bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-04-04: Eribulin differentially disrupts TGF-β signaling pathway in BT-549 and HCC1937 breast cancer cell lines
Authors: Kaul R , Risinger AL , Mooberry SL 
Published: February 2018

Abstract
Microtubule targeting agents (MTAs) continue to be valuable in treating breast cancer. While these drugs were classically identified as only antimitotic agents, recent evidence demonstrates that the ability of MTAs to disrupt key signaling components in interphase cells likely contributes to their anticancer actions. Yoshida and colleagues demonstrated that eribulin reverses TGF-β-induced epithelial-to-mesenchymal transition (EMT) in preclinical models of triple negative breast cancer (TNBC) within 7days. To gain a deeper understanding of the interphase effects of eribulin in comparison with other MTAs on the TGF-β signaling pathway, we tested the hypothesis that a short-term, 2 h treatment of TNBC cells with MTAs would disrupt TGF- β signaling. The effects of the microtubule destabilizers eribulin and vinorelbine and the microtubule stabilizers paclitaxel and ixabepilone on downstream targets of the TGF-β pathway were evaluated in two TNBC cell lines. In the mesenchymal type BT-549 cells, eribulin and vinorelbine significantly inhibited TGF-β induced expression of Snail and Slug, while the microtubule stabilizers had no effect on their expression. In the basal-like 1 type HCC1937 cells, the microtubule destabilizers inhibited the expression of Snail when compared to vehicle and stabilizer-treated cells, but caused increased expression of Slug. These data suggest that MTAs have different effects on the TGF-β signaling pathway in distinct molecular contexts. Our efforts are directed towards deciphering the effects of eribulin and other MTAs on the TGF- β pathway and how this contributes to differential sensitivity. Preliminary data suggest that eribulin initiated inhibition of Snail and Slug in BT-549 cells is mediated by the scaffold protein NEDD9 and we are testing whether the differential levels of expression of NEDD9 help explain the differences in the effects of eribulin in BT-549 and HCC1937 cells. These results will begin to decipher differences among MTAs in different molecular contexts and might help identify biomarkers for optimal therapies. Funding for this work was provided by Eisai Inc.
Citation Format: Kaul R, Risinger AL, Mooberry SL. Eribulin differentially disrupts TGF-β signaling pathway in BT-549 and HCC1937 breast cancer cell lines [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-04-04.
Abstract P5-08-03: Poly-ligand profiling and target identification from formalin-fixed-paraffin embedded HER2+ breast cancer specimens
Authors: O'Neill HA , Tinder TT , Maher V , Rosenow M , Richards M , Santhanam R , Wei X , Domenyuk V , Miglarese MR , Spetzler D 
Published: February 2018

Abstract
We have previously described the ADAPT Biotargeting System™as a novel platform for highly multiplexed poly-ligand profiling of complex phenotypes such as drug response. Here we report extended capabilities of the this platform for target identification directly from formalin-fixed-paraffin embedded (FFPE) tissues using aptamer libraries enriched toward HER2+ breast cancer. Standard mass spectrometry-based biomarker and drug target discovery from FFPE tissues can be challenging due to limited amounts of tissue, harsh conditions of fixation and extraction and the general problem of masking by highly abundant proteins. A single stranded-oligodeoxynucleotide aptamer library was enriched on HER2+ FFPE breast cancer specimens and conjugated with biotin as well as a label transfer reagent, Sulfo-NHS-SS-Diazirine (Sulfo-SDAD). The biotinylated-SDAD conjugated library (B-SDAD-EL) was applied to HER2+ FFPE tissues and photocrosslinked to cognate binding partners within the FFPE sample in order to preserve aptamer-protein interactions under harsh denaturing conditions required for protein extraction and sample preparation. Aptamer-protein complexes were affinity purified and the label was transferred from bound aptamers to their binding partners under reducing conditions that enable proteomic digestion and high resolution mass spectrometry detection. An open database search was performed where the precursor ion tolerance was set to ± 500 Da for database searching, which enabled identification of peptides containing the transferred label as well as additional unknown variable modifications induced by the tissue fixation process. We identified proteins with known roles in HER2+ breast cancer along with several potentially drugable targets not previously associated with HER2 positivity. Differential expression of candidate targets was orthogonally confirmed by immunohistochemistry. By nature of its extreme molecular complexity and its ability to be enriched or “trained,” toward phenotypes of interest, the ADAPT Biotargeting SystemTM can be deployed to advance precision medicine by identifying predictive biomarkers and drug targets with novel associations to complex interactomes.
Citation Format: O'Neill HA, Tinder TT, Maher V, Rosenow M, Richards M, Santhanam R, Wei X, Domenyuk V, Miglarese MR, Spetzler D. Poly-ligand profiling and target identification from formalin-fixed-paraffin embedded HER2+ breast cancer specimens [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-08-03.
Abstract P5-23-03: Gene expression profiling in male breast cancer
Authors: Dubrovsky E , Raymond S , Chun J , Schnabel F 
Published: February 2018

