bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-01-08: Imaging overview of metaplastic carcinomas of the breast; a study of 46 cases
Authors: Langlands FE , Dall B , Dodwell D , Shabaan AM , Sharma N 
Published: August 2014

Abstract
Background: Metaplastic breast cancer (MBC) is a rare form of breast cancer affecting &lt;1% of breast cancer patients. Previous studies report that the size of MBC is greater than conventional invasive ductal carcinoma at presentation. This may reflect the rapid growth rate of MBC or the difficulty in diagnosis. Imaging characteristics of MBC are not well described but the few published reports suggest that MBC often mimics benign lesions on imaging. The aim of this study therefore is to review the clinical presentation, baseline imaging features, surgical management and final surgical pathology of MBC in a large UK breast cancer unit.
Methods: All female patients diagnosed with MBC during the time period Jan 2005-2012 were identified from the pathology database at Leeds University Teaching Hospitals Trust. Pathology reports were reviewed and data on MBC type (following the WHO classification), size, grade, nodal and molecular marker status was extracted. Mammography, Ultrasound (USS), CT and MRI features were recorded. Follow-up was complete until May 2013.
Results: 46 patients were identified with a median age of 61yrs and a 5yr survival of 32.6% (median 50 months). Of the 46 cases, 33 presented symptomatically (71.7%), 37 (80.4%) showed a mass on mammography of which 28 (75.7%) was ill defined, 4 (10.8%) well defined and 5 (13.5%) spiculated. All 46 cases had a mass on USS.
The imaging score was Bi-rads (Breast Imaging-Reporting and Data System) 5 in 23 cases, Birads 4c in 17 cases and 4a,b in 6 cases.
Thirteen patients had MRI. This was performed either to determine disease extent or for neoadjuvant chemotherapy monitoring. All but one of the tumours was seen as a solid mass with some central necrosis the other was seen as an area of nodular enhancement. Nine cases had a staging CT scan for metastatic disease which was negative in all cases.The average size was 28mm (range 11-75mm), 8 (17.3%) were histological grade 3, 5 (10.9%) cases had involved lymph nodes and 28 (60.8%) cases were triple receptor negative. Only 2 cases were HER2 positive.
Conclusion: In this series metaplastic cancers were symptomatic in &gt;70%, tended to be large at the time of presentation and only 11% of cases had nodal involvement which is consistent with previous reports. Review of our radiology revealed that all modalities used (mammogram, USS and MRI) reliably showed characteristics suggestive of malignancy. Features suggestive of malignancy include spiculated or irregular ill defined masses on mammography or ultrasound and on MRI large irregular masses with central necrosis and rim enhancement following contrast. These are characteristic or suggestive of malignancy which is contrary to many previous studies of MBC that suggest MBC is difficult to pick up on imaging and commonly exhibits benign features.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-01-08.
Abstract P2-04-06: Successful results of a population-based organized mammography screening program in a developing country: The Turkish experience
Authors: Ozmen V , Ozkan-Gurdal S , Kayhan A , Ozaydin N , Cabioglu N , Ozcinar B , Aribal E 
Published: August 2014

Abstract
Objective: This study aims to determine the feasibility of a population-based organized mammography screening in a developing country (Bahcesehir, Istanbul, Turkey) and to find out the starting age for screening.
Material and methods: Women aged 40–69 were invited for screening at 2-year intervals starting in January 2009. Digital 2-view mammograms were obtained, and mammograms were double read by two independent radiologists who were experienced in breast imaging. The women were recalled in consensus for additional work-up including spot compression/magnification mammograms or breast ultrasound. Outcomes were measured from final assessment or histopathologic confirmation. The participation rate for second round, recall rate, number of biopsies, the women diagnosed with cancer and patient and tumor characteristics were evaluated.
