bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-12-08: Final efficacy results from a single-arm multicenter phase II study evaluating first-line trastuzumab, bevacizumab, and capecitabine (HAX) therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)
Authors: Martín M , Makhson A , Gligorov J , Lichinitser M , Lluch A , Semiglazov V , de Ducla S , Mitchell L , Tjulandin S 
Published: August 2014

Abstract
Background: After median follow-up of 8.8 months, the primary efficacy results from the HAX study [Martín et al., Oncologist 2012] demonstrated a 73% overall response rate (ORR) according to RECIST (primary endpoint), median progression-free survival (PFS) of 14.4 months and a safety profile typical of the component agents; overall survival (OS) data were immature at that time. We present final efficacy results.
Methods: Patients with measurable HER2-positive LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 15 mg/kg day 1, trastuzumab 6 mg/kg day 1 (8 mg/kg loading dose in cycle 1), and capecitabine 1000 mg/m2 bid days 1–14, repeated every 3 weeks until progression, unacceptable toxicity, or withdrawal of consent.
Results: At the time of data cut-off, median follow-up was 31.8 months (range 1.2–44.5 months). Median duration of study therapy was 9.0, 9.4, and 10.3 months for bevacizumab, capecitabine, and trastuzumab, respectively. More than 8 cycles were administered in 67%, 65%, and 70%, respectively. Efficacy results in the intent-to-treat population (n = 88) and clinically important subgroups are shown below.
Patient subgroupBest ORR,% (95% CI)PFS events, n (%)Median PFS, months (95% CI)Deaths, n (%)Median OS, months (95% CI)1-year OS rate,% (95% CI)All patients (n = 88)75 (65-84)70 (80)14.2 (10.5-14.9)40 (45)31.8 (26.3-38.2)94 (86-98)ER and/or PgR positive (n = 37)73 (56-86)32 (86)14.1 (8.5-17.0)19 (51)31.8 (24.4-42.6)100 (*-*)ER and PgR negative (n = 51)77 (63-87)38 (75)14.5 (10.5-18.9)21 (41)33.1 (23.6-44.5)90 (77-96)No prior chemotherapy (n = 37)81 (65-92)27 (73)14.9 (10.5-24.8)14 (38)31.8 (26.3-44.4)94 (80-99)Prior chemotherapy (n = 51)71 (56-83)43 (84)13.6 (8.5-14.8)26 (51)30.9 (24.3-42.1)94 (82-98)Taxane pretreated (n = 28)57 (37-76)26 (93)9.5 (5.2-14.0)17 (61)27.4 (21.4-33.2)93 (74-98)Prior anti-HER2 therapy (n = 22)73 (50-89)18 (82)12.1 (5.2-17.0)11 (50)30.9 (24.3-*)95 (72-99)Age &gt;60 years (n = 25)72 (51-88)16 (64)14.2 (10.5-21.7)11 (44)33.2 (22.0-*)100 (*-*)*Not reached
The most common grade ≥3 adverse events were hand-foot syndrome (26% of patients), diarrhea (11%), and hypertension (11%). The majority of deaths (38/40) were from progressive/underlying disease. The cause of the two remaining deaths was described as unknown; one was reported at the primary analysis and the other occurred 19 months after last study drug administration, following progression. Detailed long-term safety results will be presented.
Conclusion: Long-term follow-up results from the HAX study show that this is an active and tolerable first-line triplet therapy for HER2-positive mBC, demonstrating median OS of 31.8 months.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-08.
Abstract P4-13-06: Ligation of dectin-1 on tumor infiltrating dendritic cells promotes breast cancer rejection
Authors: Wu T-C 
Published: August 2014

Abstract
Human breast cancer microenvironment displays features of T helper2 (Th2) immunity which promotes tumor development via IL-13/IL13 receptor pathway. This is driven by breast cancer cell-derived thymic stromal lymphopoietin (TSLP) which, by inducing OX40L expression on DCs, contributes to the Th2 immunity conducive to breast tumor development.
