bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-09-03: microRNAs and Target Gene Networks in Breast Cancer Cell Lines
Authors: Santarpia L , Diao L , Baggerly K , Boulbes D , Di Leo A , Calin GA , Symmans FW , Esteva F , Hortobagyi GN , Pusztai L. 
Published: April 2011

Abstract
Background: MicroRNAs (miRNAs) are a class of small endogenous RNA molecules that post-transcriptionally inhibit gene expression. Several miRNAs have been involved in the regulation of several cellular processes during oncogenesis.
Objective: We simultaneously analyzed 18 different breast cancer cell lines (BCC) for miRNA and mRNA expression profiles in order to identify regulatory miRNA target gene networks and novel miRNA-directed therapeutic targets.
Materials and Methods: We preprocessed the mRNA and miRNA expression data using R software (justRMA) and performed quantile normalization using background-subtracted log ratio distributions across arrays. We identified 39 hsa-miRNAs with the largest variation across samples and examined the Spearman correlations of miRNAs with the Affymetrix probesets. We calculated false discovery rates for probe sets with stringent correlation coefficients. We performed hierarchical clustering using the 39 miRNAs and correlated dendograms branches with basal/luminal classes. Potential miRNA target genes were identified. We performed pathway analyses by using all 39 miRNA target genes. Western blot analyses were performed to confirm regulation of specific proteins. Results: We demonstrated 39 deregulated miRNAs and 10612 mRNA targets genes in BCC. Twenty-three miRNAs were upregulated in basal and downregulated in the luminal groups targeting 6790 genes, and 16 miRNAs downregulated in basal and upregulated in luminal cells, targeting 3822 genes. The first direct comparison screening for the 39 miRNAs and all mRNAs identified 29 direct pairs where the correlation magnitude was above 0.9. MiR-221/222, -31, -143/145, -34a, -200 were the most and consistently deregulated miRNAs in all luminal and basal like BCC. We identified genes, such as CD59, PDGF-β and discoidin domain receptor tyrosine kinase 1-DDR1 and different cancer network pathways, such as cell cycle and cell surface markers, potentially regulated by a subset of these miRNAs. Interestingly, we found that the expression of single genes might be regulated by several miRNAs.
Conclusions: We found a specific miRNA signature and respective genome targets that well defined different clusters of BCC. Breast cancer cell lines are associated with changes in expression of multiple miRNAs that, in turn, disrupt a network of genes that either activate or inhibit important cellular functions. A better understanding of the network of genes and cellular pathways regulated by these miRNAs will enable to understand breast cancer pathogenesis and miRNA based breast cancer therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-09-03.
Abstract P3-09-06: microRNA Signature of Columnar Cell Hyperplasia from Patients with High Risk of Breast Cancer
Authors: Nilsson S , Landberg G 
Published: April 2011

Abstract
Background: Columnar cell hyperplasia (CCH) is considered to originate in normal terminal duct lobular units (TDLUs) and is potentially the first histologically identifiable alteration in the development of breast cancer. In order to detect early pathological changes in breast tissue, which could reveal the underlying mechanism to cancer progression, we investigated the microRNA (miRNA) expression profile in TDLUs and CCH. Material and Methods: Epithelial cells and surrounding stroma of TDLUs and CCH from formalin-fixed paraffin embedded tissue (FFPE) from patients with high risk of developing breast cancer were laser capture microdissected and RNA was extracted. MiRNA expression profiles were obtained using a qRT-PCR-based array analyzing 667 human miRNAs. Results: Increased levels of ERα were present in the epithelial cells of CCH as previously reported. Immunohistochemical staining for the stromal activation marker smooth muscle actin (SMA) was negative in fibroblasts surrounding both TDLUs and CCH, suggesting lack of major activation of the stroma. Interestingly, array analysis revealed changes in miRNA expression pattern in both epithelial and stromal compartments. Correlation analyses of the array results indicated a high reproducibility (r2:0.82-0.94) supporting stable miRNA profiles in TDLUa and CCH. MiRNA array analysis of paired samples from specimens with both TDLUs and CCH resulted in significant (P&lt;0.05) decreased levels of 15 miRNAs in epithelial cells of CCH and downregulation of 18 miRNAs in the stroma. Examples of altered miRNAs in the epithelial cells are miR-532-3p, miR-886-3p, let-7c, miR-491-5p, miR-365, and example miRNAs in the stroma are miR-195, miR-99a, miR-224, miR-19b, miR-423-5p. Further validation
of a selection of miRNAs in a patient material using in situ hybridization is currently being performed to verify the array results. Discussion: This data will potentially link these miRNAs to the development of TDLUs towards CCH and possibly lead to the discovery of new markers for precancerous conditions and potentially new therapeutic targets.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-09-06.
Abstract P3-10-11: Clinical Significance of Progesterone Receptor and HER2 Status in Estrogen Receptor-Positive, Operable Breast Cancer with Adjuvant Tamoxifen: Consistent Prognostic Impact of HER2 Status Over Time
Authors: Moon YW , Park S , Sohn JH , Kang DR , Koo JS , Park HS , Chung HC , Park B-W 
Published: April 2011