Results: Between January 2009 and January 2013, 5938 (89.4%) of 6640 women aged between 40-69 years old accepted mammographic invitation. Most of them (58%) were at 40-49 age group, and the average 2-year attendance for second rounds were 82.6% and 81.2%, respectively. Spot recall rates were 16.8% and 25.6% for the first and second rounds, respectively. Core biopsy was required in 108 patients (1.8%), whereas BC was diagnosed in 50 patients (0.84%). Twenty-four patients (48%) detected with BC were at 40-49 age group. There were 39 patients (78%) with invasive BC and 11 patients (22%) with ductal carcinoma in situ (DCIS). Stages of 39 patients with invasive BC were Stage I (n = 26; 52%), II (n = 10; 20%) and III (n = 3; 6%), respectively. The majority of patients (88%) had breast conserving surgery, and sentinel lymph node biopsy only (72%) as axillary procedure. Of invasive cancers, 92% were found to be hormone receptor positive, and 59% had low Ki67 levels (≤15). However, HER2-neu positivity (8%) along with triple negative cancers (3%) were less frequently detected.
Conclusion: These findings suggest the prevailing view that mammographic screening increases early breast cancer detection rate which has a less aggressive biology. Screening mammography program can be successfully implemented in a developing country, Turkey effectively. However, more experienced dedicated breast cancer screening team and continuous increasing efforts are required to decrease our relatively high recall rates.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-04-06.
Abstract P2-05-03: Role of tumor immune environment in tumor initiation and growth rates in mouse mammary tumor models
Authors: Stanton S , Gadd E , Rastetter L , Slota M , Koehnlein M , Treuting P , Disis M 
Published: August 2014

Abstract
The role of the tumor immune environment is critical in human breast cancer tumorigenesis and response to therapy: tumors with a Th1 immune activating environment (high cytotoxic CD8+ T cells and low FoxP3 and myeloid derived suppressor cells (MDSC)) show improved response to chemotherapy and improved disease free survival and prognosis, where tumors with a Th2 immune suppressive environment (increased FoxP3, increased MDSC, and decreased CD8 T cells) shows poor response to chemotherapy and worse disease free survival and prognosis. There has not been good correlation with animal models of mammary tumorigenesis and human response to chemotherapy because in mouse models (1) tumor implant models do not show the tumor immune infiltration seen in human tumors (2) xenograph models are not immunocompetent (3) the tumor immune infiltration has not been evaluated the spontaneous mouse mammary models. We evaluated the tumor immune environment in relation to time to tumor development and rate of tumor growth in two commonly used transgenic mouse models: TgMMTV-neu and C3(1)Tag to better define role of the tumor immune environment in tumorigenesis in spontaneous mouse mammary tumor models.
Spontaneous tumorigenesis was studied in 80 TgMMTV-neu and 58 C3(1)Tag mice who were observed for tumor development from 6 weeks until tumor ∼1000 mm3. Differences in (1) time to tumor development (2) rate of tumor growth (3) tumor immune environment were evaluated. Between the transgenic mouse models, TgMMTV-neu mice (n = 10) developed tumors later, around 35.0 weeks, and the tumors grew slower with an average growth rate of 47.9 mm3/week than C3(1)Tag mice which developed tumors around 18.2 weeks with an average growth rate of 88.1 (p = 0.006). The tumor infiltration of MDSC inhibitory cells were higher in the C3(1)Tag mice than the TgMMTV-neu mice and approaches significance (17.4% of all lymphocytes in C3(1)Tag and 4.1% in TgMMTV-neu p = 0.08). Furthermore, there are increased CD8+ T cells in TgMMTV-neu mouse tumors than in C3(1)Tag (34.08% CD3+ cells in TgMMTV-neu mice and 22.38% in C3(1)Tag mice, p = 0.07) with similar FoxP3 levels (6.4% in TgMMTV-neu and 10.2% in C3(1)Tag mice p = 0.2) therefore the CD8/FoxP3 ratio in TgMMTV-neu mice is 5.3 where the CD8/FoxP3 ratio in C3(1)Tag mice is 2.2. These data demonstrate that C3(1)Tag mice have more aggressive tumorigenesis than the TgMMTV-neu mice and a more immunosuppressive tumor environment (higher MDSC, lower CD8, and smaller CD8/FoxP3 ratio) supporting the tumor immune environment plays an important role in tumorigenesis.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-03.