Abstract
Background:
Tumor gene expression profiling tests are widely used to quantify risk of recurrence of breast cancer and guide systemic therapy in early stage breast cancer. These assays have not been well validated in a male cohort. The purpose of this study was to determine the current rates of genomic testing in male breast cancer (MBC), the distribution of risk of recurrence scores (RRS) in early stage MBC, and the effect of RRS on systemic treatment patterns.
Methods:
The National Cancer Database was queried and found to include 6,227 cases of pathologic T1/T2 and N0/N1 MBC from 2008-2014 with known genomic testing status. Of the 1478 (23.74%) male patients who had gene expression profiling performed, variables of interest included age at diagnosis, stage, estrogen receptor status (ER), RRS, and treatment. We compared the treatment patterns of the 1,343 patients who had RRS available and the 4,527 patients who were not tested. A similar analysis was performed in female breast cancer (FBC) patients to serve as a point of reference. Statistical analysis included multivariate logistic regression and Pearson's chi-square test.
Results:
Of the 1,478 (23.74%) cases of MBC who had gene expression profiling, the most significant variables included: younger age, non-Black race, diagnosis after 2010, tumor Grade II, Estrogen Receptor (ER) positivity, and N0 or N1mi disease. Of those who had results, the distribution of RRS was 59.3% low, 27.4% intermediate, and 13.3% high. A similar distribution was found in 154,705 women who were tested during the same study period. Risk scores in men were significantly associated with tumor grade and size, but not nodal status. 83.4% of men with a low RRS were treated with hormone therapy alone, with an adjusted odds ratio (AOR) of 7.18 (CI 5.78-8.91, p&lt;0.001). Also, 61.8% of men with a high RRS received combination chemotherapy and hormone therapy, with an AOR of 5.16 (CI 3.60-740, p&lt;0.001).
Conclusion:
Although there is limited literature supporting the use of genomic assays in MBC, our study found similar rates of testing in men and women with early stage breast cancer. Treatment patterns varied significantly based on risk stratification, implying that physicians are using gene profiling assays to help guide treatment in MBC. Understanding the role for genomic profiling in MBC is particularly important as these results will be incorporated into the new AJCC 8th edition staging system. Long term follow up is needed to determine whether these tests accurately predict prognosis and recurrence in a male cohort.
Citation Format: Dubrovsky E, Raymond S, Chun J, Schnabel F. Gene expression profiling in male breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-23-03.
Abstract P6-06-04: Targeting replication stress in triple negative breast cancer treatment regimen: An emerging approach
Authors: Rajamanickam S , Park JH , Bates K , Timilsina S , Eedunuri VK , Onyeagucha B , Subbarayalu P , Abdelfattah N , Jung KH , Favours E , Mohammad TA , Chen H-IH , Vadlamudi RK , Chen Y , Kaipparettu BA , Arbiser JL , Rao MK 
Published: February 2018

