bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of nab-paclitaxel and bevacizumab cooperation in inhibition of breast tumor growth and metastasis.
Authors: Volk L , Stutzman A , Flister M , Hall K , Chihade D , Desai N , Trieu V , Ran S 
Published: December 2010

Abstract
Abstract #1032
Background: Nab-paclitaxel, also known as Abraxane®, is paclitaxel formulated in nanoparticles that consist of human albumin encapsulating the hydrophobic drug moiety. This drug has shown numerous advantages including linear pharmacokinetics, significantly higher tumor retention, and increased maximal-tolerated dose due to reduced toxicity. We previously showed that combination of Abraxane and anti-VEGF-A antibody, bevacizumab, is significantly more efficacious in suppression of breast tumor xenografts and metastasis as compared to treatments with each of these drugs alone. We hypothesized that the mechanism underlying the therapeutic success of the combined therapy might include bevacizumab-dependent abrogation of the stress response elicited by paclitaxel in the tumor cells surviving chemotherapy.&#x2028; Materials and Methods: Cultured MDA-MB-231 cells were treated with 0, 2.5, 5, 10, and 30 nM of Abraxane followed by detection of angiogenic (VEGF-A), prosurvival (p42 & p44 kinase, bcl-2) and inflammatory (IL-6, IL-8, and TNF-α) proteins using Western blotting and ELISA. MDA-MB-231 tumors were extracted from mice upon cessation of intravenous (IV) Abraxane therapy (10 to 30 mg/kg, qdx5) followed by Western blot and immunohistochemical analyses.&#x2028; Results: In vitro, Abraxane treatment increased expression of VEGF-A, p42/44 kinase, bcl-2 as well as total and phosphorylated p65 subunit of NF-κB. Treated cells secreted 25- to 30-fold higher concentrations of inflammatory cytokines IL-6, IL-8, and TNF-α into conditioned media as compared with untreated control cells. Likewise, significant increases in bcl-2 and inflammatory cytokines were observed in tumors extracted immediately after paclitaxel therapy in vivo as confirmed by both Western blotting and immunohistochemical analyses.&#x2028; Discussion: These findings suggest that paclitaxel elicits VEGF-A dependent prosurvival and proinflammatory stress responses in tumor cells surviving the cytotoxic therapy. Activation of these pathways suggests that concurrent therapy with VEGF-A neutralizing antibody might significantly improve the efficacy of paclitaxel-based therapies by counteracting the stress responses in the therapy-spared tumor cells.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1032.
Selective inhibition of VEGFR2 activity with a human anti-VEGF monoclonal antibody decreases tumor growth and macrophage infiltration in an orthotopic model of breast cancer.
Authors: Dineen SP , Lynn KD , Roland CL , Payton LA , Brekken RA 
Published: December 2010

Abstract
Abstract #1034
In general tumor associated macrophages confer a negative prognosis in patients with breast cancer. This is due in part to the fact that macrophages can promote angiogenesis and mediate the angiogenic switch in tumors. Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis as well as a macrophage chemotactic protein. Inhibition of VEGF is an attractive therapeutic strategy that has shown to be beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth appears to involve more than its effect on endothelial cells. We have previously shown that 2C3 (PGN-310), a mouse monoclonal antibody that prevents VEGF from binding to VEGF receptor 2, decreases tumor growth, angiogenesis, and macrophage infiltration into pancreatic tumors. In this study, we test a fully human version of 2C3, termed r84 (PGN-311), for its effect on established orthotopic MDA-MB-231 breast tumors in SCID mice. Orthotopic tumors were established by injecting one million MDA-MB-231 cells into the mammary fat pad of SCID mice. Therapy with saline (n=5), bevacizumab (n=8), 2C3 (n=5), or r84 (n=9) at 250 μg/ip injection twice weekly was initiated on day 26 post tumor cell injection (mean initial tumor volume = 150 mm3) and continued for approximately 3 weeks. Upon sacrifice, tumor weight was determined and the tumor and other organs were snap frozen or fixed in formalin and paraffin-embedded for histology. Anti-VEGF therapy inhibited growth of orthotopic breast tumors (on day 48, Mean ± SEM: control, 822 ± 160; bevacizumab, 344 ± 29; 2C3, 309 ± 69; r84, 368 ± 38 mm3;all p &lt; 0.001 vs control). Furthermore, immunohistochemical analysis of tumors from control and anti-VEGF treated animals demonstrated that each anti-VEGF therapy reduced microvessel density and macrophage infiltration. Additionally, we also determined that inhibition of VEGF activity with 2C3 reduces VEGF-induced migration of MDA-MB-231 cells in vitro in a transwell assay. In summary, we demonstrate that r84 a unique fully human anti-VEGF antibody is effective in reducing tumor microvessel density, macrophage infiltration into tumors, and the growth of breast tumors implanted into SCID mice. These data suggest that inhibition of VEGF receptor 2 activity with an anti-VEGF monoclonal antibody is sufficient for effective blockade of the pro-tumorigenic activities of VEGF.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1034.
