bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-02-01: Eribulin induces vascular remodeling and reoxygenation in advanced breast cancer patients: A comparative study with bevacizumab
Authors: Ueda S , Saeki TS , Takeuchi H , Shigekawa T , Yamane T , Kuji I , Osaki A 
Published: March 2017

Abstract
Purpose: Eribulin mesylate (eribulin) is a first-in-class halichondrin B-based microtubule dynamics inhibitor. To understand the mechanism of vascular remodeling of eribulin, we compared optical hemodynamic and blood biomarker changes between eribulin and bevacizumab.
Methods: Patients with advanced breast cancer with stage III/IV were eligible for the study. Patients were assigned to receive either eribulin or single-agent bevacizumab. Diffuse optical spectroscopic imaging (DOSI) measured tissue concentrations of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb) and oxygen saturation (SO2) of breast tumors before and day 7 after the first infusion. Peripheral blood samples were obtained from the patients to measure plasma concentration of VEGF, bFGF, FLT-3L, EGF, G-CSF, TNFα, IL1b, IL4, IL6, IL8, IL10, IL12p40, and TGF-β1.
Results: Baseline DOSI measurement of all 29 patients (eribulin, n = 14 and bevacizumab, n = 15) revealed significantly higher tumor concentrations of O2Hb, HHb, and tHb than that in the normal breast tissue. Eribulin significantly decreased in HHb concentration and increased SO2 during the observation period. This trend was not observed for bevacizumab. Instead, bevacizumab significantly decreased the concentration of O2Hb and tHb. The blood biomarker study revealed that both eribulin and bevacizumab decreased plasma concentrations of VEGF and bFGF, but only eribulin suppressed the plasma concentration of TGF-β1.
Conclusions:
Optical imaging technology revealed that eribulin, but not bevacizumab, induced tumor reoxygenation after the start of infusion. Eribulin had a potent anti-angiogenic properties as well as bevacizumab, while suppression of TGF-β1 observed by only eribulin could be associated with remodeling of the microvasculature through suppression of activated stromal cells.
Citation Format: Ueda S, Saeki TS, Takeuchi H, Shigekawa T, Yamane T, Kuji I, Osaki A. Eribulin induces vascular remodeling and reoxygenation in advanced breast cancer patients: A comparative study with bevacizumab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-01.
Abstract P4-03-14: Stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer
Authors: Reddy JP , Atkinson RL , Larson RA , Burks JK , Smith D , Debeb BG , Ruffell B , Creighton C , Reuben JM , Krishnamurthy S , Symmans WF , Brewster A , Van Laere SJ 
Published: March 2017

Abstract
Introduction: We hypothesized that normal breast tissue in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype.
Materials and Methods: Normal breast tissue at least 5cm away from primary tumors were obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ stem cell markers or the CD68 macrophage marker and correlated with IBC status. Automated quantitation of positive cells was employed for the validation cohort. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples.
Results: 8 of 8 IBC normal tissue samples expressed CD44+CD49f+CD133/2+ stem cell markers in the initial cohort as opposed to 0/60 non-IBC normal tissue samples (p=0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was 25.7 in the IBC validation cohort as opposed to 14.2 in the non-IBC validation cohort (p=0.007). 7 of 8 IBC samples expressed CD68+ macrophages in initial cohort as opposed to 12/48 non-IBC samples (p=0.001). In the validation cohort the median number of CD68+ cells was 3.7 in the IBC cohort vs 1.0 in the non-IBC cohort (p=0.06). Normal tissue of IBC patients was positively associated with a tumorigenic stem cell signature (p=0.02) and with a 79-gene IBC gene signature (p&lt;0.001).
Conclusions: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages. Further, normal tissue of IBC patients has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that normal tissue from IBC patients is distinct from non-IBC normal tissue and may support the hypothesis that a primed normal breast contributes to the development of IBC symptoms upon oncogenic insult. Validation of these results in additional normal tissue in cancer-free women would better determine causality.
Citation Format: Reddy JP, Atkinson RL, Larson RA, Burks JK, Smith D, Debeb BG, Ruffell B, Creighton C, Reuben JM, Krishnamurthy S, Symmans WF, Brewster A, Van Laere SJ. Stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-14.
Abstract P4-08-03: Mathematical modeling of the unfolded protein response pathway in breast cancer cells
Authors: Shajahan-Haq AN , Demas DM , Clarke R , Baumann WT 
Published: March 2017