Abstract
Purpose: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer, focusing on the progesterone receptor (PR) and HER2 over time.
Patients and Methods: A total of 819 patients with ER-positive, operable breast cancer were enrolled. All received adjuvant tamoxifen. Prognostic value of the PR status and HER2 status was evaluated using Cox regression before and after 5 years post-surgery.
Results: PR and HER2 status were inversely correlated (P = .014). PR-negativity was a time-dependent poor prognostic factor for recurrence before 5 years post-surgery (P = .049), but not after 5 years post-surgery (P = .566).
However, HER2 overexpression and younger age (35 years or less) were consistent prognostic factors for recurrence over all time periods, whereas N stage and histologic grade, which are known prognostic factors, were no longer informative after 5 years post-surgery, except for N3 disease. Conclusion: In ER-positive, operable breast cancer, the prognostic impact of PR status along with N stage and histologic grade were strong for the first 5 years post-surgery, but disappeared thereafter. However, HER2 overexpression was a consistent poor prognostic factor, suggesting that an alternative adjuvant strategy, possibly involving incorporation of prolonged HER2-targeted therapy should be evaluated for HER2-overexpressing tumors.
Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-11.
Abstract P3-10-13: Prognostic Value of Genomic Analysis after Neoadjuvant Chemotherapy for Breast Cancer
Authors: Mayer EL , Shak S , Miller K , Rugo H , Carey L , Ryabin N , Pomeroy C , Yoshizawa C , Winer EP , Burstein HJ 
Published: April 2011

Abstract
Background
Oncotype DX® Recurrence Score® (RS) provides both predictive and prognostic information for estrogen receptor positive (ER+) breast cancer. Whether RS evolves after exposure to chemotherapy (C), or if RS post-neoadjuvant C has prognostic capacity for outcomes after bevacizumab, is not known. Methods
DFCI 05-055 treated patients (pts) with residual invasive disease following neoadjuvant C with sequential bevacizumab-containing regimens. Archival FFPE tissue was obtained from participants at 3 potential timepoints: pre-C core biopsy, post-C surgical residual disease, and core biopsy at time of systemic recurrence. Standard RS testing was performed on all samples.
Results
A total of 162 pts were enrolled on the parent study; of that, 118 samples from 80 pts were available for testing, including 48 pre-C core biopsies, 68 post-C surgical samples, and 34 paired samples before and after C. Comparison of ER/PR/HER2 testing by local IHC vs RT-PCR for the pre-C core biopsies showed excellent concordance. For the entire cohort of 80, 20 pts (25%) experienced distant recurrence (9 ER+, 11 ER-by IHC). RS risk distribution in this group included 14 high, 3 intermediate (int), and 3 low. High RS was positively associated with distant recurrence for the entire cohort (t-test p=0.04); this association remained consistent whether RS was tested pre-C (t-test p=0.07) or post-C (t-test p=0.02). Specimen characteristics of the 34 paired pre-C/post-C samples are described below. Of the 34 paired samples, RS was highly correlated before and after exposure to neoadjuvant C, (r=0.85, 95% CI 0.72-0.92), suggesting little, if any, change in RS from C exposure. Specific changes over time included 24 without change in RS group, 3 high to int, 1 high to low, 1 int to low, and 5 low to int. Testing by RT-PCR remained consistent for ER (r=0.91, 95% CI 0.82-0.95), PR (r=0.79, 95% CI 0.62-0.89) and HER2 (r=0.88, 95% CI 0.76-0.94) before and after neoadjuvant C. Two pts had biopsy samples from systemic recurrence; testing showed RS, ER, PR, HER remained in similar range from core biopsy to surgery to disease recurrence.
Conclusions
In this evaluation of samples pre-and post-neoadjuvant C, high RS determined either before or after neoadjuvant C predicted for disease recurrence after adjuvant bevacizumab treatment. RT-PCR and IHC values for ER/PR/HER2 were concordant. Paired RS and RT-PCR ER/PR/HER2 remained correlated despite interval exposure to neoadjuvant C. Post neoadjuvant C RS may provide valid prognostic information for breast cancer disease recurrence and warrants further study.
Specimen Characteristics for Paired Samples (n=34)