Effect of anticoagulation therapy on bleeding and thromboembolic events (TEs) in the AVADO phase III study of docetaxel (D) ± bevacizumab (BV) in inoperable locally recurrent (LR) or metastatic breast cancer (mBC).
Authors: Wardley A , Lohrisch C , Joy A , Young S , Yi F , Marme A , Dreosti L , Albanell J , Muñoz M , Miles DW 
Published: December 2010

Abstract
Abstract #1035
Background: In first-line mBC, the anti-VEGF monoclonal antibody BV (Avastin®) has demonstrated PFS improvement when combined with taxanes in two large phase III trials (E2100 and AVADO). Thromboses and bleeding are among the possible side effects of BV. Pts receiving full-dose anticoagulation therapy have historically been excluded from clinical trials of BV due to the hypothetical risk of bleeding and TEs. AVADO enrolled pts receiving full-dose anticoagulation provided that their level of anticoagulation was stable for ≥2 weeks prior to study entry. We investigated the incidence of bleeding and arterial and venous TEs (ATEs; VTEs) in pts receiving concomitant anticoagulation therapy in AVADO.&#x2028; Methods: Pts with inoperable LR or mBC, with no CTx 6 months prior to randomisation (12 months if taxane-based), ECOG PS 0–1 and adequate LVEF were eligible for enrolment. 736 pts were randomised to D 100mg/m2 + placebo (PL) or D + BV 7.5 or 15mg/kg. D was administered q3w for ≥9 cycles, BV/PL q3w until disease progression or unacceptable toxicity. Anticoagulation therapy was defined as coumarin, heparin or low molecular weight heparins.&#x2028; Results: Safety data are available from 730 pts. Grade ≥3 TEs and grade ≥3 bleeding were each reported by six pts (1.2%) who received BV, compared with nine pts (3.9%) and two pts (0.9%), respectively in the control arm. Eleven pts received anticoagulants at study entry (PL: 4, BV 7.5mg/kg: 6, BV 15mg/kg: 1) and 73 pts began anticoagulants during the study (PL: 21, BV 7.5mg/kg: 26, BV 15mg/kg: 26). No grade ≥3 ATEs were reported in pts receiving anticoagulation therapy either before or during the study.&#x2028; &#x2028; Conclusions: The rate of grade ≥3 ATEs, VTEs and bleeding events was relatively low in the entire study and did not appear to increase with BV use. The incidence of TEs and bleeding events was not increased relative to the control arm in the subpopulation of pts receiving anticoagulants concurrently with BV, although patient numbers are small, particularly for bleeding events.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1035.
ALDH1 is a useful marker of basalness in human breast cancer and its stem/progenitor cells.