In order to reprogram the inflammatory pro-tumor Th2 (iTh2) into anti-tumor Th1 microenvironment, we tested the impact of targeting the innate receptors on DCs to render them resistant to tumor environment. We show that intratumoral delivery of b-glucan, a natural ligand for dectin-1 expressed on DCs, blocks the generation of iTh2 cells leading to decreased IL-13 in the tumor microenvironment and prevents breast cancer development in vivo. β-glucan inhibits OX40L expression on tumor-associated DCs which is due to a block in STAT6 phosphorylation. β-glucan-treated DCs, when exposed to breast cancer supernatant, secrete higher levels of IL-12p70 and do not expand iTh2 cells thereby enabling the T helper 1 cells secreting IFN-γ. Importantly, β-glucan exposed DCs expand CD8+ T cells that express CD103, a ligand for E-cadherin. These CD8+ T cells, which produce higher IFN-γ, Granzyme A and Granzyme B, accumulate in the tumors leading to enhanced tumor necrosis in vivo. DC reprogramming by β-glucan is dependent upon dectin-1 engagement. The ligation of TLR7/8 (CL075) and TLR3 (polyI:C) show the same effect in Th2 response inhibition but no effect on the functions of CD8+ T cells. Taken together, our data demonstrate that exploiting pattern recognition receptors on tumor-infiltrating DCs enables cancer rejection.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-13-06.
Abstract P4-14-01: A time course study of genomic instability in breast cancer patients receiving neoadjuvant therapy with or without bevacizumab
Authors: Møller EK , Moen Vollan HK , Nord S , von der Lippe Gythfeldt H , Edvardsen H , Silwal-Pandit L , Krohn M , Fleischer T , Schlitchting E , Borgen E , Garred Ø , Fangberget A , Holmen MM , Skjerven H , Lundgren S , Wist E , Naume B , Børresen-Dale A-L , Kristensen VN , Engebraaten O 
Published: August 2014

Abstract
Tumor heterogeneity is an area of intense research, revealing tumors with high complexity consisting of different subclones and infiltrating cells. Identification of subclones that are resistant to therapy may be critical to improve treatment outcome.
The NeoAva study is a randomized phase II, clinical trial of Her2 negative breast cancer patients treated in a neoadjuvant setting with chemotherapy (FEC and taxane) +/- bevacizumab. Core needle biopsies were obtained at screening and after 12 weeks, and the tumor was surgically removed after 25 weeks. DNA copy number changes in the tumors were analyzed using Affymetrix SNP Array 6.0. Allele specific copy number changes were assessed using the Allele-Specific Copy number Analysis of Tumors (ASCAT) algorithm (Van Loo, Norgard et al., PNAS 2010) and allele-specific Piecewise Constant Fitting (asPCF) algorithms (Nilsen, Liestol et al., BMC Genomics 2012). Measures of genomic instability were obtained through the complex arm-wise aberration index (CAAI) that captures local rearrangements (‘firestorms’) (Russnes, Vollan et al., Sci Transl Med 2010).
Changes in copy number aberrations between the three different time points were observed in almost all tumors. Some tumors showed a decrease in tumor percentage and aberrations after just 12 weeks of treatment, where others showed loss of aberrations only at the time of surgery (25 weeks). Most of the tumors that did retain aberrations at all time points during treatment, did not demonstrate any decrease in tumor size. Other profiles indicated subclonal reduction, where some aberrations are kept throughout treatment and others disappear. Many of the tumors shrinking in size showed fewer whole arm aberrations than before treatment, but retained their focal amplicons. Some of the tumor aberrations seem to disappear after 12 weeks, but to reappear after 25 weeks, but with the addition of novel aberration.
Complex rearrangements were identified in 67% of tumors before treatment. The most frequent ‘firestorms’ were found on 20p, 11q and 8p. Some events were persistent through therapy, but the majority changed. An association between complex tumor genomes and patients having progressive disease/non-responders were observed.
These results show the complex structure of a tumor and suggest that heterogeneity will influence the response to treatment. The subclonal patterns of tumors may be of great importance for clinical decision-making, as well as for monitoring treatment efficacy.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-14-01.
