bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-16-07: Selective use of post-mastectomy radiation therapy in the neoadjuvant setting
Authors: Warren Peled A , Wang F , Stover AC , Rugo HS , Melisko ME , Park JW , Alvarado M , Ewing CA , Esserman LJ , Fowble B , Hwang ES 
Published: August 2014

Abstract
Background: Neoadjuvant chemotherapy, once reserved for locally advanced breast cancer, has become more common in Stage II disease. While one of its proven benefits is an increase in the frequency of breast conserving surgery, many women will undergo mastectomy despite an excellent clinical response. Indications for post-mastectomy radiation (PMRT) following neoadjuvant therapy are not well defined. Some studies have suggested that certain subgroups of women (young age, triple negative disease) with negative nodes or 1–3 positive nodes after chemotherapy have a significant risk of local-regional failure without PMRT. We conducted a single-institution retrospective study of women undergoing neoadjuvant chemotherapy and mastectomy without PMRT to assess clinical outcomes among this cohort.
Methods: 101 women with initial stage I-III disease (20% stage I, 72% stage II, 8% stage III) received neoadjuvant chemotherapy (doxorubicin-based +/− taxane) followed by mastectomy without PMRT between 2005 and 2011. Mean age was 49 years (range 22–81 years). 16% were BRCA+. 66 patients (65%) had clinically negative axillary nodes at presentation, 34% had N1 disease and 1% had N2 disease. Subtype by IHC was 61% luminal A, 11% luminal B (ER+, Her2+), 20% triple negative and 8% ER−, Her2+. At the time of surgery, 81% were node negative and 19% had 1–3 positive nodes. Pathologic complete response (pCR) (breast + axilla) occurred in 28%. Median follow-up was 34 months (range 5.5–84.5 months).
Results: There were 2 (2%) local-regional failures (1 axillary recurrence at 52 months after mastectomy and 1 chest wall recurrence at 10 months). Both of these recurrences were in patients with negative nodes and luminal A tumors; patients had 2.2 and 2.5 cm of residual invasive cancer, respectively, and negative margins at mastectomy. There were no local-regional failures in women with triple negative cancers, those with 1–3 positive nodes, or patients younger than 40. Additionally, there were no failures in women with a pCR, including those with initial stage IIIA-B disease.
Conclusions: Among carefully selected patients fulfilling low risk criteria for local-regional recurrence, PMRT following neoadjuvant chemotherapy may be omitted without compromising local-regional control.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-16-07.
Abstract P4-17-08: Tissue Expander/Implant Breast Reconstruction with and without Postmastectomy Radiation: Predictive Factors for Complications
Authors: Nguyen SKA , Oxley P , Rastegar R , Joffres M , Kwan W 
Published: August 2014

Abstract
Purpose: 1) Review our complication rates with implant/expander reconstruction for breast cancer 2) Determine factors for complications, especially with postmastectomy radiation (PMRT)
Materials and Methods: Data were collected through chart review of all patients (2004–2008) from an academic hospital undergoing implant/expander reconstruction. SAS was used for two or multi-variable analyses (logistic regression) to determine predictive factors for complications. Among PMRT patients, we evaluated complications rates by risk factors.
Results: 237 patients underwent implant/expander reconstruction. Median time from implant placement until last follow-up was 173 days. 21.5% developed major complications (needing operative time or infection needing intravenous treatment). Diabetes was the most consistent factor associated with major complications (46.7 vs 20.1%, p = 0.02 and p = 0.009 in multivariable analysis). Radiation was linked to capsular contractures (18.6 vs 10.1%, p = 0.02). Chemotherapy (25.0 vs 19.0%, p = 0.26) or radiation (26.3 vs 19.1%, p = 0.21) did not predict major complications. Among patients receiving PMRT (80 patients), 26.2% had major complications, 34 had immediate PMRT on the expander and 44 had PMRT to the chest wall, followed by delayed reconstruction with expander/implant placement. In these, delayed reconstruction increased dehiscence (0 vs 18.2%, p = 0.009) compared to immediate reconstruction, with a trend for higher incidence of major complications in the delayed reconstruction group (14.7 vs 34.1%, p = 0.05). 40 Gy/16 versus 50–50.4 Gy/25-28 (28 vs 24%, p = 0.78) was not associated with major complications. Diabetes and smoking were associated with several complications.
Conclusions: Diabetes is associated with a higher rate of major complications after expander/implant reconstruction while radiation increases capsular contractures. If PMRT is indicated, putting in an expander before radiation results in less morbidity than delayed reconstruction. Also, 40 Gy/16 versus 50–50.4 Gy/25-28 do not differ much in terms of complication rates.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-17-08.
Abstract P5-01-15: Anti-ER monoclonal antibody SP1 seems more sensitive in the identification of ER alpha positive breast cancer cases than anti-ER monoclonal antibody 1D5
Authors: Madeira KP , Daltoé RD , Sirtoli GM , Rezende LCD , Carvalho AA , Silva IV , Rangel LBA 
Published: August 2014