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-13.
Abstract P3-10-15: Quantitative Gene Expression by RT-PCR in Classic and Variant Forms of Lobular Carcinoma in Estrogen Receptor Positive Invasive Breast Cancer
Authors: Anderson JM , Yoshizawa C , Winer EP , Watson D , Millward C , Tan V , Shak S , Baehner FL 
Published: April 2011

Abstract
Background: Classic lobular carcinoma is characterized by a distinctive morphology, loss of E-cadherin commonly due to mutation or deletion of CDH1 on chromosome 16q, and a variable clinical course (Pestalozzi J Clin Oncol. 2008 26:3006). Variants (pleomorphic, solid and alveolar) with distinct morphologies and potential differences in outcome have been described (Rosen 2009). Herein we explore the patterns of quantitative gene expression as measured by the 21 gene Oncotype DX® assay observed between ductal NOS (DC) and classic and variant lobular carcinomas. Material and Methods: All tumors analyzed in the Genomic Health laboratory from 6/1/04-3/31/10 were included. Central path used WHO criteria for classification of classic lobular (CL), solid & alveolar lobular (SAL), and pleomorphic lobular (PL) carcinomas. Quantitative expression of 16 cancer related genes was measured on a scale from 0 to 15 (relative to reference genes) where a 1 unit increment is associated with an ∼2-fold change in expression. Descriptive statistics for RS & individual genes [ER, PR, invasion gene group (IGG) & proliferation gene group (PGG)] among the different subtypes were obtained. Comparisons of means among the subtypes were adjusted to control the overall error rate under any complete or partial null hypothesis.
Results: DC accounted for 90.4% of 133,234 cases, CL 8.2%, SAL 0.7% and PL 0.8%. For all types a continuous range of RS was observed. DC had the greatest percentage of high risk RS followed by SAL, PL and CL. DC had the highest RS and CL had the lowest RS. SAL had the highest ER expression and CL had the lowest expression, but these results may refect a submission bias and are not population based. The proportion with the ER+/PR-phenotype was slightly different among the subtypes: SAL (24.2%) and PL (19.5%) had a higher incidence compared to DC (15%) and CL (15.6%). SAL had the highest PGG expression; CL had the lowest. DC had the highest IGG; CL had the lowest.
Discussion: Classic lobular carcinoma and the lobular carcinoma variants are characterized by differential patterns of gene expression. Outlier cases are not infrequent within each of the special subtypes in this large observational cohort. The variation in gene expression, noted by histologic subtype, will be presented in detail.
RS Distributions in Ductal NOS, Lobular and Lobular Variants

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-15.
Abstract P3-10-17: The Fractal Analysis of Tumor Histology Is an Independent Prognostic Factor in Breast Cancer Patients
Authors: Magliocco A , Eliasziw M , Tambasco M 
Published: April 2011

Abstract
Background: Despite the usefulness of standard clinical prognosticators for breast cancer patients, recommendations for systemic adjuvant therapy are not entirely straightforward. Hence, there is a need for a more accurate independent prognosticator that provides additional information to improve risk assessment and associated therapeutic decisions. Methods: We used fractal dimension analysis to quantitatively assess the morphologic complexity of breast epithelium. To investigate the relationship between fractal dimension and patient survival we applied fractal analysis to pan-cytokeratin stained tissue microarray (TMA) cores derived from a series of 408 patients with over 10 years follow up, and analyzed three TMA cores for each patient. A data-oriented approach was used to stratify patients according to low (&lt;1.56), intermediate (1.56-1.75), and high (&gt;1.75) fractal dimension. Univariate statistical analyses were performed to show the relationship between outcome and fractal dimension, tumour size, tumour grade, lymph node status, estrogen receptor status, and HER-2/neu status. Multivariate analysis was performed to assess the relative effect of these prognosticators on disease-specific and overall survival.
Results: Patients with higher fractal score had significantly lower disease-specific 10-year survival (69.4%, 56.4%, and 25.0%, for low, intermediate, and high fractal dimension, respectively, P&lt;0.001). Overall 10-year survival showed a similar association with fractal dimension. Cox regression analysis showed fractal dimension, lymph node status, and grade to be the only significant (P&lt;0.05) independent predictors for both disease-specific and overall survival. Fractal dimension had the highest hazard ratio for overall survival 2.7(95% confidence interval (CI)=1.6-4.7); P&lt;0.001), and the second highest for disease-specific survival 2.6(95% CI=1.4-4.8; P=0.002) versus 3.1(95% CI=1.9-5.1; P&lt;0.001) for lymph node status. Discussion: Except for lymph node status, morphologic complexity of breast epithelium as measured by fractal dimension is more strongly and significantly associated with disease-specific and overall survival than standard clinical prognosticators. Furthermore, it is independent of standard prognosticators, and unlike tumour grade, it provides prognostic information that can be objectively assessed from TMA cores.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-17.
Abstract P3-10-20: The Prognostic Relevance of Serum CA27.29 level in Primary Breast Cancer Patients before Adjuvant Chemotherapy — Results of the German SUCCESS Trial
Authors: Neugebauer JK , Rack BK , Schindlbeck C , Schrader I , Tesch H , Schneeweiss A , Zwingers T , Lichtenegger W , Beckmann MW , Sommer HL , Friese K , Janni W 
Published: April 2011