Abstract P4-15-02: The PI3K inhibitor GDC-0032 enhances the efficacy of standard of care therapeutics in PI3K alpha mutant breast cancer models
Authors: Sampath D , Nannini MA , Jane G , Hong R , Parsons KL , Belvin M , Friedman LS , Wallin JJ 
Published: August 2014

Abstract
The phosphoinositide 3-kinases (PI3Ks) are lipid kinases that activate the PI3K signaling pathway and play an essential role in regulating breast tumor cell growth, migration, and survival. Activating and transforming mutations in the PIK3CA gene (PI3K alpha) are commonly found in HER2+ breast cancer and ER+ breast cancer. GDC-0032 is a selective, orally bioavailable inhibitor with a Ki of 0.29 nM for PI3K alpha with 30 fold less inhibition of PI3K beta. In addition, GDC-0032 has increased single agent activity against PI3K alpha mutant and HER2 amplified cancer models in vitro and in vivo. The aim of our study was to evaluate the efficacy of GDC-0032 in breast cancer models in combination with standard of care therapeutics including taxanes, endocrine therapies, and HER2 targeted therapies.
We evaluated cell viability for a range of dose concentrations of GDC-0032, as single agent and in combinations, in eleven breast cancer cell lines that harbor mutations in PI3K alpha (K111N, E545K, H1047R) and/or over-expressed HER2. GDC-0032 was combined with taxanes (paclitaxel and docetaxel), endocrine therapies (fulvestrant and tamoxifen) or anti-HER2 agents (trastuzumab, pertuzumab or ado-trastuzumab-emtansine) and synergy quantified using the Chou and Talalay method of Combination Index (C.I.). The combination of GDC-0032 with taxanes, endocrine therapies or anti-HER2 therapies were synergistic in the breast cancer cell lines tested based on C.I. values of less than 1.0. The combination of GDC-0032 with docetaxel in vitro resulted in decreased viability as a result of increased cell death. The in vitro results translated in vivo as GDC-0032 enhanced the anti-tumor activity of docetaxel and paclitaxel in MCF7 (E545K) xenografts that resulted in increased tumor regressions when GDC-0032 was dosed daily or intermittently on the same schedule as the taxane. In addition, the combination of GDC-0032 and fulvestrant or tamoxifen resulted in greater efficacy in the MCF7 xenograft model when compared to either agent alone. Enhanced efficacy was also observed when GDC-0032 was combined with trastuzumab or ado-trastuzumab-emtansine in the HER2+ BT474M1 (K111N) xenograft model. Moreover, the triple combinations of GDC-0032/trastuzumab/pertuzumab or GDC-0032/trastuzumab/docetaxel resulted in durable tumor regressions that were sustained in the HER2+ KPL-4 (H1047R) and BT474M1 xenograft models, respectively. All drug combinations with GDC-0032 were well tolerated in vivo based on minimal changes in body weight. Collectively, our preclinical data demonstrate that GDC-0032 enhances the efficacy of standard of care therapeutics in PI3K alpha mutant breast cancer models and provides a strong rationale for further evaluation in patients.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-02.
Abstract P4-15-07: MicroRNA signature of breast cancer brain metastasis for novel targeted therapies
Authors: Sethi S , Ahmad A , Ali-Fehmi R , Mittal S , Dyson G , Sarkar F 
Published: August 2014

Abstract
Rationale:
MicroRNAs (miRNAs) are recently described novel small non-coding endogenous RNAs which critically regulate cancer progression, invasion and metastasis. Altered expression of miRNAs has been proposed to control the invasive capability of cancer cells. Modulating altered miRNAs is a novel approach for targeted therapy for cancer. Breast cancer is the most common cancer among women in the US. Breast cancer-related mortality and morbidity are primarily due to metastatic disease especially brain metastasis which also impacts patients’ quality of life. Molecular mechanisms of brain metastasis of breast cancer are largely unknown.
Study Objectives:
Identifying molecular miRNA signatures in breast cancers which metastasize to the brain can assist in designing novel targeted therapies to prevent and eliminate brain metastasis.
Design:
RNA was extracted from formalin fixed paraffin embedded tumor tissues from a cohort of breast cancer patients with brain metastasis, and age, stage and follow-up matched breast cancer cases without brain metastasis. miRNA expression profiling was done using EQIXON microarray. Quantitative real-time PCR (qRT-PCR) was used to validate abnormal expression of miRNAs. Data was statistically analyzed using Kruskal-Wallis test to determine the clinical significance of the findings.
