bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose-dense (DD) doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (P) with trastuzumab (T) and lapatinib (L) in HER2/neu-positive breast cancer is not feasible due to excessive diarrhea: updated results.
Authors: Dang C , Lin N , Moy B , Come S , Lake D , Theodoulou M , Troso-Sandoval T , Dickler M , Gorsky M , D'Andrea G , Modi S , Seidman A , Drullinsky P , Partridge A , Schapira L , Wulf G , Gilewski T , Atieh D , Mayer E , Isakoff S , Sugarman S , Fornier M , Traina T , Bromberg J , Currie V , Robson M , Burstein H , Overmoyer B , Ryan P , Kuter I , Younger J , Schumer S , Tung N , Zarwan C , Schnipper L , Chen C , Winer E , Norton L , Hudis C 
Published: December 2010

Abstract
Abstract #2108
Background: DD q 2 weekly (w) AC → P + T x 1 year (y) has an acceptable safely profile w/ congestive heart failure (CHF) rate of 1/70 pts (Dang, JCO 2008). Lapatinib (L) is effective in HER2 (+) BC. We conducted a pilot study of dd AC → w P + T + L to determine its feasibility and cardiac safety.&#x2028; Methods: Enrolled pts had HER2 (+) BC; LVEF &gt; 50%. Rx consisted of AC at 60/600 mg/m2 x 4 q 2 w (w/ pegfilgrastim 6 mg day 2) → P at 80 mg/m2 x 12 q w + T x 1 y; L (1000 mg daily beginning w/ P + T and continued x 1 y). MUGA is obtained at baseline and at months (mo) 2, 6, 9, and 18. Rx is considered feasible if 1) &gt; 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is &lt; 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or &lt; G 3 toxicity (unacceptable).&#x2028; Results: From March 2007 to April 2008, we enrolled 95 pts. Median (med) age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable &lt; G 3 toxicities (15 G 3 diarrhea, 4 G 1/2 diarrhea, 1 G 3 rash, 2 G 2 rash, 1 G 3 dyspnea and also had G 3 diarrhea, 1 G 3 ↑QTc also had G 3 diarrhea, 1 G 3 ↑ALT also had G 3 diarrhea, 1 G 3 paronychia, 1 G 3 pneumonitis, 1 asymptomatic LVEF ↓, 1 myocarditis) and 5 for other reasons (2 personal reason, 1 PCP pneumonia, 1 progression, 1 P hypersensitivity). Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib. Med LVEF at baseline is 67% (N=95), at mo 2 is 68% (N=90), at mo 6 is 65% (N=53), and mo 9 is 65% (N=28). To date there are no patient drop-outs due to significant LVEF declines after dd AC; one patient dropped during PTL out due to an asymptomatic LVEF decline.&#x2028; Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (&gt; 20% pts required L dose reduction) primarily due to excessive G 3 diarrhea. These results have led to the modification of Design 2 (Arm D) of ALTTO. We will report updated results.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2108.
Role of the prostaglandin receptor EP3 in regulating vasculogenic mimicry of inflammatory breast cancer.