Abstract
Background: While tumor markers are frequently used to assess treatment efficacy in metastatic breast cancer, there is lack of evidence regarding the role of MUC-1 markers in primary disease. The value of CA27.29 in the adjuvant setting was prospectively evaluated in the German multicenter SUCCESS study.
Material and Methods: The German SUCCESS trial is a multicenter phase III study comparing FEC-Docetaxel (Doc) vs. FEC-Docetaxel-Gemcitabine (Doc-G) and 5 versus 2 years of Zoledronate as adjuvant treatment in patients with node positive or high risk node negative primary breast cancer. In this trial serum CA27.29 level has been prospectively evaluated in 3202 patients before and immediately after adjuvant chemotherapy as well as 2 and 5 years thereafter. CA27.29 was measured with the ST AIA-PACK CA27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). The cutoff for positivity was &gt;31 U/ml. Results: Mean CA27.29 serum level before adjuvant chemotherapy was 19,3 U/ml (SD +/− 15,5) in both arms. 8,0% (n=127) of patients in the FEC-Doc-G arm and 7,4% (n= 120) in the FEC-Doc arm had marker levels of more than 31 U/ml. Mean CA27.29 serum levels were significantly higher in patients with lobular carcinoma (p=0.001), with positive lymph nodes (p=0.02) and post-menopausal patients (P&lt;0.001). After a median follow-up period of 34 months 233 patients relapsed and 108 patients died. CA27.29 before chemotherapy was a significant prognostic marker for disease-free survival (DFS) (P&lt;0.0001) and overall survival (OAS) (P&lt;0.0001) in univariate and multivariate analysis. Conclusion: These findings indicate the independent prognostic relevance of serum CA27.29 levels in primary breast cancer patients before adjuvant treatment. Further follow-up within the SUCCESS trial will show whether initial CA27.29 level could serve as a tool for adjuvant treatment monitoring.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-20.
Abstract P3-10-24: Fibroblast Growth Factor Receptor 1 Amplification and Overexpression in Breast Cancer Tissue Microarrays Using Chromogenic In Situ Hybridization and Immunohistochemistry
Authors: Nuciforo P , Burzykowski T , Lambertini C , Gardner H , Liu WH , Lee B , Barzaghi-Rinaudo P , Rheinhardt J , Barrett C , Linnartz R , Dugan M , Hackl W , Eiermann W , Pienkowski T , Crown J , Robert N , Pawlicki M , Martin M , Finn R , Lindsay M-A , Slamon D , Press M 
Published: April 2011