Abstract
Over 70% of all breast cancers are estrogen receptor positive (ER+) and are treated with endocrine therapies such as aromatase inhibitors or ER-disruptors as part of the standard of care. However, endocrine resistance remains a major clinical challenge for the successful treatment of this disease. ER+ breast cancer cells can escape endocrine therapy-mediated cell death through adaptations in the unfolded protein response (UPR), an evolutionarily conserved cellular stress response pathway that is linked to many other pathways (autophagy, metabolism, anti-oxidant response). To better understand how the UPR pathway promotes endocrine resistance, we built a mathematical model from quantitative measurements of key UPR signaling molecules following treatment of ER+ MCF7 cells (endocrine sensitive, estrogen dependent) with dithiothreitol (DTT). DTT disrupts or prevents protein disulfide bonding and is a potent inducer of the UPR. The same measurements were also made in two MCF7-derived resistant cell lines: LCC1 (sensitive to ER-disruptors, estrogen independent) and LCC9 (resistant to ER-disruptors, estrogen independent). Determining the (minimal) changes to the MCF7 mathematical model needed to adequately capture the data from the resistant cell lines allows us to create specific hypotheses for how the UPR adapts to help produce resistance to endocrine therapies. These hypotheses, in turn, can lead to drug targets for reversing resistance.
Citation Format: Shajahan-Haq AN, Demas DM, Clarke R, Baumann WT. Mathematical modeling of the unfolded protein response pathway in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-08-03.
Abstract P4-12-04: Breast cancer subtype, age and lymph node status as predictors of local recurrence following breast-conserving therapy
Authors: Braunstein LZ , Taghian AG , Niemierko A , Salama L , Capuco A , Wong JS , Punglia RS , Bellon JR , MacDonald SM , Harris JR 
Published: March 2017

Abstract
Purpose/Objectives: Advances in breast-conserving therapy (BCT) have yielded local control rates comparable or superior to those of mastectomy. Here, we sought to identify risk factors associated with isolated local recurrence (LR) following BCT.
Materials/Methods: This study included a multi-institutional cohort of 2,233 consecutive breast cancer patients who underwent BCT between 1998 and 2007. Patient characteristics and disease parameters were stratified by age, subtype and nodal status. Biologic subtype was approximated by receptor status and tumor grade. No patients received HER2/neu-directed therapy. The association of clinicopathologic features with LR was evaluated using Cox proportional hazards regression models.
Results: At a median follow-up of 106 months, 69 LR events (3.1%) were observed. Among the overall cohort, 10-year freedom from LR was 95.9%. On univariate Cox regression analysis, risk factors associated with LR included subtype other than luminal A (hazard ratio [HR] for luminal B = 3.01, HER2 = 6.29, triple negative [TNBC] = 4.72; p&lt;0.001 for each), younger age (HR of oldest versus youngest quartile = 0.43; p=0.005), regional lymph node involvement (HR for 4-9 involved nodes = 3.04; &gt;9 nodes = 5.82; p&lt;0.01 for each), positive resection margins (HR = 2.43; p=0.005), and high-grade disease (HR = 5.37; p &lt;0.001). Presence of LVI (HR = 1.56; p=0.06) or 1-3 involved nodes (HR = 1.55; p=0.07) approached significance. Multivariate Cox regression demonstrated an association with LR among those with non-luminal A subtypes (HR for luminal B = 2.64, HER2 = 5.42, TNBC = 4.32; p&lt;0.001 for each), younger age (HR for age &gt;50 = 0.56; p=0.01), and any nodal disease (HR=1.06 per involved node; p&lt;0.004).
Conclusions: BCT yields favorable outcomes for the large majority of patients, although increased LR was observed among those with non-luminal A subtypes, younger age, and increasing lymph node involvement. Risk factors for LR following BCT appear to be converging with those following mastectomy in the current era.
Citation Format: Braunstein LZ, Taghian AG, Niemierko A, Salama L, Capuco A, Wong JS, Punglia RS, Bellon JR, MacDonald SM, Harris JR. Breast cancer subtype, age and lymph node status as predictors of local recurrence following breast-conserving therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-04.
Abstract P4-12-07: CCND1 amplification in early breast cancer patients: Correlation with subtypes and prognosis
Authors: Hanf DC , Fasching PA , Villalobos IE , Gasparyan A , Wachter D , Santiago A , Guzman R , Weihbrecht S , Hanf V , Hartmann A , Beckmann MW , Press MF 
Published: March 2017