Abstract P2-05-05: Canine invasive mammary carcinoma as a spontaneous model for insulin-like growth factor-1 receptor-overexpressing triple negative breast cancer
Authors: Jaillardon L , Nguyen F , Loussouarn D , Godard T , Abadie J , Siliart B , Campone M 
Published: August 2014

Abstract
Background: Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative subtype, making this model relevant for the investigation of new therapeutic pathways. Insulin-like growth factor-1 receptor (IGF-1R) is extensively involved in malignant transformation, proliferation and metastasis in human breast cancer and multiple clinical trials have used IGF-1R inhibitors with encouraging results.
Aims: To quantify IGF-1R expression in canine triple-negative invasive mammary carcinoma (TN-CMC) and assess its prognostic value (overall, specific and disease-free survival). To validate the dog as a spontaneous animal model for preclinical trials targeting IGF-1R in triple-negative breast cancer.
Material and methods: 104 triple-negative canine invasive mammary carcinomas (Estrogen receptor negative, Progesterone receptor negative, not HER2 overexpressing) were included. Bitches were followed for at least 2 years after mastectomy. TN-CMC were classified as basal-like (Cytokeratin-CK 5/6 positive and/or Epidermal Growth Factor Receptor-EGFR positive) and non-basal-like (CK 5/6 and EGFR negative). IGF-1R expression (clone G11) was quantified using the same scoring system as for HER2 in breast cancer.
Results: 68.3% (n = 71/104) of the TN-CMC were classified as basal-like and 31.7% (n = 33/104) as non-basal-like. 45.2% (n = 47/104) of TN-CMC overexpressed IGF-1R (score 3+), of which 70.2% (n = 33/47) were basal-like and 61.7% (n = 29/47) were grade III. Univariate and multivariate analyses revealed that IGF-1R overexpression (score 3+) was associated with significantly shorter overall, specific and disease-free survivals (median: 163, 332 and 278 days respectively) than weak (score 1+) IGF-1R expression (median: 842 days, not achieved and 1011 days respectively).
Conclusion and perspectives: IGF-1R overexpression is common and related to a poor outcome in canine triple-negative invasive mammary carcinoma. Preclinical studies using the dog as a spontaneous animal model for triple-negative breast cancer could be considered to investigate new therapies targeting IGF-1R.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-05.
Abstract P2-05-08: Combined neoadjuvant iniparib and carboplatin in locally advanced or metastatic canine mammary tumors (MT) to support human clinical studies
Authors: Morio F , Becavin S , Gogny A , Nguyen F , Albaric O , Labrut S , Séveno C , Vrignaud P , Juin P , Campone M , Abadie J , Ibisch C 
Published: August 2014

Abstract
INTRODUCTION
Among breast cancers, the triple negative subtype (negative for hormone receptors and not overexpressing HER2) has the worst prognosis and its response to Iniparib has been investigated in clinical trials. Further investigations are needed to optimize drug schedule and patient selection criteria. Iniparib antitumor mechanism is not completely understood, as well as iniparib diffusion kinetic into tumoral tissues. We address these questions in spontaneous canine invasive mammary carcinomas, which are a good model for this cancer subtype (Ibisch et al., World Veterinary Cancer Congress 2012), in a neoadjuvant setting. To our knowledge, this is the first study of iniparib administration in cancer-bearing dogs.
MATERIAL AND METHODS
Twenty female dogs with spontaneous MT with malignant criteria (tumor size, speed of growth, ulceration, relapse, or metastasis) were included. All tumors were described as rapidly growing. Dogs received a first infusion of iniparib at day 0 and a combination of carboplatin and iniparib at day 7. Biological materials (tumor biopsies and blood) were collected before and 5 minutes after iniparib infusion for pharmacokinetic and metabolism studies. Tumor response was evaluated by caliper measurements and histopathological analysis of mammary tumors and draining lymph nodes. A chain mastectomy was performed 3 or 4 weeks later. Histological records included the subtype of carcinoma (WHO 1999), Elston & Ellis grade, presence of emboli, lymph node metastasis and IHC stainings using ER, PR, Her2 (scored according to Wolff et al.2007), CK5/6, EGF-R and Ki67. Intensity of necrosis and apoptosis was evaluated using PAS coloration and immunohistochemistry for caspase 3, at DO on tumor biopsies and at surgery. Toxicity of the protocol was evaluated and its efficiency on invasive carcinomas was compared to surgery alone (control group of 27 female dogs with invasive mammary carcinomas treated by chain mastectomy alone).