Abstract
Background: Accurate pathological analysis of biopsies is crucial for conclusive and precise disease diagnosis, prognosis and therapeutic guidelines. Evaluation of estrogen receptor (ER) expression in breast cancer (BC) is imperative in determining the disease prognosis, and patients' eligibility for hormonotherapy. Herein, ER alpha status was evaluated in 61 BC cases using two different anti-ER alpha monoclonal antibodies, SP1 (rabbit) and 1D5 (mouse).
Methods: Primary BC cases registered in two reference hospitals, with correspondent written informed consent, were used to generate in house tissue microarray platforms. ER alpha expression was accessed by immunohistochemistry using the monoclonal antibodies anti-ER alpha, SP1 and 1D5. Staining scoring followed the Allred method (PS, proportion score or percentage of stained cells; IS, intensity score). Concordance and correlation parameters were calculated using Kappa factor; Pearson, Spearman's, or intraclass correlation coefficient (CF). Staining patterns were compared by paired T-Test and Wilcoxon test.
Findings: SP1 and 1D5 provided equivalent results (Concordance rate, 96.7%; Kappa factor, 0.921), whereas SP1 was more prone for positive results than 1D5 (2 samples diverged). Total concordance of PS was obtained (Pearson and intraclass CF, 0.7351 and 0.6193, respectively); however, concordance between the antibodies seems more accurate in higher PS values. Excellent SI correlation between antibodies was observed throughout the population (Spearman's CF, ρ=0.9150). Following the Allred score, 17 out of 42 positive BC samples diverged; always pointing 1D5 to weaker staining than SP1. When calculating Spearman's CF of Total Score (TS) within the population, excellent correlation between both the antibodies (ρ=0.9238) was noted; nonetheless, results were less concordant result among the BC positive cases (ρ=0.7743). Indeed, 20 samples were differentially classified using the antibodies (only 3 had higher TS with 1D5). Considering the mean TS of all samples, or of invasive ductal carcinoma, SP1 provided higher scores than 1D5 (p &lt; 0.05).
Interpretation: Despite the equivalence between the anti-ER alpha monoclonal antibodies, SP1 and 1D5, the former has proven superior to the latter with respect to the IS and TS. Therefore, we suggest the clinical use of SP1 while diagnosing BC, due to its higher accuracy in examining ER status; thus, enabling more accurate therapeutic decisions to treat the disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-15.
Abstract P5-03-03: Antitumor Activity and Cancer Stem Cells Effect of Cetuximab in Combination with Ixabepilone in Triple Negative Breast Cancers (TNBC)
Authors: Tanei T , Rodriguez AA , Dobrolecki L , Choi DS , Landis M , Chang JC 
Published: August 2014