Results:
Over 2000 unique miRNA sequences were profiled in each case. The upregulated miRNAs included miR-3927-5p, miR-216b and miR-10b and the down regulated miRNAs were miR-4280, miR-3174 and miR-1244 and miR20b. Validation of the deregulated miRNAs by q RT-PCR showed statistically significant difference in the expression levels in the breast cancers with brain metastasis compared to breast cancers without brain metastasis (Kruskal-Wallis test; p &lt; 0.001).
Conclusions:
A unique set of miRNAs were deregulated in breast cancers with brain metastasis. This panel of altered miRNAs have clinical relevance since they can be silenced by antagomirs (chemically modified anti-miRNA oligonucleotides) to treat and prevent brain metastasis. These molecular microRNA signature-based novel targeted prophylactic and therapeutic strategies could improve patients’ quality of life and overall survival in the era of personalized and precision medicine.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-07.
Abstract P4-15-08: Discovery of a potent inhibitor of CREB-mediated gene transcription that completely suppresses the growth of triple-negative breast cancer cells
Authors: Xiao X , Li B , Xie F , Fan Q , Xue C , Qian D 
Published: August 2014

Abstract
Background: Breast cancers are a heterogeneous group of diseases with distinct and complex mechanisms of pathogenesis. Triple-negative breast cancers (TNBC) form a subgroup of breast cancers with poor prognosis. TNBCs lack the expression of estrogen receptor (ER), progesterone receptor (PR) or HER2 and no targeted therapies exist. The cyclic-AMP (cAMP) response element binding protein (CREB) is a stimulus-induced transcription factor activated by multiple extracellular signals through phosphorylation. The transcription activity of CREB depends on its phosphorylation at Ser133 by mitogen- and stress-activated protein serine/threonine kinases, which are often dysregulated in TNBCs. The phosphorylated CREB (p-CREB) can then bind the mammalian transcription co-activator, CREB-binding protein (CBP), via the kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. This binding event will further recruit other transcriptional machinery to the gene promoter to initiate CREB-dependent gene transcription. CREB is overexpressed in breast cancer tissues compared to normal mammary tissues and the level of expression inversely correlates with disease-free survival. Genetic studies have shown that inhibition of CREB's activity leads to decreased breast cancer cell proliferation. We describe here the discovery of a potent small molecule inhibitor of CREB-mediated gene transcription with in vitro and in vivo activity in TNBCs.
Methods: The small molecule inhibitor (compound 1) was reporter earlier by us (Li and Xiao ChemBioChem 2009). Starting from this lead compound, we designed and synthesized a more potent compound 2. The in vitro antiproliferative activity and apoptosis induction were evaluated in MDA-MB-231 and MDA-MB-468 cells with MTT assays and flow cytometry, respectively. In vivo activity was investigated in a human xenograft model of MDA-MB-468. The CREB target gene expression was investigated by Western blot and qRT-PCR analysis.
Results: Starting from compound 1, which is a low micromolar and cell-permeable inhibitor of CREB-mediated gene transcription, we designed and synthesized compound 2. Compound 2 potently inhibited CREB-mediated gene transcription with IC50 ∼80 nM. In vitro, this compound inhibited proliferation of MDA-MB-231 and MDA-MB-468 cells with concomitant activation of apoptosis and necrosis. In contrast, compound 2 was not toxic to normal human mammary epithelial cells. In vivo, compound 2 completely suppressed the growth of MDA-MB-468 cells at a dose not toxic to the mice.
Conclusion: Compound 2 potently inhibited CREB-mediated gene transcription and TNBC cell growth in vitro and in vivo. These results suggest that CREB is a promising druggable target for TNBCs.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-08.