Authors: Jolicoeur F , Garcia de la Fuente I , Gaboury L , Balicki D 
Published: December 2010

Abstract
Abstract #104
Background: The basal cell subtype is a particularly aggressive form of breast cancer. The molecular mechanisms which underlie the aggressive course of basal cell breast cancer, as well as its corresponding tumor markers are currently under intense study. In addition, there is increasing evidence that cancer stem/progenitor cells are integral to the formation and perpetuation of breast cancer. Together with their progenitors, cancer stem cells may determine the therapeutic outcome and the clinical course of cancer. The first isoform of aldehyde dehydrogenase (ALDH1) has recently been reported to be a marker of breast stem/progenitor cells. Thus, we undertook this study to determine whether the immunohistochemical detection of ALDH1 in fixed breast cancer tissues correlates with selected basal and luminal cell surface markers.&#x2028; Methods: Formalin-fixed, paraffin-embedded specimens were studied in triplicate using tissue microarrays from 57 breast cancer patients. In addition to ALDH1 staining, each of the following markers were studied using immunohistochemistry (IHC) in each sample: ER, PR, HER-2, the basal cell markers EGFR/HER1, CK5, CK14, CK17, SMA, and the luminal cell markers CK19, and EMA.&#x2028; Results: ALDH1 staining was performed using IHC and subsequently evaluated using the Quick score. The Quick score takes into account both the percentage of positive cells, as well as the corresponding staining intensity. Our results suggest that breast cancer samples expressing the triple negative phenotype (ER-, PR-, HER-2 negative) together with one or more basal cell markers (EGFR/HER1,CK5, CK14, CK17, SMA) are associated with an elevated Quick score for ALDH1 staining, when compared with samples lacking the expression of these markers.&#x2028; Conclusions: As it has been demonstrated that IHC detection of ALDH1 detects stem/progenitor cells in fixed breast samples, our results suggest that an elevated Quick score is associated with the enrichment of IHC basal cell markers in these samples. We are currently focusing on a larger number of breast cancer samples so that correlations can be studied as a function of therapeutic outcome and overall survival of breast cancer patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 104.
Identification of NPM1 as a potential high-penetrance gene in hereditary breast cancer.
Authors: Ren Z , Teugels E , De Brakeleer S , Sermijn E , Bonduelle M , Fontaine C , De Greve J 
Published: December 2010

Abstract
Abstract #1042
Background: In a major proportion of breast cancer patients with a strong familial cancer history no BRCA1 or BRCA2 mutations are detected which prompted us to explore other proteins on the BRCA1/2 pathway. Previously we have identified BARD1 (De Brakeleer et al, SABC 2006) as a rare high penetrance breast cancer predisposing gene. Nucleophosmin (NPM1) is a multifunctional protein that is ubiquitylated and stabilized by the BRCA1-BARD1 complex and thus is part of the BRCA1 pathway. Somatic protein truncating mutations in NPM1 are frequent events in acute myeloid leukemia (AML).&#x2028; Aim: This study was aimed at determining whether NPM1 germline mutations may contribute to the breast cancer predisposition in families where no BRCA1 or BRCA2 mutation is found.&#x2028; Methods: NPM1 mutation analysis was performed on genomic DNA extracted from blood of 198 breast cancer patients with strong indications for a hereditary form of the disease and 110 controls. All the 11 exons of the NPM1 gene were separately amplified by PCR. Since a high number of processed NPM1 pseudogenes are dispersed throughout the human genome, PCR primers had to be designed carefully. The PCR products were subsequently analyzed by denaturing gradient gel electrophoresis (DGGE) and when an abnormal migration pattern occurred, sequencing analysis was performed to determine the exact nucleotide-sequence alteration which was verified against the pseudogene sequences.&#x2028; Results: Out of the six novel sequence variations, only one occurred in an exon: a duplication of thymidine located in the 3' non-coding sequence of exon 12 (c.1042dupT). The remaining 5 variants were located in intron sequences close to the exon borders. Two variants flanking exon7 (c.460-31G&gt;A and c.524+42G&gt;A) were always linked, and occurred at the same high frequency in breast cancer patients and controls. Two intron sequence variants were only found in one patient. One was a duplication of a sequence in intron 8 (c.582+52dupT) and the other a sequence deletion in intron 3 (c.139-9delT). One sequence variation located close to exon 11 (c.771-46C&gt;A) was found in 7 familial breast cancer patients in 4 high incidence families but not in unaffected family members and in none of the control samples. This mutation leads to an alternative splicing of the NPM1 mRNA and is predicted to modify the carboxyterminal end of the protein, removing a nucleolar locating signal.&#x2028; Discussion: A germline mutation in NPM1 was found only in familial breast cancer cases. This mutation may result in the synthesis of a C-terminal truncated NPM1 protein conferring high susceptibility to breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1042.