Abstract
Purpose: The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is the microtubule-stabilizing agent has been expected to be more sensitive than the conventional taxanes. The aim of this study was to investigate whether the EGFR monoclonocal antibody cetuximab, in combination with ixabepilone is a more effective treatment, and kill cancer stem cells more effectively as compared to chemotherapy alone in TNBC.
Experimental Design and Results: Breast CSC populations were evaluated with FACS analysis (CD44+ and CD24−/low, or Aldefluor+) and mammosphere formation efficiency (MSFE). In vitro, we demonstrated that in triple negative cell lines (MDA-MB-231 and SUM159), cancer stem cell populations were decreased after treatment of cetuximab, or cetuximab plus ixabepilone. In vivo, cetuximab in combination with ixabepilone treatment caused significant tumor regression (cetuximab vs. cetuximab+ ixabepilone; tumor volume fold change P &lt;0.05 (MDA-MB-231), P &lt;0.0001 (SUM159) in triple negative breast cancer xenografts. Thus, cetuximab decreased CSC population in xenograft tumors. Decrease in autophagy (LC3b, p62 and autophagosomes) were seen in cetuximab-treated tumors.
Conclusions: These studies demonstrate that cetuximab in combination with ixabepilone is more effective than chemotherapy alone in TNBC by affecting CSCs, as well as bulk tumor. These data support a neoadjuvant phase II study comparing ixabepilone vs. ixabepilone +cetuximab in TNBC patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-03.
Abstract P5-04-05: E-Cadherin is Required for In Vivo Growth of Inflammatory Breast Cancer: Importance of Mesenchymal-Epithelial Transition (MET) and Role of HIF1α
Authors: Chu K , Boley KM , Cristofanilli M , Robertson FM 
Published: August 2014

Abstract
Background: Inflammatory breast cancer (IBC) is the most aggressive and deadly form of breast cancer and is phenotypically distinct from other forms of locally advanced breast cancer. The 5-year survival for IBC patients (40%) has not improved even with the implementation of multi-disciplinary care and targeted therapies (e.g. anti-HER2 or anti-estrogen therapies). Lymph node involvement is common at first diagnosis and the accelerated metastasis program that characterizes IBC account for a disproportionate number of the 40,000 women who will die from breast cancer. The most common molecular marker for IBC is the cell adhesion surface glycoprotein, E-Cadherin. Classically, E-Cadherin is thought to be a tumor suppressor and its loss is associated with the epithelial-mesenchymal transition (EMT) and acquisition of an invasive phenotype. The importance of EMT in metastasis is well accepted in numerous tumor models although the presence of EMT in patient samples is rarely demonstrated. Given the propensity of IBC to metastasize, one would expect a strong EMT signature in IBC cell lines, however the persistent robust expression of E-Cadherin in IBC patient tumors and in IBC cell lines, with a lack of expression of ZEB1, a transcriptional repressor of E-cadherin and diminished expression of genes within the transforming growth factor beta signaling pathway, suggests otherwise.
Methods: To further define the role of E-Cadherin in IBC, we used the SUM149 IBC cell line to manipulate E-Cadherin via shRNA knockdown and by overexpression of ZEB1 a known transcriptional repressor of E-cadherin.
Results: While the lack of E-Cadherin or ZEB1 overexpression in SUM149 cells led to an EMT phenotype in vitro, E-Cadherin was required for in vivo growth of SUM149 tumor cells. Gene profiling identified novel E-Cadherin signaling pathways including an hypoxia gene signature through HIF1a as well as cytokine responsive pathways. The requirement of HIF-1a for in vivo growth of SUM149 cells was confirmed by shRNA knockdown of HIF-1a.
Conclusions: The absolute requirement for E-Cadherin and maintenance of the mesenchymal-epithelial transition in IBC tumor growth is demonstrated. Furthermore, a novel functional link between E-Cadherin and HIF-1a and in their critical role in survival of IBC tumors is identified for the first time and warrants further investigation.
Supported in part by The Susan G Komen Organization Promise Grant KG081287 (FMR and MC)
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-05.
Abstract P5-04-07: Epithelial-mesenchymal transition phenotype in breast cancers is associated with clinicopathologic factors indicating aggressive biologic behavior and poor clinical outcome
Authors: Bae YK , Kim A , Choi JE , Kang SH , Lee SJ 
Published: August 2014