Authors: Robertson FM , Simeone A , Lucci A , Woodward W , Reuben J , Ueno N , Cristofanilli M 
Published: December 2010

Abstract
Abstract #2127
Background: Inflammatory breast cancer is an aggressively angiogenic, metastatic and lethal variant of breast cancer. One of the characteristics of aggressive tumors types such as IBC is the ability of tumor cells to undergo vasculogenic mimicry (VM), which is the formation of organized capillary like structures in vitro and in vivo much like endothelial cells, providing a conduit for oxygen and nutrients to reach hypoxic and nutrient deprived tumor cells that have outgrown their adjacent vascular supply. Using genomic and proteomic profiling as well as Western blotting, immunohistochemistry, invasion assays using the modified Boyden chamber assay as well as digital imaging, we evaluated the signal transduction pathways involved in regulating proliferation, invasion, and VM by IBC tumor cells.&#x2028; Results: We found that cyclooxygenase-2 (Cox-2), which produces the bioactive lipid, prostaglandin E2 (PGE2) is one gene that is highly expressed IBC tumor cell lines, SUM149 and SUM190. The biological activity of PGE2 occurs via binding of PGE2 to one of 4 members of a G protein coupled receptor family, designated as the EP receptors, EP1, EP2, EP3 and EP4. Western blot analysis and immunochemistry revealed that EP3 receptor protein is produced at very high levels by both IBC tumor cell lines to a significantly (p&lt;0.05) greater extent than either human MCF-7 or MDA-MB-231 non-IBC breast tumor cells. Since EP3 is known to be an inhibitory prostanoid receptor, we evaluated the dose dependent effects of the EP3 agonist, sulprostone, on proliferation, invasion, and VM. Sulprostone [0.1, 1, 10 and 100 μm] inhibited proliferation of SUM149 and SUM190 IBC cells in a dose and time dependent manner to a significantly greater extent (p&lt;0.01) than MCF-7 or MDA-MB-231 breast tumor cells. Sulprostone inhibited invasion of SUM149 IBC tumor cells, with no effect on invasion of a basement membrane by the MDA-MB-231 human non-IBC breast tumor cells. SUM149 IBC tumor cells undergo VM, which was completely inhibited by 10 μM sulprostone at 24 hrs, as visualized by Periodic Acid Schiff (PAS) staining and digital imaging. The ability of sulprostone to completely inhibit VM occurred in conjunction with inhibition of production of laminin 5-γ2 fragments and matrix metalloproteinase-2 (MMP-2) activity. Studies are currently underway to determine the in vivo effect of sulprostone on IBC tumor growth, VM, and metastasis of SUM149 IBC xenografts.&#x2028; Discussion: These results suggest that targeting EP3 may provide a selective advantage for abrogating not only proliferation, and invasion but also vasculogenic mimicry that is a key component of the rapid angiogenic program observed in IBC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2127.
A phase II, randomized, open-label, dose-finding study of TAS-108, a novel steroidal antiestrogen, administered orally in postmenopausal women with advanced or metastatic breast cancer.
Authors: Iwata H , Inaji H , Nakayama T , Yamamoto N , Noguchi S , Ikeda T 
Published: December 2010

Abstract
Abstract #2132
Background: A phase II study was conducted to identify the recommended dose of TAS-108, a novel steroidal antiestrogen with full ERα antagonist, mainly metabolized by CYP3A4, in post menopausal Japanese women with advanced or metastatic breast cancer. This study was prepared referring to the multi-center phase II trial that performed in four countries (USA, Russia, Mexico and Chile), and performed in Japan. Both studies are not the same designs.&#x2028; Patients and Methods: Patients with ER and/or PgR positive were eligible if they had one or two standard endocrine therapies, with or without one prior chemotherapy, for advanced disease. TAS-108 was administered orally at three different doses (40mg/80mg/120mg per day) for 24 weeks. The treatment was terminated if PD was observed. In this clinical study, clinical benefit (CB, CR+PR+SD for at least 24 weeks) rate as the primary end point was evaluated. The secondary endpoints were overall response rate and best overall response using RECIST; time to progression; adverse events (AEs) graded by CTC-AE (ver.3.0). Endometrial thickness (ET) and bone mineral density (BMD) as specific items of hormonal therapy were evaluated by transvaginal or transabdominal ultrasound, and dual-energy X-Ray absorptiometry method, respectively.&#x2028; Results: Ninety eight patients were enrolled and randomized. One ineligible patient in the 120mg dose group dropped out without administration; therefore a total of ninety seven patients were administered and assessed for efficacy and safety. Thirty three patients received 40mg, 32 received 80mg and 120mg. The three treatment groups were well balanced. CB was observed in 10 patients (30.3%) in the 40mg group, and 8 patients (25.0%) in both the 80mg and 120mg groups. Retrospective analysis showed TAS-108 had effectiveness to patients who had failed on prior tamoxifen (TAM) or aromatase inhibitors (AI) treatment, including relapse during the adjuvant therapy or within 6 months from its completion. CB rate at the three doses respectively were 25.0/33.3/25.0% in 14 (4/6/4) patients failed on TAM, and 30.8/31.6/20.0% in 70 (26/19/25) patients failed on AI.&#x2028; TAS-108 was well tolerated and most of the AEs were Grade1 or 2. The most frequent drug-related AEs were hot flush (22 patients, 22.7%, 7/8/7 patients in 40/80/120mg), perspiration (11 patients, 11.3%, 2/3/6), nausea (9 patients, 9.3%, 1/3/5), arthralgia (6 patients, 6.2%, 0/3/3). Neither remarkable change nor apparent dose-related trend among the three groups was observed in ET or BMD.&#x2028; Conclusion: According to the protocol, 40mg was chosen as the recommended dose of TAS-108 for breast cancer. It was suggested that TAS-108 has clinical benefit for patients with breast cancer who have failed on prior TAM or AI treatments.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2132.