Impact of SNPs in ERα corepressor SMRT on breast cancer risk and response to endocrine therapy.
Authors: Hartmaier RJ , Skaar TC , Rae J , Wang J , Li L , Oesterreich S 
Published: December 2010

Abstract
Abstract #1043
Approximately 1/3 of hormone dependent breast cancers do not respond to tamoxifen treatment. The fact that these tumors are intrinsically resistant suggests that underlying genetic factors are responsible for this phenotype. The two major types of genetic variation are single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). SNPs are the most common form of genetic alteration with an estimated 10 million SNPs across the genome and likely influence both disease susceptibility and response to therapy.&#x2028; Traditionally, researchers have attempted to identify SNPs associated with a clinical outcome in a “top-down” approach by conducting linkage and SNP association studies. However, here we report on a “bottom-up” approach whereby SNPs are first tested in vitro for a functional effect. This awards two benefits over a “top-down” approach: 1) identification of functional SNPs and 2) detailed characterization of the SNP so that the clinical association studies can be designed accordingly.&#x2028; Tamoxifen acts by blocking estradiol (E2) from binding to the estrogen receptor (ERα) and by recruiting corepressors, which then actively repress gene transcription. The critical role of corepressors, especially SMRT, in the proper action of tamoxifen makes them likely to be involved in tamoxifen resistance. Thus, we used a “bottom-up” approach to identify SNPs in ERα corepressors which affect the ability of tamoxifen to suppress ERα function.&#x2028; Here we report the detailed in vitro characterization of a number of SNPs in SMRT (NCoR2) with respect to altered ERα function in the presence of tamoxifen. Further, these SNPs are currently being genotyped so that associations can be made in a population of women receiving tamoxifen as either preventative or adjuvant therapy in which extensive surrogate markers for ERα function were collected during the 1-year follow (hot flash rate, hot flash intensity, lipid profiles, and bone mineral density).&#x2028; Through the discovery of common polymorphisms affecting Tamoxifen response, we hope to identify new diagnostic criteria to predict which patients will respond to anti-estrogen therapy and which will be better candidates for another line of therapy, such as aromatase inhibitors.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1043.
T cell marker metagene predicts a favourable prognosis in estrogen receptor negative and Her2 positive breast cancers.