Abstract
Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. EMT in epithelial tumors is a reversible process and expected to be involved in invasion, metastasis and chemoresistance of cancer cells. EMT-inducing factors down-regulate E-cadherin and up-regulate extracellular matrix proteins such as fibronectin. Cancer tissue may display a wide spectrum of expression phenotypes of EMT-related proteins. However, little is known about the clinical significance of the different EMT phenotypes in breast cancers. We investigated expression pattern of EMT-related proteins, E-cadherin and fibronectin in 1,498 invasive breast carcinomas by using immunohistochemistry on tissue microarrays. EMT phenotypes were divided into complete type (E-cadherin-negative and fibronectin-positive); incomplete type, including hybrid (E-cadherin-positive and fibronectin-positive) and null (E-cadherin-negative and fibronectin-negative) types; and a wild type (E-cadherin-positive and fibronectin-negative). We correlated EMT phenotype with clinicopathologic characteristics and patients survival. Loss of E-cadherin was observed in 140 (9.3%) cases and fibronectin was expressed in cancer cells of 320 (21.4%) cases. Twenty three (1.5%) cases were categorized as complete type, 414 (27.6%) as incomplete type (hybrid type, 297; null type, 117), and 1,061 (70.8%) as wild type. Complete EMT phenotype was significantly associated with advanced pT stage, lymph node metastasis, high histological grade, and triple negativity (p &lt; 0.001). Overall survival and disease-free survival rates were significantly worse in the complete type, better in the incomplete type and best in the wild type (p = 0.002 and p &lt; 0.001, respectively). In multivariate Cox proportional hazard model analysis, the complete EMT phenotype was not an independent prognostic factor for both overall and disease-free survival. In conclusion, breast cancer patients with EMT phenotype showed less favorable outcomes than those with wild type as it was strongly associated with clinicopathologic factors indicating aggressive biologic behavior.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-07.
Abstract P5-06-01: Active pak6 induces aneuploidy in breast cancer cells.
Authors: Paul BA , Lu ML 
Published: August 2014

Abstract
The natural history of breast cancer remains largely undefined. More than 50% of clinical specimens exhibit aneuploidy. Among these aneuploid cancers, nearly half have chromosome copy numbers approaching tetraploid. The high incidence of aneuploidy in advanced breast cancer is thought to be a byproduct of chromosome mis-segregation resulting from mutations in tumor suppressor genes regulating cell cycle checkpoints and corresponding to disease progression. However, recent large-scale sequencing projects have revealed that most tumors contain approximately 14–20 different mutant genes, suggesting heterogeneity exists throughout the genomes of cancer cells. This notion revives the concept that aneuploidy resulting from chromosome mis-segregation or other similar mechanisms may play an active role leading to transformation and disease progression.
A novel p21-activated kinase 6 (PAK6) was recently identified to be an androgen receptor (AR) and estrogen receptor (ER) interacting protein. An estrogen-stimulated PAK6 activation was observed in BT474 breast cancer cells. This activation is mediated by estrogen-stimulated activation of PKA. At the cellular level, active PAK6 promotes transformation to metastatic phenotypes in MCF7 breast cancer cells as evidenced by increases in cell motility, matrigel invasion, and soft agar growth. Further characterization of MCF7 cells expressing a constitutively active PAK6 mutant revealed an accumulation of cells with higher ploidy as compared to that of parental cells. Using a proteomic approach to determine the PAK6 downstream target, we identified that Cdt1, a DNA pre-replicative complex subunit, is overexpressed in response to PAK6 activation. In eukaryotes, the expression and stability of Cdt1 are strictly regulated to ensure only one round of DNA replication in each cell cycle. Deregulated overexpression of Cdt1 has previously been demonstrated to induce aneuploidy and malignant transformation due to re-initiation of DNA replication within the same S-phase. The identification of Cdt1 overexpression in response to PAK6 activation provides a plausible mechanism for the observed accumulation of higher ploidy cells in MCF7 cells expressing active PAK6. Taken together these findings suggest a direct link between hormonal signals, DNA replication, and maintenance of genomic integrity.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-06-01.
Abstract P5-07-01: Defining the mechanism of breast cancer growth by chemokine receptor CXCR7 and Epidermal Growth Factor Receptor coupling interaction.
Authors: Salazar N , Muñoz D , Singh RK , Lokeshwar BL 
Published: August 2014