Abstract
Background: Mechanisms of progress and recurrence of early breast cancer (BC) have gained importance since several targeted therapeutic options in metastatic breast cancer have been introduced over the last years, especially in hormone receptor positive BC. This study investigates the amplification of cell cycle regulator cyclin D1 gene (CCND1) amplification as one possible progression mechanism.
Patients & Methods: Patients from an unselected cohort of early BC patients were included into this study. A tissue microarray (TMA) was available for n=832 patients with early breast cancer. CCND1 amplification was assessed after FISH (Abbott Vysis LSI CCND1 SpectumOrange/CEP11 SpectrumGreen Probes Kit). A CCND1/CEP11-ratio ≥ 2.0 was considered as amplification. Staining was successful in 545 tumor cores. Amplification results were correlated with clinical patient and tumor characteristics and survival analyses were performed with regard to distant disease free survival and overall survival.
Results: CCND1 amplification was found in 13.6% of patients. Triple negative, luminal A like, luminal B like and HER2 positive tumors were amplified in 7.5%, 7.8%, 18.6% and 15.7% respectively (p = 0.010). CCDN1 amplification was significantly associated with a higher grading and a higher body mass index. Furthermore an amplification was seen more frequently in lobular BC and ductal BC than other histological subtypes.
Survival analysis showed a reduced DDFS for patients with CCDN1-amplification. 5 year DDFS rates were 90.6% for non-amplified tumors and 86.0% for amplified tumors (p, log-rank =0.066 ). 5 year OS rates were 93.0% for non-amplified tumors and 90.1% for amplified tumors (p, log-rank =0.119).
Adjusted for age, tumor size, nodal status and molecular subtype, cox regression showed HR of 1.3 (95% CI: 0.76-2.5, p=0.46) for DDFS and a HR of 1.33 (95% CI: 0.7-2.53, p=0.38) for OS.
Conclusion: With a 13.6% prevalence in all breast cancer patients, mainly present in luminal B like cancers, CCND1-amplification is a genetic aberration associated with an unfavorable prognosis. Within hormone receptor positive women CCDN1 amplification might play a role in treatment resistance mechanisms in early breast cancer patients.
Citation Format: Hanf DC, Fasching PA, Villalobos IE, Gasparyan A, Wachter D, Santiago A, Guzman R, Weihbrecht S, Hanf V, Hartmann A, Beckmann MW, Press MF. CCND1 amplification in early breast cancer patients: Correlation with subtypes and prognosis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-07.
Abstract P4-21-34: Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-Positive metastatic breast cancer after prior pertuzumab-based therapy
Authors: Iyengar NM , Smyth L , Lake D , Gucalp A , Singh JC , Traina TA , DeFusco P , Dickler MN , Fornier MN , Goldfarb S , Jhaveri K , Modi S , Troso-Sandoval T , Argolo D , Jack K , Ulaner G , Jochelson M , Baselga J , Norton L , Hudis CA , Dang CT 
Published: March 2017

Abstract
Background: The combination of taxanes with trastuzumab (H) and pertuzumab (P) for first line treatment of HER2-positive metastatic breast cancer (MBC) is associated with improved progression-free survival (PFS) and overall survival (OS). Treatment per physician's choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is common, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown.
Methods: This is a single arm phase II trial of gemcitabine (G) with HP. Eligible patients had HER2-positive (IHC 3+ or FISH ≥ 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Patients received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. Using a Simon optimal 2-stage design, 21 patients were enrolled in stage 1. The successful 3-month PFS rate for stage 1 was set at 57% to allow accrual to stage 2 for a total of 45 patients. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months.
Results: As of June 9, 2016, 28 patients are enrolled; 21 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 16/21 (76%) are progression free; 5 patients have progressed. The 3 month-PFS results for evaluable patients will be updated. There are no cardiac or febrile neutropenic events to date. Initially, 5 of 22 (23%) patients required G dose reduction (4 due to grade 3 neutropenia and 1 due to grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2.
Conclusions: The preliminary 3 month-PFS is 76% (95% CI 55% to 89%) in evaluable patients, and updated data will be presented. These findings suggest clinical benefit when P is continued beyond progression.
Citation Format: Iyengar NM, Smyth L, Lake D, Gucalp A, Singh JC, Traina TA, DeFusco P, Dickler MN, Fornier MN, Goldfarb S, Jhaveri K, Modi S, Troso-Sandoval T, Argolo D, Jack K, Ulaner G, Jochelson M, Baselga J, Norton L, Hudis CA, Dang CT. Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-Positive metastatic breast cancer after prior pertuzumab-based therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-34.
Abstract P5-02-06: The impact of the introduction of breast cancer screening on a symptomatic breast cancer unit
Authors: Moloney BM , Malone C , Sweeney K , Barry K , McLoughlin R , Larke A , Walsh S , O Connell AM , Ennis R , McCarthy PA , Kerin MJ 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P5-06-03: A solution to the APOBEC mutation paradox in breast cancer
Authors: Harris RS , Starrett GJ , McCann JL , Carpenter MA 
Published: March 2017