Authors: Rody A , Ruckhaeberle E , Holtrich U , Gaetje R , Engels K , Hanker L , Solbach C , Ahr A , Metzler D , Karn T , Kaufmann M 
Published: December 2010

Abstract
Abstract #1048
Background: Lymphocyte infiltration (LI) is often seen in breast cancer and has been suggested as a marker of host antitumor immune response but its importance remains controversial. A positive correlation of Her2 amplification/overexpression and LI has been described which was associated with a more favorable outcome. In rapidly proliferating tumors LI is a good prognostic indicator correlating with lymph node negativity, smaller tumor size, lower grade. However the impact of monocytes, B- and T-lymphocytes on prognosis are still a matter of debate.&#x2028; Material and Methods: A database of 2110 primary invasive breast cancer samples from 14 microarray datasets was established. Only Affymetrix HG-U133A microarrays were included for full comparability. Feature reduction was achieved by generating metagenes from genes with strong correlation in unsupervised clustering. The relationship of the five major metagenes with different cell types in the sample as well as differentiation programs/pathways associated with specific expression profiles was analyzed.&#x2028; Results: A large cluster of approximately 600 genes with functions in immune cells was consistently obtained in all datasets. The redundant information from several ProbeSets allowed the construction of robust metagenes which can be used as surrogate markers for the amount of different immune cell types in the breast cancer sample. However, rather complex relationships of these immunological metagenes with standard parameters of the tumors were observed. When different subgroups of tumors were analyzed for disease free survival the IgG metagene as a surrogate marker for B cells had no significant prognostic value. In contrast high expression of the T cell surrogate marker (LCK metagene) was beneficial among all subgroups of ER-negative tumors. Moreover a positive prognostic value of LCK metagene expression was also revealed for those ER-positive tumors with a Her2 overexpression. In addition a trend for a better response to neoadjuvant chemotherapy was detected for those ER negative tumors associated with lymphocyte infiltration as deduced from high expression of both IgG and LCK metagenes.&#x2028; Conclusions: Tumor associated lymphocytes could represent an anti tumor response but on the other hand they might promote tumor progression by shifting the cytokine milieu toward angiogenic factors, inflammatory cytokines and matrix metallo-proteinases. Thus it is crucial to precisely define the specific subtypes of immune cells which are associated with the tumor. Our results demonstrate that this task can be accomplished by a detailed analysis of the expression of metagenes. These surrogate markers define subgroups of tumors with different prognosis.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1048.
Monocytes/macrophages and natural killer cells characterize the tumor microenvironment of inflammatory breast cancer in Egyptian patients.
Authors: Mohamed MM , El-Shinawi M , Cavallo-Medved D , Sobhy M , Nouh MA , Abdelwahab SF , Sloane BF 
Published: December 2010

Abstract
Abstract #1054
Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. IBC incidence appears to be higher in Egypt as compared to USA. Although the role of leukocytes in regulating breast cancer dissemination has been studied extensively, their role in IBC progression is not well understood. Previously, we showed that human monocytes augment the invasiveness and proteolytic activity of IBC cell lines. Aim: To compare the immunophenotype of IBC and non-IBC and to identify IBC tumor-infiltrated immune cell that may be associated with poor prognosis of IBC.&#x2028; Methods: We enrolled two groups of patients: IBC (n=13) and non-IBC (n=27) being treated at Ain Shams University hospitals. All patients underwent modified radical mastectomy. IBC patients had 7 or more metastatic axillary lymph nodes whereas non-IBC patients had 3 or less metastatic axillary lymph nodes. During surgery, blood draining from the breast tumor microenvironment, through branches of axillary vein, and peripheral blood was collected. Total mononuclear cells were isolated from collected blood and their phenotype was examined using flow cytometry. Monoclonal antibodies specific for cell surface markers for particular cells types were used: namely T-helper cells (CD3+CD4+), T-cytotoxic cells (CD3+CD4-), natural killer (NK) cells (CD56+) and monocytes/macrophages (CD14+). Results: Within each group we compared the leukocytic composition of blood collected from the tumor drainage to that of peripheral blood in IBC and non-IBC patients. 1) In IBC, we detected a significant increase in the mean percentage of NK cells and monocytes collected from the tumor site, but no significant difference in CD8+ and CD4+ cells. 2) In non-IBC, the percentage of CD4+ T cells collected from the tumor site was significantly higher than from peripheral blood. No significant differences were detected in CD8+, CD56+ and CD14+ cells.&#x2028; We compared the leukocyte composition of blood collected from both IBC and non-IBC patients. 1) In peripheral blood of IBC patients, we detected a significant increase in CD4+ T cells, but no significant differences in CD8+, CD56+ and CD14+ cells when compared to non-IBC patients. 2) When we compared the leukocyte content of blood collected from the tumor site in IBC and non-IBC, we found a significant increase in CD56+, and CD14+ cells and a significant decrease in CD4+ T cells in IBC, but no significant difference in CD8+ T cells. Conclusion: Differences in the immunophenotype of IBC versus non-IBC suggests a role for these immune cells in the metastatic dissemination and progression of IBC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1054.