Internalization and retention of nanodiamonds by MCF-7 cells in vitro: a potential drug delivery platform.
Authors: Khan SA , Ivancic DZ , Zaichuk T , Huang H , Chen M , Lam R , Zhang M , Chatterton RT , Ho D 
Published: December 2010

Abstract
Abstract #2134
Background: Selective uptake and prolonged retention of drugs will facilitate pharmacotherapy to the breast. This may be accomplished by complexing of drugs to carbon-based nanodiamond (ND) particles, 2-8nm size. ND particles are attractive for this purpose because they are inert and non-toxic.We tested the uptake and retention of ND particles by the estrogen receptor positive breast cancer cell line MCF-7.&#x2028; Methods: Polylysine coated ND were labeled with fluorescein isothiocyanate (FITC-ND), and examined by UV-visible spectra and found to be stable. MCF-7 cells were cultured on Lab-Tek II chamber slides using DMEM with 10% FCS, insulin, sodium pyruvate, L-glutamine, and Pen/Strep. To assess the efficiency of ND internalization, we added 10ug/ml ND-FITC in complete media to the chamber slides and incubated for 30 min, 1 hr, 3 hr, 4 hr, 17 hr, and 24 hr. FITC-ND was withdrawn from the medium after an initial exposure of 17 hr by washing of cells, and retention of fluorescence was measured at intervals, up to 3 days after withdrawal. To assess the ability of MCF-7 cells to take up NDs under low metabolic conditions MCF-7 cells were incubated in serum-free medium. As a control soluble FITC alone was incubated at 10 ug/ml with MCF-7 cells. Cells were imaged on the laser confocal microscope and FITC detection at 488nm was analyzed by three dimensional Z stack imaging.&#x2028; Results: Fluorescence was initially associated with the membrane surface, and later was visualized in the cytoplasm and in the perinuclear zone. Cellular uptake of FITC and ND-FITC occurred at 30 minutes and reached a maximum at 17 hr of incubation. After washing of cells, the retention studies showed little decrease in the intensity of the ND-FITC signal within the cells up to 96 hours. The FITC molecule was readily released from the cells by passive diffusion within 24 hours while NDs appeared to be compartmentalized in cytoplasmic vesicles.&#x2028; &#x2028; Conclusions: Internalization of ND particles within the cell cytoplasm occurs within a relatively short time, and the ND particles are retained for at least 96 hours following removal from the culture medium. This prolonged retention is likely to be an advantage when considering novel routes of drug delivery to the breast, such as transdermal or intraductal approaches.&#x2028; Funded by Avon.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2134.
Nanoparticle albumin-bound (nab) IDN5404: a novel vascular disrupting agent with potent antitumor and antiangiogenic effects.
