 of 32 (34%) patients with metastatic BC. We found that serum levels of IL1a, IL2, TGFα, and TNFβ in patients that were above the median levels of HD sera were higher in patients with EMT-CTCs in the blood (higher IL1a concentration in patients with over expression of Snail1, Zeb1, and Twist1; IL2 with Zeb1; TGFα with Snail1; TNFβ with Zeb1, and Twist1). Further, the higher ratio of proinflammatory/anti-inflammatory cytokines, was associated with the presence of at least one EMT-TF, e.g., IL8/IL10 (p=.005) and TNFα/IL10 (p=.037). Discussion: Patients with proinflammatory cytokine (IL1a, IL2, TGFα, and TNFβ) levels above the median levels of HD or who had a predominantly proinflammatory cytokine profile were more likely to have at least one EMT-TF in their blood. These data are consistent with the hypothesis that proinflammatory cytokines promote EMT, which may be involved in tumor aggressiveness and disease progression.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-07.
P1-02-08: Modulation of EMT by Targeting E-Cadherin Restores Radiation Sensitivity in Human Breast Cancer Cells.
Authors: Munshi A , Yuan Y , Liu J , Meyn RE 
Published: June 2012

Abstract
E-cadherin is the major adhesion protein associated with epithelial cells and loss of its expression is diagnostic of the epithelial to mesenchymal transition (EMT). Findings from our laboratory, suggest that EMT, detected as the loss of E-cadherin expression, may regulate tumor cell radiosensitivity, i.e. cells that have undergone EMT are relatively radioresistant compared to the lines that have retained the epithelial phenotype, which typically are relatively radiosensitive. To definitively test this hypothesis we compared expression levels of E-cadherin and other EMT related markers in ER-a negative (MDA-MB-231 and Hs578t) and ER-a positive (MCF-7) human breast cancer cells. We observed that many ER-a negative lines, were also E-cadherin negative, and the ER-a positive lines were positive for E-cadherin expression. Clonogenic cell survival assays showed that the cell lines expressing estrogen receptor (MCF-7) and had high expression of E-cadherin, were also more sensitive to increasing doses of radiation. Treatment of MCF-7 cells with 100nM siRNA to E-cadherin for 72 hrs made the cells more resistant to radiation with the surviving fraction changing from 42.3% in control cells to 56.4% in siRNA treated cells. In contrast, ER negative cells (MDA-MB-231 and Hs578t) had no detectable expression of E-cadherin and were more radioresistant. We transfected MDA-MB-231 and Hs578t cells with a CDH1 -expression vector and isolated stable clones, which were then tested for radiosensitivity. Cells transfected with the backbone vector (pCMV) served as controls. Restoring E-cadherin expression radiosensitized both, MDA-MB-231 and Hs578t cells, compared to the control vector cell line, suggesting that restoration of E-cadherin expression in mesenchymal-like cells produces a radiosensitizing effect. These observations suggest that ER-a signaling might regulate E-cadherin and implied that this regulation might influence EMT and radioresistance. Overall, our results suggest that the EMT status of breast cancer cells governs their response to radiation. A detailed investigation of the mechanism is ongoing.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-08.
P1-03-06: Fibroadenomatoid Changes Have a Higher Occurrence Rate in Middle-Aged Benign Breast Disease Patients with the Trend Retained in Cancer Patients.
Authors: Bekhash A , Hooke JA , Chen Y , Kovatich AJ , Kvecher L , Mural RJ , Shriver CD , Hu H 
Published: June 2012

Abstract
Background: Fibroadenoma (FA) is a common benign breast lesion known to have a high incidence rate in younger women. There are controversial reports whether FA elevates the risk of developing breast cancers. In clinical practice, FA may be surgically removed due to multiple reasons making it complicated to study its impact on the development of breast cancers that have a higher incidence rate in older women. Fibroadenomatoid change (FAC), also known as fibroadenomatous hyperplasia, is an uncommon lesion with histologic features similar to that of FA but lacking well-defined borders and usually discovered incidentally on breast biopsy specimens. FAC is not surgically targeted. The Walter Reed Army Medical Center, through the Clinical Breast Care Project, has enrolled over 2000 subjects undergoing a biopsy; all the pathology was reviewed by a single pathologist. These subjects provide an opportunity to study the age-dependent pattern of FAC in different patient populations.
Methods: Subjects were enrolled following IRB-approved protocols with data collected through two comprehensive questionnaires, a Core Questionnaire and a Pathology Checklist. A total of 1964 female subjects were identified for this study, including 1135 benign/atypical, 192 in situ, and 637 invasive cancer patients. Patients were divided into three age groups: &lt;=45 years, 46–65 years, and &gt;=66 years. Chi-Square test in the SAS was used for statistical analysis.
Results: As shown in the table, FA occurrence rate decreases significantly with increasing age in benign disease patients. FAC, on the other hand, shows a significantly higher occurrence rate in middle-aged patients with benign findings, and this trend is retained in the invasive or in situ cancer populations. FAC rate is also significantly higher in patients with cancer (invasive, or invasive and in situ combined) compared to benign patients in each age group with p-values ranging from 0.0001 to 0.019 (not shown).

Discussion: Our preliminary results suggest that FAC occurs more often in middle-aged patients. It's significantly lower occurrence in patients with benign findings may be partially explained by the fact that breast cancer patients undergo more extensive surgeries, thus providing more breast tissue for pathologic evaluation. Otherwise, the increased FAC rate may suggest its role as a risk factor for cancer development. Since FAC may be considered a miniature FA that is not surgically targeted, it may be used as a window for the study of FA on its impact in cancer development. Further study needs to be performed to explain why FA and FAC have different age-dependent patterns and whether FA or FAC is a risk factor for breast cancer development.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-06.