Abstract
Triple-negative breast cancers (TNBCs) represent aggressive heterogeneous subtype of breast cancer with poor clinical outcome. TNBCs have been reported to have high levels of replication stress due to i) various oncogene activations (C-myc or EGFR) ii) germline BRCA mutations iii) “BRCAness” in the absence of BRCA mutations in sporadic TNBCs. Replication stress is known to cause genomic instability, promote tumorigenesis and plays a critical role in therapy resistance in TNBCs. Therefore, targeting replication stress has emerged as an effective approach for better TNBC treatment through further downregulation of the remaining checkpoints to induce catastrophic failure of TNBC cells proliferation. Herein, we evaluated the anticancer efficacy of Carbazole Blue (CB), a synthetic analogue of Carbazole, on TNBC cells growth and progression. Our results demonstrated that CB inhibits short and long term viability of TNBC (MDA-MB-231, MDA-MB-468 and BT549) cells in a dose dependent manner without affecting normal mammary epithelial (MCF-10A) cells. In addition, CB treatment significantly reduced proliferation of TNBC cells, as evidenced by the BrdU proliferation assay. Consistent with this, our results further demonstrated that CB treatment induced G1/S cell cycle arrest and apoptosis in TNBCs. Importantly, systemic delivery of CB using nanoparticle-based delivery approach suppressed breast cancer growth without inducing toxicity, in preclinical orthotopic xenograft and PDX mouse models of TNBC. Furthermore, our gene microarray analysis revealed that CB treatment modulates the expression and activity of several genes known to be involved in DNA replication (CDC6, CDT1, MCMs, Claspin, POLE and PCNA) and associated DNA repair machinery such as (XRCC3, Exo1 and RAD51), which play pivotal roles in replication stress. Our results for the first time highlight the potential use of CB as a novel and potent therapeutic agent for treating TNBCs. As exploiting replication stress to treat cancer is gaining major interest, compound/s that may induce replication stress and inhibit DNA repair ability of cancer cells, has immense translational potential.
Citation Format: Rajamanickam S, Park JH, Bates K, Timilsina S, Eedunuri VK, Onyeagucha B, Subbarayalu P, Abdelfattah N, Jung KH, Favours E, Mohammad TA, Chen H-IH, Vadlamudi RK, Chen Y, Kaipparettu BA, Arbiser JL, Rao MK. Targeting replication stress in triple negative breast cancer treatment regimen: An emerging approach [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-06-04.
Abstract P6-13-04: IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer
Authors: Soliman H , Rehmus E , Shah V , Srkalovic G , Mahtani R , Levine E , Mavromatis B , Srinivasiah J , Kassar M , Gabordi R , Yoder E , Qamar R , Audeh W ,   IMPACt Investigators Group I
Published: February 2018

Abstract
Background: IMPACt is a prospective, case-only study to measure the effect of MammaPrint (MP) and BluePrint (BP) on treatment decisions in breast cancer patients. Here, we report the results of the primary objective in women aged ≥18 years with histologically proven invasive stage I-II, hormone receptor (HR) positive, and HER2-negative breast cancer. Methods: The study included 369 women from 18 US institutions. The recommended treatment plan was captured before and after receiving results for MP and BP. Treatment was started after obtaining results. In addition to the effect of results on physician treatment decisions involving chemotherapy (CT) and physician confidence, the distribution of MP High Risk (HR) and Low Risk (LR) patients was also evaluated. Results: MP classified patients to 62% (n=228) LR and 38% (n=141) HR. Treatment decisions were changed for 25% (n=92) of women after receiving MP and BP results. Of the LR patients initially prescribed CT, 68% (45/66) had CT removed from their treatment recommendation. Of the HR patients who initially were not prescribed CT, 66% (42/64) had CT added. Overall, 89% (202/228) of LR patients did not receive CT, and likewise 84% (119/141) of HR patients did receive CT after receiving MP. Among those who did not change treatment (n=277), 68% of physicians reported having greater confidence in their prescribed therapy. Conclusions: The IMPACt trial shows MP generates a 25% overall treatment change in clinical practice. The highest impact is for women with LR results, where 68% are spared chemotherapy in favor of endocrine therapy alone. Additionally, 73% of physicians report having higher confidence in treatment decisions for their patient after MP.
Table 1: Treatment changesTreatment Decision Pre- to Post-MPMP HRMP LRTotalCT to CT772198no CT tp CT42547CT to no CT04545no CT to no CT22157179Total141228369
Citation Format: Soliman H, Rehmus E, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, Srinivasiah J, Kassar M, Gabordi R, Yoder E, Qamar R, Audeh W, IMPACt Investigators Group I. IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-13-04.
Abstract PD7-13: Molecular characterization and mortality from breast cancer in men
Authors: Massarweh SA , Sledge GW , Miller DP , McCullough D , Petkov VI , Shak S 
Published: February 2018