Authors: Trieu V , D'Cruz O , Piacente M , Huang T , Faxon S , Ahmed S , Desai N 
Published: December 2010

Abstract
Abstract #2138
Background: The tumor vasculature is an established target for the therapy of solid tumors. IDN5404 is a thiocolchicine dimer with antitubulin and topisomerase 1 inhibitor properties. In this study, nab-formulated IDN5404 was examined for antitumor effects in three xenograft models and for antiangiogenic as well as vascular disrupting activity (VDA) in the avian embryonic chorioallantoic membrane (CAM) assays.&#x2028; Materials and Methods: Subcutaneous human breast (MX-1 and MDA-MB-231), colon (HT29), and prostate (PC3) tumors were grown in athymic nude mice and treated intravenously (IV) with nab-5404 alone at 10, 20, 30, or 40 mg/kg (q3dx4 or q4dx3) and in combination with IV or intraperitoneal (IP) nab-paclitaxel (Abraxane; 10, 15 or 30 mg/kg, qdx5 or q4dx3). The effect of dose, schedule, and sequence of combination regimen was tested. Nab-5404 was administered 24-hr before, concurrently or 24-hr after Abraxane administration. The effect of nab-5404 on embryonic angiogenesis was examined in vivo using the standard chick CAM assay with 3-day old embryos (n = 18). The quail CAM assay was used to determine the time course of VDA. Quail embryos (n = 36) were exposed to nab-5404 (1 to 16 µg/ml) on day 7 and digital CAM images were acquired over a 60 min period for scoring VDA.&#x2028; Results: Significant dose-dependent tumor growth inhibition (TGI) was observed in all xenograft models. In the MX-1 and HT29 models, nab-5404 (30 mg/kg, q3dx4) exhibited potent antitumor activity (P &lt; 0.0001, ANOVA, vs. saline) alone and in combination with Abraxane (TGI for MX-1: 65% and 76%; TGI for HT29: 44% and 74% respectively). Nab-5404 was similarly effective with the q4dx3 schedule. In addition, when Nab-5404 (20 mg/kg, q4dx3) was administered 24-hr before, concurrently or 24-hr after Abraxane (5 mg/kg, q4dx3), the combination resulted in TGI of &gt;99%, 88%, and 72% respectively. Using the in vivo chick CAM assay, nab-5404 inhibited embryonic angiogenesis by over 90% at 5 µg/CAM without affecting viability. Furthermore, rapid collapse of blood vessels was observed within 30 min in the viable quail CAM assay when embryos were exposed to nab-5404 at 4-16 µg/ml.&#x2028; Discussion: Nab-5404 alone and in combination with Abraxane demonstrated significant TGI in xenograft models of human breast, colon or prostate cancer. This effect was shown to be due to the rapid VDA of nab-5404. Maximum antitumor activity was seen when nab-5404 was administered 24 hr before Abraxane. Nab-5404, a microtubule-destabilizing vascular disruptive agent, potentiates the cytotoxic effects of nab-paclitaxel, a microtubule-stabilizing agent and the data suggest that these two agents may be utilized effectively in combination.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2138.
Daily injections of the glutathione disulfide mimetic NOV-002 ameliorates hematologic toxicities from neoadjuvant chemotherapy in breast cancer patients enrolled in the NEO-NOVO trial, and significantly increases circulating dendritic cells.