RESULTS
Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors. Clinical evidence of toxicity was minimal (15% of dogs with nausea, 60% with transient polyuria-polydipsia). Tumor stabilization was observed before surgery in all dogs but one. Median survival has not been reached.
CONCLUSION
Iniparib at 35mg/kg combined with carboplatin at 300 mg/m2 seemed well tolerated in this study and deserves further investigations. The degree of necrosis and apoptosis in the treated tumors can be evaluated with these techniques. Iniparib pharmacokinetic and metabolism studies in cancer-bearing dogs are ongoing.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-08.
Abstract P2-06-03: The BRCA1 promoter methylation is one of the mechanisms of th BRCA1 dysfunction of triple-negative breast cancer
Authors: Yamashita N , Tokunaga E , Tanaka K , Saeki H , Oki E , Kitao H , Morita M , Maehara Y 
Published: August 2014

Abstract
Background: Triple negative breast cancer (TNBC) is typically associated with aggressive tumor phenotype and poor prognosis. TNBC is also considered highly heterogeneous disease. A better understanding of molecular and histopathological features of TNBC is of great importance, in order to develop a new therapeutic strategy and to improve the prognosis of TNBC. TNBC has many similarities with basal-like breast cancer, and is also associated with BRCAness. The major role of BRCA1 is to respond to DNA damage by participating in cellular pathways for DNA repair, mRNA transcription, cell cycle regulation, and protein ubiquitination. BRCA1 function loss leads to impaired homologous recombination mediated DNA repair. A loss of BRCA1 may thus be a biomarker of responsiveness to DNA damaging agents such as PARP inhibitor and cis/carboplatin. Germline mutations in BRCA1, however, account for approximately 5% of breast cancer cases, somatic mutations in BRCA1 rarely occur. Instead, lower than normal expression of BRCA1 is reported to be an important contributing factor in sporadic tumors. The BRCA1 promoter methylation may thus play an important role in the BRCA1 function loss in sporadic breast cancer.
Aim: To evaluate the clinical importance of BRCA1 promoter methylation in breast cancer.
Materials and Methods: Specimens were obtained from 71 TNBC and 163 non-TNBC patients who underwent surgery without neoadjuvant therapy in our department between 1990 and 2011. BRCA1 promoter methylation was investigated by using combined bisulfate and restriction analysis (COBRA). The BRCA1 mRNA expression was evaluated by quantitive RT-PCR. The BRCA1 protein level was assessed by immnohistochemistry. Loss of heterozygosity(LOH) at the BRCA1 locus was analyzed with microsatellite markers (D17S855 and D17S579) using our microsatellite analysis system. Copy number variations(CNVs) were analysed by SNP-CGH array (Illumina, HumanOmni2.5-8).
Results: We found 12 patients with BRCA1 promoter methylation and all of them were TNBC (p&lt;0.0001). BRCA1 promoter methylation was associated with lymphovessel invasion (p = 0.009), high nuclear grade (p = 0.03), low BRCA1 mRNA expression (p = 0.002) and low BRCA1 protein expression (p&lt;0.0001). CNVs were observed more frequently in TNBC(p = 0.012). High CNVs significantly correlated with BRCA1 LOH (p = 0.0025), but not with BRCA1 promoter methylation among TNBC patients.
Conclusions: The BRCA1 promoter methylation is considered to be a specific feature of aggressive phenotype of TNBC and to be one of the mechanisms of BRCA1 dysfunction in breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-03.
Abstract P2-07-02: A novel megadeletion mouse model for mechanistic studies on the 8q24 non-coding breast cancer susceptibility locus
Authors: Smits BMG , Gould MN 
Published: August 2014

Abstract
Genome-wide association studies (GWAS) have identified over 80 variants associated with breast cancer susceptibility. These loci have low-penetrance and are common in the population. Some of the alleles are associated with specific types of breast cancer, and/or associate differentially between certain ancestral populations. The vast majority of common, low-penetrance breast cancer susceptibility variants are located in non-protein coding genomic regions. It is hypothesized that the polymorphisms along the risk-associated alleles alter regulatory elements to modulate gene expression regulation. How such gene regulatory effects affect the susceptibility to breast cancer is completely unknown. To begin to study in vivo mechanisms underlying such non-protein coding breast cancer-associated loci, novel mammalian genetic models are indispensable.
