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Supplementary Methods from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 3 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 9 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 7 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 6 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 2 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 1 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 4 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Supplementary Table 8 from Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Background: Survival rates of breast cancer patients are high, and the majority of women is Methods: We conducted a cross-sectional, hospital-based monocentric questionnaire study of women diagnosed with breast cancer. Recruitment was carried out from January to March 2011 for women diagnosed with and treated for primary breast cancer between 2005 and 2010 at Charité University Hospital Berlin. Results: The study included 492 breast cancer patients without recurrence. In total, 81.3% of the women returned to work, and 30.2% of the women felt a reduction of financial opportunities. Financial problems were named by at least 20% of the patients as being the main cause for a reduced quality of life. Conclusion: Long-term, disease-free breast cancer survivors reported a significant change in their work-related factors as well as changes in their financial opportunities.

Introduction The assessment of papillary lesions continues to be a challenging area in breast radiology and pathology. The management of intraductal papillomas without atypia of the breast remains controversial. The purpose of the present study was to determine diagnostic accuracy of radiographical diagnosis, core biopsy, and surgical excision in papillary breast lesions. Material and methods By using files from 1995 to 2010, 151 cases of intraductal papilloma with or without atypia were identified. Patients were stratified as follows: core biopsy followed by surgical excision (n = 61), core biopsy alone (n = 19), and surgical excision alone (n = 71). Results The upstage rate of intraductal papillomas without atypia on core biopsy to atypia or malignancy on excision was 8.9%. Excision specimens revealed intraductal papillomas without atypia in 68 out of 71 cases, and atypical papillomas in 3 cases. Conclusion Our findings suggest that radiographic and histopathological diagnosis of intraductal papillomas show high accuracy and good concordance. In cases where the radiographic diagnosis reveals suspicious lesions core biopsy represents the first choice.

The biological behavior and the optimal management of benign breast lesions with uncertain malignant potential, the so-called B3 lesions, found in breast needle core biopsies is still under debate. We addressed this study to compare histologic findings in B3 needle core biopsies with final excision specimens to determine associated rates of malignancy. Consecutive needle core biopsies were performed in a 3-year period (January 1, 2006-December 31, 2008). Biopsies were image-guided (31 by ultrasound, 85 stereotactic vacuum-assisted, 6 unknown) for evaluation of breast abnormalities. We reviewed 122 needle core biopsies with B3 lesions of 91 symptomatic patients and 31 screen-detected women and compared the B3 histologic subtypes with the final excision histology. A total of 1845 needle core biopsies were performed and B3 lesions comprised 6.6% of all B categories. The most common histologic subtype in biopsies was flat epithelia atypia in 35.2%, followed by papillary lesions in 21% and atypical ductal hyperplasia in 20%. Reports on excision specimens were available in 66% (81 patients). Final excision histology was benign in 73 (90.2%) and malignant in 8 (9.8%) patients (2 invasive cancer, 6 ductal carcinoma in situ). Of all B3 subtypes, atypical ductal hyperplasia and flat epithelial atypia were associated with malignancy, whereas only atypical ductal hyperplasia was accompanied by invasive cancer. Of all lesions, flat epithelial atypia was most frequently found in excision specimens (18%). In our study, flat epithelial atypia and atypical ductal hyperplasia are common lesions of the B3 category in needle core biopsies of the breast. Both lesions are associated with malignancy, whereas only atypical ductal hyperplasia was related to invasive cancer. We conclude that an excision biopsy after diagnosis of flat epithelial atypia is recommended depending on clinical and radiologic findings.

Purpose. Core biopsy is considered to be a highly accurate method for gaining preoperative diagnosis of breast cancer. The purpose of this study is to compare the results of core biopsy with those of the surgical excision specimen. Experimental design. A total of 567 core biopsies with subsequent surgical excision were performed. Results. In 488 patients, invasive breast cancer was diagnosed in the preoperative biopsy and in 486 patients (99.6%) the surgical specimen showed identical results. In 160 of the 502 patients (32%) with invasive breast cancer, DCIS was found in the surgical specimen but was not diagnosed in the biopsy. Estrogen and progesterone receptor demonstrated a high rate of agreement, Her2/neu analysis showed a complete concordance in 54% of patients. Conclusions. Core biopsies allow diagnosis of invasive breast cancer with high accuracy. Levels of agreement have to be improved for the detection of DCIS and Her2/neu status.