Authors: Diaz-Montero C , Paphitis N , Onicescu G , Zhu Y , Verma N , Garrett-Mayer E , Schuhwerk KC , Pazoles CJ , Glück S , Montero AJ 
Published: December 2010

Abstract
Abstract #2141
Background: Chemotherapy induced anemia is a common problem in breast cancer. Anemic events [Hgb&lt;10 g/dL, use of erythropoietin stimulating agents (ESAs), or transfusion] are likely to occur in 30-40% of breast cancer patients (pts) receiving doxorubicin-cyclophosphamide (AC) and docetaxel (T). Owing to the increased risk of cancer mortality, tumor progression, and thrombovascular events associated with ESAs, other alternatives are needed. Febrile neutropenia with AC-T is a dose-limiting event and occurs in 10-20% of pts without prophylactic G-CSF. NOV-002 has been previously shown to stimulate hematopoiesis and reduce chemotherapy related hematologic toxicities, as well as have immunomodulatory properties. Methods: To determine the effect of daily NOV-002 on hematopoiesis and chemotherapy induced hematologic toxicities, weekly blood counts were obtained on all pts enrolled in the NEO-NOVO trial (Montero, et. al. SABCS 2008). Pts do not receive prophylactic G-CSF in the absence of prior febrile neutropenia with chemotherapy. To determine if NOV-002 is associated with induction of circulating dendritic cells (DCs), flow cytometry analysis is performed on whole peripheral blood prior to therapy and on day 1 of each cycle. DCs are defined as: lineage-/HLA-DR+; CD11b+/CD11c+. P-values were obtained from the signed rank test. Results: Thus far, 102 chemotherapy cycles have been administered to 16 pts. Baseline (BL) hemoglobin (Hgb), absolute neutrophil counts (ANC), and DCs are listed below.&#x2028; &#x2028; No grade 3-4 anemia has been observed. ESAs have been used in 2 pts (12.5%), and no blood transfusions were required. One pt (6.25%) had febrile neutropenia (0.9% of all cycles). Grade 3 neutropenia on day 1 of cycles 1-8 occurred in 2 pts (12.5%) or 1.9% of all cycles. One pt had dose delay by 1 week due to neutropenia. Cycle 5 day 1 (C5D1) DCs were significantly higher relative to BL with a trend towards being higher at C8D1. Moreover, median ANCs were significantly higher on C8D1, while median Hgb remained stable between C5D1 and C8D1. Conclusions: Anemic events and febrile neutropenia were much lower than expected with the addition of NOV-002 to AC→T, likely due to its hematopoietic properties. DC induction may be an important anti-tumor mechanism of action of NOV-002.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2141.
Induction of apoptosis in vitro and in vivo effects of a synthetic nitroflavone derivative on murine mammary adenocarcinoma cells.
Authors: Ca´rdenas MG , Blank VC , Zotta E , Marder NM , Roguin LP 
Published: December 2010

Abstract
Abstract #2145
Background: Flavonoids are polyphenolic compounds found in dietary components of vegetable origin. They exhibit multiple biological activities, such as antiproliferative, anxiolytic, antiallergic, antiangiogenic and antioxidant actions. We have previously demonstrated that the synthetic flavone 2'-nitroflavone (2'-NF) exerts a strong antimitogenic activity in various human and murine tumor cell lines, without disturbing the proliferation of non-neoplasic cells. In order to elucidate the mechanism of antitumor action, we first studied the in vitro ability of 2'-NF to induce apoptosis in a cell line derived from a murine mammary tumor (LM3), and then investigated its in vivo growth inhibitory effects.&#x2028; Methods and results: Different experimental assays were performed to evaluate the in vitro apoptotic response of 2'-NF. Thus, when LM3 cells were treated in the presence or absence of 20 µM of 2'-NF, an increment in the proportion of hypodiploid cells was evident after 24 and 48 h of incubation. A typical DNA ladder fragmentation pattern was visualized by agarose gel electrophoresis and an increment in the total expression of the pro-apoptotic Bax protein was obtained by western blot after 24 hours of exposure to 2'-NF. Caspase 3 activity was also determined by fluorescence detection of the cleaved substrate Ac-DEVD-AMC after 24 hours of treatment.&#x2028; In order to study the in vivo antitumor action, female BALB/c mice were first injected subcutaneously with 300000 LM3 cells. After 7 days, 1, 10 or 40 mg/kg of 2'-NF dissolved in 0.2 ml of vehicle (5% DMSO, 0.05% Tween-80, NaCl 0.15 M) were administrated i.p. twice a week for 3 weeks. During the treatment, tumor sizes were measured every 3 days and, at the end of the treatment, tumors were excised, measured and weighted. On average, treated-mice tumor volume was reduced between 70% (p&lt;0.01) and 43% (p&lt;0.05) with 10 and 40 mg/kg doses, respectively. No significant volume reduction was observed with 1mg/kg dose. Besides, tumors weight decreased approximately 50% (p&lt;0.05) both with 10 and 40 mg/kg doses. TUNEL assay performed on tumor slices from treated (10mg/kg dose) and non treated mice showed that 2'-NF induces apoptosis on mammary tumors. In addition, western blot analyses of tumor lysate supernatants revealed an upregulation of the total levels of Bax and Fas receptor proteins in 2'-NF treated tumors with a concomitant downregulation of the antiapoptotic protein Bcl-2. Finally, toxicity studies performed in different organ-tissues from animals injected with 40 mg/kg of 2'-NF showed no histological alterations.&#x2028; Conclusion: Taken together, our results suggest the potential therapeutic use of 2'-NF as an antitumor agent, capable of inducing apoptosis both in vitro and in vivo in breast cancer cells without generating systemic toxic effects.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2145.