A prototype non-coding breast cancer susceptibility locus is the gene desert (i.e. a large genomic region devoid of known protein-coding genes) on human chromosomal band 8q24. The gene desert is flanked by MYC, PVT1 and FAM84b. It harbors 2 common, low-penetrance breast cancer susceptibility variants. We developed a novel megadeletion mouse model lacking a 450-Kb non-coding region orthologous to the breast cancer-associated 8q24 gene desert region. Mice homozygous for the megadeletion are viable. Analysis of the transcript levels of the flanking genes reveal organ-specific effects of the megadeletion mutation. Through genetic crosses with well-known transgenic mouse breast cancer models, we will examine the region's effect on mammary cancer multiplicity, size, latency and metastasis. Additional phenotyping and gene expression analysis will reveal novel insight in the mechanisms underlying this non-protein coding breast cancer-associated gene desert locus. The conclusions will extend beyond the 8q24 locus and will aid in understanding the influence of common, low-penetrance breast cancer loci in the etiology of breast cancer.
[The mouse model was generated with help from University of Wisconsin Paul P. Carbone Comprehensive Cancer Center funds. The work is supported by a DoD MUSC-Baylor BRIDGE scholarship awarded to BMGS].
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-02.
Abstract P2-07-04: HER2 overexpressing breast cancers are more frequent in carriers of TP53 DNA-binding domain mutations than in carriers of oligomerization-site mutations
Authors: Fitarelli-Kiehl M , Giacomazzi J , Santos-Silva P , Ashton-Prolla P 
Published: August 2014

Abstract
Germline TP53 mutations are associated with Li-Fraumeni Syndrome (LFS), an autosomal dominant disorder characterized by predisposition to multiple early-onset cancers including breast cancer (BC), the most prevalent tumor among women. The majority of germline TP53 mutations are missense substitutions clustered within the DNA-binding domain of the gene that disrupt the structure and function of the protein. Recently, the germline mutation p.R337H (c.1010G&gt;A), lying in the oligomerization domain of p53, was reported at a high frequency in Southern and Southeastern Brazil. This mutation appears to result in a more subtle defect in the protein, which becomes functionally deficient only under particular conditions and specific tissues. Recent reports suggest that BC are HER2-postive in a high proportion (63-83%) of TP53 mutation carriers. Histopathologic features of breast cancers among carriers of oligomerization domain mutations have not been reported. Our objective was to analize HER2 status in breast cancers from carriers of germline TP53 mutations, both in the DNA-binding and oligomerization domains. We retrospectively reviewed the immunohistochemistry data of breast cancers from 64 carriers of TP53 p.R337H and 6 carriers of nonfunctional germline TP53 mutations (p.G245S, p.R273H, p.G244D or c.672+1G&gt;T). All patients were recruited from the cancer genetics clinic at Hospital de Clínicas de Porto Alegre, Brazil. Germline TP53 mutations were identified by Sanger sequencing of the entire coding sequence and flanking intronic regions. Immunohistochemistry (IHC) was performed using standard procedures. HER2 expression was assessed using a 0 to 3+ scale according the ASCO-CAP Guidelines. All of the six patients with nonfunctional TP53 mutations showed strong (3+) HER2 staining by IHC in their breast tumors. In the group of p.R337H carriers, 23.4% showed significant HER2 overexpression (3+), 21.9% presented ambiguous HER2 results (2+), and 54.7% showed weak or no HER2 expression (1+ or 0). Thus, HER2 overexpressing breast cancers were more frequent in carriers of TP53 nonfunctional (DNA binding domain) mutations (p≤0.001) than in those carrying the oligomerization domain mutation. Preliminary results from this study suggest that germline mutations in different domains of the TP53 gene may predispose to breast cancer through different mechanisms.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-04.