Abstract
Fibroblast growth factor receptors 1 (FGFR1) belongs to a subfamily of receptor tyrosine kinases (RTKs), which are involved in proliferation and apoptosis. FGFR1 amplification and mRNA overexpression occurs in ∼10% of breast cancers and has been associated with poor outcome. However, studies assessing FGFR1 amplification and protein overexpression in a large collection of breast tumors are lacking. In this prospective, we examined a series of primary breast cancers samples derived from the BCIRG trials assembled into 15 tissue microarrays. FGFR1 gene amplification was studied using chromogenic in situ hybridization (CISH) and evaluated with respect to association with level of protein expression and clinicopathological parameters. FGFR1 gene amplification was significantly associated with high protein levels as determined by immunohistochemistry (P&lt;0.0001, 3294 pts with available matched CISH and IHC records). Overall, the incidence of FGFR1 amplification found was 9.7% (160 out of 1646 pts. with available clinicopathological records) without a statistically significant difference between Her2- (78 out 720 pts., 11%) and Her2+ (82 out of 926 pts., 9%) cancers. In both cohorts, the hormone receptor-positive (ER+/PR+) cancers showed statistically significant higher levels of FGFR1 amplification compared to hormone receptor-negative tumors. In the analysis of the association of FGFR1 and the presence of PIK3CA mutations, the incidence of FGFR1 amplificationwas greatly reduced in mutant vs. wt PI3KCA tumors. In these cohorts, a clear relationship between FGFR1 amplification status and clinical outcome was not detected. Data from this large study confirms recently reported incidences of FGFR1 amplification in breast cancer and shows for the first time an association between FGFR1 gene amplification and protein overexpression. Moreover, the lower incidence of FGFR1 amplification in PIK3CA mutated cancers suggests that these are largely exclusive molecular events that could benefit from different targeted therapies.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-24.
Abstract P3-10-25: The Prognosis of Metaplastic Breast Cancer Patients Compare to Triple-Negative Breast Cancer Patients
Authors: Cho DH , Jang JH , Lee SK , Choi M-Y , Koo MY , Hur SM , Bae SY , Kim SM , Choe J-H , Lee JE , Kim J-H , Kim JS , Nam SJ , Yang J-H 
Published: April 2011

Abstract
Background: Metaplastic breeast cancer (MBC) is a rare, heterogenous cancer characterized by admixture of adenocarcinoma with metaplastic elements, low hormone receptor expression and poor outcome. This study was planned to assess the clinicopathological chacteristics and immunohistochemical findings of MBC compared to invasive ductal carcinoma (IDC) including the triple-negative subtype (TN-IDC). Material and Methods: We retrospectively reviewed the medical records of 47 MBC and 1,346 IDC patients. Two hundred eighteen TN-IDC patients were included in the 1,346 IDC patients. Between 2005 and 2009, these patients were undergone surgical treatment at the Samsung Medical Center. Patients were reviewed clinicopathologic factors, immunohistochemistry of biologic factors such as ER, PR, HER-2, p53, Ki67, cytokeratine (CK) 5/6, epidermal growth factor receptor (EGFR), and treatment modalities (type of operation, use of chemotherapy, radiotherapy and hormone therapy). Result: The MBC patients presented with a larger tumor size (&gt;T1, 66.0% vs. 44.3.%, P = 0.008), lower lymph node involvement (N0, 73.3% vs. 55.6%, P = 0.03), higher histologic (HG) and nuclear grade (NG) (HG3, 70.0% vs. 41.5%, P = 0.001; NG3,82.6% vs. 46.9%, P &lt; 0.001), fewer estrogen receptor (ER), progesterone receptor (PR) and HER2 positivity (ER+, 4.3% vs. 69.2%, P &lt; 0.001; PR+, 6.4% vs. 63.5%, P &lt; 0.001; HER2+, 0% vs. 27.6%, P &lt; 0.001), higher p53, CK5/6 and EGFR expression (p53+, 63.8% vs.38.8%, P &lt; 0.001; CK5/6+, 71.9% vs.21.5%, P &lt; 0.001; EGFR+, 93.9% vs.21.6%, P &lt;0.001) and more TN subtypes (93.6% vs. 16.2%, P &lt; 0.001) compared to the IDC group. There was no significant difference in clinicopathological characteristics with MBC and TN-IDC except EGFR over expression (EGFR+, 93.9% vs.69.0%, P = 0.017). In follow-up duration (median 30 months, range 2-56 months), seven (14.9%) MBC patients and 98 (7.2%) IDC patients recurred. The 3-year disease-free survival (DFS) rate was 78.1% in the MBC group and 91.1% in IDC group (P &lt;0.001). The 3-year DFS rate was not significantly difference between MBC group and TN-IDC group (78.1% vs. 84.9%, P = 0.114). However, in patients with lymph node metastasis who underwent adjuvant chemotherapy, the 3-year DFS rate was 44.4% in MBC group and 72.5% in TN-IDC group (P = 0.025).
Discussion: In our result, MBC show poorer clinical outcome than IDC. It is not shown significant difference between MBC and TN-IDC. However, MBC patients with nodal metastasis have poorer prognosis than TN-IDC patients with metastasis despite adjuvant chemotherapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-25.