Docetaxel and carboplatin followed by sequential capecitabine as first line treatment in patients with locally advanced or metastatic breast cancer.
Authors: Lorenzo A , Modolell A , Valero P , Murillo L , García-Bueno JM , Yubero A , Machengs I 
Published: December 2010

Abstract
Abstract #2155
Background: Anthracyclines and docetaxel (D) are the most active agents in metastatic breast cancer (BC). New regimens are being assesed to improve chemotherapy efficacy. D and carboplatin (C) has shown to be an active treatment in metastatic BC. Capecitabine (X) and D is also an active combination, despite the fact the toxicity profile needs to be improved. Sequential administration of D and X could lead to an improved toxicity profile compared with concomitant administration. We designed this study to evaluate activity and toxicity profile of treatment with D and C followed by sequential X in patients with locally advanced or metastatic BC.&#x2028; Methods: Patients with locally advanced or metastatic BC, at least one measurable lesion, age ≥ 18 years, ECOG PS ≤ 2, and adequate bone marrow and hepatic functions, were included in the study. Prior chemotherapy or radiotherapy for advanced disease was not allowed. Patients received 6 cycles of D 75 mg/m2 iv D1 and C AUC5 iv D1, every 21 days followed by 12 cycles of X 2000 mg/m2/day o.r. D1-14 in a 21 days course.&#x2028; Results: twenty patients have been analyzed. Median age was 55 years old (range 36-73), ECOG PS 0-1 94.4%; 90.0% of patients had infiltrating ductal carcinoma and 57.9% of patients had stage I-II at diagnosis. Main sites of metastatic disease were bone (35.0%), liver (25.0%) and lung (25.0%). Conservative surgery was performed in 35% of patients and mastectomy in 40%. Previous radiotherapy and chemotherapy was administered in 50.0% and 70.0% of patients, respectively. A total of 108 cycles of D and C (median 6, range 2-6) and 71 cycles of X (median 6, range 2-10) were administered. Median relative dose intensity was 96% for D and C and 95% for X. Over 17 evaluable patients for efficacy, 2 achieved complete response and 4 partial response; the ORR was 35.3% (95% CI:12.6-58.1). During D and C treatment, grade III/IV toxicities per patient were neutropenia (25.0%), leucopenia (10.0%), mucositis (5.0%), oedema (5.0%), febrile neutropenia (5.0%) and thrombophlebitis (5.0%). Most common grade II toxicities were nausea (20.0%), vomiting (15.0%) and asthenia (20.0%). During X treatment, grade III/IV toxicities per patient were neutropenia (7.1%) and hand-foot syndrome (7.1%). Main grade II toxicity was hand-foot syndrome (14.3%). Two patients finished treatment after 2 and 6 cycles of X due to diarrhea, oedema and anorexia, and hand-foot syndrome.&#x2028; Conclusion: In this preliminary analysis, D and C followed by sequential X seems to be an active and well-tolerated regimen as first line treatment in patients with locally advanced or metastatic BC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2155.