Abstract
Background: Limited data exist on the molecular biology, treatment, and outcomes of breast cancer in men and much of our understanding in this area remains largely an extrapolation from data in women with breast cancer.
Methods: We studied men and women with hormone receptor (HR)-positive breast cancer and 21-gene test (RS) results. Patients with negative nodes, micrometastasis, and 1-3 positive nodes were included. Differences in clinical characteristics and gene expression were determined and distribution of RS results was analyzed and correlated with 5-year breast cancer specific survival (BCSS) and overall survival (OS).
Results: There were 3806 men and 571115 women. Men were older than women (mean age 64.2 vs. 59.1 years, p&lt;0.001). RS &lt;18 predominated in both genders, but RS ≥31 was more frequent in men (12.4% vs. 7.4%, p&lt;0.001) as were very low scores (RS &lt;11) (33.8% vs. 22.1%, p&lt;0.001). Mean gene expression was higher in men for the ER, proliferation, and invasion groups. ER was lowest and PR highest in women &lt;50 years, with a progressive increase in ER with age. Men &lt;50 years had slightly lower ER and PR compared to older men. Survival data was available from SEER for 322 men and 55842 women. 5-year estimates for BCSS differed significantly between RS groups for both men (p=0.003) and women (p&lt;0.001). For men, the 5-year BCSS was 99.0% and 95.9% with RS &lt;18 and RS 18-30, respectively, and for women it was 99.5% and 98.6%, regardless of nodal status. RS ≥31 was associated with a 5-year BCSS of 81.0% in men and 94.9% in women. The prognostic utility of RS was evident in both men and women, despite the progressive increase in adjuvant chemotherapy use with higher RS results. 5-year BCSS and OS were overall lower in men than in women.
Conclusion: This large genomic study reveals some distinctive biologic features of breast cancer in men and an important prognostic role for 21-gene testing in both men and women, regardless of nodal status. Future adjuvant trials in ER-positive breast cancer should focus on targeting endocrine-resistance in those patients with RS ≥31, and need to consider the weight of competing causes of mortality when investigating the value of any additional treatment beyond endocrine therapy.
Citation Format: Massarweh SA, Sledge GW, Miller DP, McCullough D, Petkov VI, Shak S. Molecular characterization and mortality from breast cancer in men [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-13.
Abstract PD8-12: Mutational processes, genome evolution and outcome in metastatic breast cancers
Authors: Patsouris A , Filleron T , Jacquet A , Goncalves A , Bonnefoi H , Letourneau C , Bachelot T , Jimenez M , Andre F 
Published: February 2018

Abstract
Background: to determine the distribution and evolution of mutational processes in metastatic breast cancers (mBC), together with their clinical relevance Methods: Whole exome sequencing (Hi-Seq, Illumina) and determination of copy number alterations (CNA) (CGH array / SNP6.0) were performed in 240 and 692 metastatic breast cancers respectively. Mutational processes were defined according to Alexandrov (Nature, 2013). Homologous Recombination Deficiency (HRD) was determined by genome wide assessment of loss-of-heteroygosity (LOH) on SNP6.0 (n = 210). Finally, genomic instability was assessed by the % of genome altered assessed by CGH / SNP6.0 Results: Whole exome sequencing showed that HR+/Her2- metastatic breast cancer presented an increased contribution of APOBEC-related signatures, as compared to early breast cancer (TCGA) (58% of the mutations vs 31%, p &lt; 0.0001). Twelve percent of the HR+/Her2- mBC acquired an hypermutator genotype ( &gt; 200 non-synonymous mutations). This acquisition of an hypermutator genotype was confirmed in five paired primary-metastatic samples. An operational APOBEC-related signature 13 was associated with a poor outcome in a multivariate analysis (HR: 1.75, 95%CI: 1.1-2.7, p = 0.017). High LOH score (HRD) was observed in 30% of HR+/Her2- mBC as compared to 13% of early HR+/Her2- early BC (p &lt; 0.0001). The opposite was observed in TNBC (43% in mTNBC versus 58% in early TNBC ,p = 0.032). High LOH score was associated with a trend for poor outcome in HR+/Her2- mBC (multivariate 1.67, 95%CI: 0.949-2.951, p = 0.075).The % of genome altered was associated with a poor outcome in multivariate analyses both in the overall and HR+/Her2- mBC (HR / 10 increase:1.144, 95%CI:1.038-1.261, p = 0.007 and HR:1.18, 95%CI:1.037-1.344, p = 0.012 respectively). Copy number analyses identified 143 genes that are more frequently amplified as compared to early breast cancers (FDR &lt; 0.01) Conclusions: metastatic HR+/Her2- metastatic breast cancer present an increased in APOBEC-related mutational burden and in LOH score as compared to early breast cancers. APOBEC-related signature 13 and genome instability are associated with a poor outcome and could be used in the future to better stratify metastatic breast cancer patients.
Citation Format: Patsouris A, Filleron T, Jacquet A, Goncalves A, Bonnefoi H, Letourneau C, Bachelot T, Jimenez M, Andre F. Mutational processes, genome evolution and outcome in metastatic breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-12.
ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation
Authors: Alsina-Sanchís Elisenda , García-Ibáñez Yaiza , Figueiredo Ana M. , Riera-Domingo Carla , Figueras Agnès , Matias-Guiu Xavier , Casanovas Oriol , Botella Luisa M. , Pujana Miquel A. , Riera-Mestre Antoni , Graupera Mariona , Viñals Francesc 
Published: February 2018

Objective—
ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-β (transforming growth factor-β) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia—a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia.

Approach and Results—

In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1
+/
−
mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1
+/
−
retinas and in turn normalize the vasculature.

Conclusions—
Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.