Abstract
Breast cancer has a major genetic component, and individual tumors can have thousands to tens-of-thousands of mutations. Large proportions are cytosine mutations in TCA and TCT trinucleotide motifs. A variety of studies have attributed this mutation signature to the APOBEC family of DNA cytosine deaminases, with previous literature favoring APOBEC3B as the most likely enzyme to bee responsible (from a total of nine active family members). However, breast tumor genomic DNA sequences from patients with a naturally occurring germline deletion of the entire APOBEC3B gene still show an intact APOBEC mutation signature.
To resolve this paradox, we tested the hypothesis that the only other functionally dimorphic APOBEC family member, APOBEC3H, may be responsible. First, we performed an unbiased genetic analysis of TCGA data sets and showed that APOBEC3B-null tumors with this mutational bias have at least one copy of the haplotype-I variant of APOBEC3H, despite weak genetic linkage between these two genes (n=14/14). Remarkably, breast tumors without APOBEC3B and APOBEC3H haplotype-I showed no evidence for an APOBEC mutation signature (n=3/3). The proportion of APOBEC signature mutations between the cohort with and the cohort without APOBEC3H haplotype-I was highly significant (p&lt;0.00001 and lower), indicating that these two enzymes alone may be fully responsible (and casting serious doubt on the potential role of APOBEC3A). Second, although deemed inactive in prior studies, we discovered that APOBEC3H haplotype-I has robust activity in biochemical assays with mutation of TCA-containing single-stranded DNA and in cellular assays with hypermutation of HIV-1 cDNA and mutation of a genomic DNA eGFP reporter gene. Third, the subcellular localization APOBEC3H haplotype-I and other expressed variants of this enzyme differed with only the latter showing significant nuclear localization in a panel of cell lines. The genomic mutagenicity and localization of APOBEC3H haplotype-I is attributable to a glycine at position 105, whereas other variants of this enzyme that have an arginine at this position, suggesting a general molecular mechanism. These studies combine to offer a parsimonious solution to the APOBEC mutation paradox with APOBEC3B and APOBEC3H haplotype-I, together, accounting for the strong “APOBEC mutation signature” observed in many breast cancers.
Citation Format: Harris RS, Starrett GJ, McCann JL, Carpenter MA. A solution to the APOBEC mutation paradox in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-03.
Abstract P5-06-05: Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers
Authors: Boucher D , Newsome D , Takemoto D , Hillier S , Wang Y , Arimoto R , Maxwell J , Charifson P , Fields SZ , Tanner K , Penney MS 
Published: March 2017

Abstract
Background: The efficacy of chemotherapeutic agents such as doxorubicin, which cause lethal DNA double-strand breaks (DSBs), is diminished by efficient repair of the damaged DNA in cancer cells. DNA-PK is a key regulator of the non-homologous end joining (NHEJ) pathway, which is responsible for repairing DSBs. Studies of nonselective inhibitors of DNA-PK have shown that cancer cells depend on DNA-PK for survival following treatment with DSB-inducing agents. However, a comprehensive characterization of DNA-PK inhibition has been hampered by a lack of selective inhibitors. Here we describe VX-984, a potent and selective inhibitor of DNA-PK, and its preclinical profile in combination with doxorubicin both in vitro and in vivo.
Methods: VX-984 was examined as a single agent and in combination with doxorubicin or pegylated liposomal doxorubicin (PLD) in a panel of breast cancer cell lines and in mouse xenograft models, respectively.
Results: In vitro, inhibition of DNA-PK by VX-984 enhanced the cytotoxic activity of doxorubicin in established breast cancer cell lines and in primary ovarian tumor explants. Notably, mean Bliss DE &gt;10% (strong synergy) were observed for doxorubicin in the presence of VX-984 in 22 of 35 breast cancer cell lines and 21 of 44 ovarian cancer cell lines in a broad cancer cell line screen. Further, the efficacy observed with VX-984 was associated with increased DNA damage as measured by phosphorylated histone H2AX (gamma-H2AX) and phosphorylated Kruppel-associated protein (pKAP1) in DU4475, MDA-MB-436 and MDA-MB-468 breast cancer cell lines, which is consistent with diminished DSB repair. In vivo, VX-984 significantly enhanced the efficacy of PLD in ovarian cancer patient-derived xenograft models and in cell line xenograft models.
Conclusions: These data provide evidence that inhibition of DNA-PK by VX-984 enhances the efficacy of doxorubicin in preclinical models and support the use of VX-984 in combination with DSB agents such as anthracyclines including PLD for the treatment of breast and ovarian cancers. VX-984 is currently in a Phase 1 clinical trial in combination with PLD.
Sponsored by Vertex Pharmaceuticals Incorporated.
Citation Format: Boucher D, Newsome D, Takemoto D, Hillier S, Wang Y, Arimoto R, Maxwell J, Charifson P, Fields SZ, Tanner K, Penney MS. Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-06-05.