Development of new capillary blood vessels is essential for the growth of cancer. Two distinct processes, vasculogenesis and angiogenesis implement the formation of the new vascular network. Recently, it was demonstrated that vasculogenesis creates the primary network of vascular endothelial cells that will become major blood vessels in malignant tumors by the recruitment of CD34(+)/vascular endothelial growth factor receptor 2 (FLK-1)(+ )endothelial progenitor cells (EPCs) to sites of the new vessel formation with subsequent differentiation into mature endothelial cell. Therefore the aim of this study was a) to quantitate EPCs in breast cancer patients and b) to evaluate if the release of EPCs into the circulation is mainly regulated by the tumor himself.CD34(+)FLK-1(+ )EPCs were measured in the peripheral circulation of patients with breast cancer (n = 47) before and after therapy. Furthermore the potential of EPCs to differentiate into endothelial cells was investigated by late-outgrowth experiments and the metabolic uptake of dil-acetylated-LDL and immunoreactivity against von Willebrand factor.In breast cancer patients the amount of CD34(+)FLK-1(+ )EPCs (percent of peripheral blood mononuclear cells) is significantly increased in women with breast cancer. Tumors larger than 2 cm showed significantly higher values of CD34(+)FLK-1(+ )EPCs. After excision of the tumor the amount of CD34(+)FLK-1(+ )EPCs rapidly declines.Our findings lead to the tumor, as source of angiogenic chemokines, is most important for recruiting CD34(+)FLK-1(+ )EPCs during breast cancer development. Therefore circulating endothelial progenitor cells may work as a new diagnostic tool in the screening and diagnosis of breast cancer.

Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER−) breast cancer tissues were investigated using GC–TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER− subtype. Beta-alanine demonstrated the strongest change between ER− and ER+ breast cancer (fold change = 2.4, p = 1.5E − 20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R = − 0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER− breast cancer. In a Kaplan–Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR = 0.6, p=3.2E-15).Biological significanceIt is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER− breast as different diseases requiring different treatment strategies.Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER− breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER− subtype as a preferential target for glutaminase inhibitors.For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER− breast cancer.

Metaplastic carcinoma of the breast is a heterogeneous neoplasia, generally composed of both epithelial and mesenchymal components. We report an unusual case of mammary metaplastic carcinoma in a 51-year-old female patient. Needle core biopsy from the tumour mass showed malignant epithelial and sarcomatous features. The resection specimen revealed a multi-directional tumour differentiation consisting predominantly of: firstly, a poorly differentiated basaloid epithelial cell type, consistent with an adenoid cystic carcinoma; secondly, areas of a spindle cell carcinoma; and, thirdly, areas with a melanocytic differentiation. This is the first report on a metaplastic carcinoma of the breast presenting as an admixture of an adenoid cystic carcinoma and melanoma.

The validated EndoPredict assay is a novel tool to predict the risk of metastases of patients with estrogen receptor positive, HER2 negative breast cancer treated with endocrine therapy alone. It has been designed to integrate genomic and clinical information and includes clinico-pathological factors such as tumor size and nodal status. The test is feasible in a decentral setting in molecular pathology laboratories. In this project, we investigated the performance of this test in clinical practice, and performed a retrospective evaluation of its impact on treatment decisions in breast cancer. During one year, EndoPredict assays from 167 patients could be successfully performed. For retrospective evaluation of treatment decisions, a questionnaire was sent to the clinical partner. Regarding the molecular EP class, samples from 56 patients (33.5%) had a low-risk, whereas 111 patients (66.5%) showed a high-risk gene profile. After integration of the clinicopathological factors the combined clinical and molecular score (EPclin) resulted in a low-risk group of 77 patients (46.4%), while 89 (53.6%) had a high risk EPclin score. The EPclin-based estimated median 10-year-risk for metastases with endocrine therapy alone was 11% for the whole cohort. The median handling time averaged three days (range: 0 to 11 days), 59.3% of the tests could be performed in three or less than three days. Comparison of pre- and post-test therapy decisions showed a change of therapy in 37.7% of patients. 16 patients (12.3%) had a change to an additional chemotherapy while 25.4% of patients (n = 33) changed to an endocrine therapy alone. In 73 patients (56.2%) no change of therapy resulted. In 6.1% of patients (n = 8), the patients did not agree to the recommendation of the tumor board. Our results show that the EndoPredict assay could be routinely performed in decentral molecular pathology laboratories and the results markedly change treatment decisions.