Abstract
Introduction: Breast cancer (BrCa) ranks second in both incidence and cancer deaths for women in the USA. Recent advances have revealed a significant contribution of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. CXCR7 is the latest CXC-chemokine receptor implicated in BrCa growth. It is endogenously over expressed in BrCa, but its mechanism of tumor growth enhancement is still not clearly defined. CXCR7 heterodimerizes with CXCR4 and binds to SDF-1 (CXCL12) and CXCL11. No direct ligand mediated physiological action has been implicated for CXCR7 in BrCa other than facilitating CXCR4-mediated cell motility, however, studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. The expression pattern of CXCR7 in BrCa tissues and its potential contribution in BrCa cell proliferation and survival were investigated in representative BrCa cell lines using knock down and knock-in experiments.
Results: CXCR7 was only expressed in ER-α positive BrCa cells (e.g., MCF-7) and was not found in BrCa cells with known metastatic potential (MDA-MB231 and SKBr3). Depletion of CXCR7 in MCF-7 BrCa cells by both siRNA and shRNA decreased cell proliferation and caused cell cycle arrest. Since CXCR7 is an atypical G-protein coupled receptor where ligand activation does not elicit conventional intracellular signaling, we hypothesized that CXCR7 regulates BrCa proliferation through interaction with EGFR or activating other potential targets of MAP-kinase activation. CXCR7 depletion reduced site-specific phosphorylation of EGFR at Tyrosine 1110 after EGF-stimulation. CXCR7 depletion also reduced phosphorylation of ERK-1/2, indicating a potentially direct interaction with mitogenic signaling in MCF-7 cells. We tested for direct interaction of CXCR7 with EGFR by co-immunoprecipitation and immunofluorescence studies. We found EGFR and CXCR7 co-immunoprecipitate and co-localize as demonstrated by confocal microscopy. Interestingly, our results also demonstrate CXCR7 and EGFR are co-localized before EGF stimulation. Further corroboration of CXCR7-EGFR interaction was established using the proximity ligation assay (PLA) technique that allowed us to visualize CXCR7-EGFR co-localization both in cell culture and in human normal and breast cancer tissue.
Conclusion: This data demonstrates an important role for CXCR7 in BrCa growth and explores the mechanism of action of direct coupling of EGFR with CXCR7.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-01.
Abstract P5-07-04: Aurora kinase regulates PKC-mediated MMP-9 expression and invasion in MCF-7 breast cancer cells
Authors: Kim JS , Noh EM , Lee YR , Hwang B-M , Jung SH , Youn HJ , Lee SJ 
Published: August 2014

Abstract
Aurora kinase is a novel family of serine/threonine kinases. Elevated expression of aurora kinase A and B is observed in many tumor cells, and dysregulation of aurora kinase has been linked to tumorigenesis. Therefore, a number of studies focused in their oncogene activities as anti-tumor targets. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM) and it is important process for breast cancer cell invasion. MMP-9 can be stimulated by activation of various cellular signaling pathways including protein kinase C (PKC), and mitogen-activated protein kinase (MAPKs), activator protein-1 (AP-1) and nuclear factor-kappaB (NF-κB) signaling pathways. Here, we show that 12-O-tetradecanoylphorbol-13-acetate (TPA), a directly PKC activator stimulation resulted in an up-regulation and phosphorlyation of aurora kinases in MCF-7 breast cancer cells. Also, Results showed that inhibition of the aurora kinases suppressed TPA-induced MMP-9 secretion/expression and cell invasion through suppression of NF-κB, AP-1, and MAPKs in MCF-7 breast cancer cell. In conclusion, this study provides new insight into the novel role of aurora kinase for expression of MMP-9 by TPA and regulation of aurora kinase by TPA through MAPKs signaling pathway.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-04.