Abstract P4-16-02: EF24 targets radiation-induced NFkB-dependent stemness in triple negative breast cancer cells
Authors: Ramraj SK , Natarajan M , Aravindan S , Herman TS , Aravindan N 
Published: August 2014

Abstract
Prognosis of patients with late stage BCa still remains poor, mostly due to development of chemoradioresistance followed by tumor recurrence. Cancer stem cells (CSCs), with higher drug efflux capability, and other stem cell-like properties were proposed to be responsible for resistance, relapse and progression of BCa. We have shown that EF24 alleviates radiation (IR)-orchestrated NFkB mediated clonal expansion. Herein, we investigated the potential of EF24 in the regulation of IR-induced NFkB dependent stemness in triple negative breast cancer cells (TNBC). MDA-MB-231 cells exposed to mock-IR or IR (2Gy) with/without EF24 were examined for transcriptional alterations of 93 EMT, CSCs self-renewal, pluoripotentcy maintenance and other stem cell markers. NFkB (p50/p65) overexpression (with or without EF24) and RelA siRNA knockout (with IR) approach were used to delineate the role of IR-induced NFkB and the selective NFkB targeting of EF24 in this setting. Nanog, Sox-2, ABCG-2, N-Cadherin, POU5F1 and Myc expression was examined with immunoblotting. IR profoundly increased the transactivation of 86 stem-cell related molecules in TNBCs that are involved in cell survival. Interestingly, muting IR-induced NFkB attenuated 85 of those genes. Notably, EF24 suppressed identical 85 genes reproducing the inhibitory signature of NFkB muting. Coherently, activating NFkB induced 87 stem-cell related molecules in TNBC and of which 86 genes were completely suppressed with EF24. Alterations in the cellular expression levels of Nanog, Sox-2, ABCG-2, N-Cadherin, POU5F1 and Myc validates the potential of EF24 in mitigating IR-induced stemness in TNBC. Together these data demonstrates, at least in TNBC cells, IR-induced NFkB mediates increased stem-like characteristics and further imply that EF24 may alleviate stemness by selectively targeting IR-induced NFkB.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-02.
Abstract P4-16-03: Effect of doxorubicin and paclitaxel on adipose-derived stem cells and breast cancer cells: Can we incorporate chemotherapy into our reconstructive strategies?
Authors: Tsuji W , Chung CW , McLaughlin MM , Valentin JE , Marra KG , Rubin JP 
Published: August 2014

Abstract
Introduction: Breast surgery often results in physical deformities that significantly diminish patient's quality of life. A natural and aesthetically pleasing breast reconstruction can be achieved through autologous fat grafting and the success of this technique has largely been attributed to the regenerative properties of adipose-derived stem cells (ASCs) within fat graft. However, in the setting of resected breast cancer, the growth stimulating and angiogenic effects of ASCs pose a risk of increasing local recurrence rates. Although the safety of autologous fat grafting in the breast cancer population has yet to be determined, potential recurrence risk may be minimized through incorporating tumor-suppressing elements in the graft. This study aimed to determine if doxorubicin and paclitaxel could be used to inhibit breast cancer cells while maintaining the viability and functionality of ASCs in vitro.
Materials and methods: Human ASCs were isolated from non-diabetic female patients between 35 and 60 years of age (n = 3). BT-474 and MDA-MB-231 were obtained from ATCC. ASCs, ASCs undergoing adipogenic differentiation, and breast cancer cells were each exposed to a range of doxorubicin-HCl (0, 10, 30, 100, 300, 1000, 3000, or 10000nM) or paclitaxel (0, 0.1, 0.3, 1, 3, 10, 30, 100, or 300nM) concentrations. Proliferation, viability, and differentiation capacity were assessed with commercially available CyQuant, MTT, and AdipoRed assay kits, respectively.
Results: Dose-dependent inhibition was observed for doxorubicin in ASCs and both breast cancer cell lines. The IC50 of doxorubicin on ASCs, BT-474, and MDA-MB-231 were 901.3, 656.5, and 333 nM, respectively. Dose-dependent inhibition for paclitaxel was only observed in BT-474 and MDA-MB-231 cells, with IC50 values of 1.809 and 3.477 nM, respectively. ASCs maintained greater than 80% viability over the range of paclitaxel concentrations tested and consequently and IC50 value could not be determined. ASCs differentiation into mature adipocytes was not inhibited by doxorubicin exposure.
Discussion: In vitro cytotoxicity studies demonstrated greater doxorubicin and paclitaxel sensitivity in BT-474 and MDA-MB-231 than in ASCs. Furthermore, the presence of doxorubicin did not inhibit ASC differentiation into mature adipocytes. These findings suggest that incorporating chemotherapeutic drugs in fat grafts for breast reconstruction following primary breast cancer surgery may be a viable option for decreasing the risk of cancer recurrence.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-03.