bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunohistochemically Defined T1N0 Breast Cancer Subgroups Have Different Clinical Outcomes. A Retrospective Turkish Oncology Group Study.
Authors: Basaran G. , Okkan S. , Caglar H. , Benekli M. , Gumus M. , Haydaroglu A. , Eralp Y. , Abali H. , Yildiz F. , Bese N. , Gursel B. , Guney N. , Derin D. 
Published: December 2010

Abstract
Introduction: T1N0 breast cancer (BC) has a very favorable outcome therefore the need of adjuvant systemic therapy is controversial. Molecular profiling studies identified BC subtypes with distinct clinical outcomes. We planned to determine whether immunohistochemically (IHC) defined subgroups of T1N0 BC patients have different clinical outcomes. Methods: Medical records of pts with T1N0 BC and known ER, PR and Her-2 status who have been treated between 1998-2008 were reviewed. Patients with bilateral disease, who had adjuvant trastuzumab therapy were excluded. Clinical/pathological, treatment characteristics were recorded and patients were subdivided into four BC subtypes: triple negative (ER, PR, HER2 negative), HER2 (ER and PR-negative, HER2-positive), luminal B (ER-positive and/or PR-positive, HER2-positive), and luminal A (ER and/or PR-positive and HER2-negative). Her-2 positivity was defined as IHC 3+ or FISH positive IHC2 2+. Survival outcome of the IHC defined subgroups were analyzed the Kaplan-Meier method and compared with the log-rank test. Results: A total of 1035 pts have been identified from 17 Medical/Radiation Oncology centers in Turkey. Median age was 51 and median follow up was 39 months. Forty-four % of patients were premenopausal, 55% had left breast involved, 73% had breast conserving surgery, 81% had invasive ductal carcinoma. T1a,b,c tumors were 7%, 30%, 63% ; grade 1,2,3 tumors were 20%, 53%, 27% respectively. HER2 was 2 + in 59 (6%) and 3 + in 111 (11%) tumors. Twelve % tumors were triple negative. Thirty-seven % patients had adjuvant chemotherapy; 80 % had adjuvant endocrine therapy 73% had adjuvant radiotherapy. Five-yr DFS and OS of the whole group were 92% and 99% respectively. So far, 19 pts had local and 24 pts had distant metastases, 4 pts had secondary cancers, 6 patients contralateral BC and 11 patients died (7/11 pts died from breast cancer). Classification based on ER, PR and Her-2 status had significant impact on 5-yr DFS (p:0.00) and OS (p:0.00). The 5-yr DFS and OS were 84%;74%;%;94% and 96%;83%;100%;99% respectively for triple negative, HER2, luminal B, and luminal A subgroups respectively. Hormone receptor and triple negative status were the two other parameters affecting survival outcome significantly (p:0.00, p: 0.007) in the univariate analyses. Conclusion: Most patients with T1N0 disease have generally a favorable clinical outcome, however even within this very early stage of BC there are subgroups with diverse clinical outcomes. Despite our short follow up with low number of events, we found that Her-2 positive and triple negative T1N0 BC have poor clinical outcomes compared to luminal T1N0 subgroups and therefore they might need special concern with respect to adjuvant systemic therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3167.
Breast Cancer Subtypes in Northern Chinese Women.
Authors: Gao J. , Zhang X. , Zhang B. , Wang J. , Liang X. 
Published: December 2010

Abstract
Introduction: Breast cancer is currently regarded as a heterogeneous disease. Gene expression analysis has identified several subtypes that differ in prognosis and therapy response. Little is known about the distribution of these subtypes among native Chinese women.Patientsand Method: From December 2006 to November 2008, 1,133 women were diagnosed with invasive breast cancer in Shanxi province cancer hospital and 818 had assessable information for ER, PR, and Her-2/neu status. Based on immunohistochemical surrogates for ER, PR, and Her-2/neu status obtained from the department of pathology, the molecular subtypes were defined as: luminal A (ER+ and/or PR+, HER2−), luminal B (ER+ and/or PR+, HER2+), basal-like (ER−, PR−, HER2−), and Her-2/neu (ER−, PR−, and HER2+).Results: Luminal A was the most prevalent breast cancer subtype (70.6%), compared with the luminal B breast cancer subtype (15%), basal-like breast cancer subtype (9.6%), and Her-2/neu breast cancer subtype (4.8%). The frequency of Her2 positive breast cancer was 19.88% in the cohort studied. The luminal B breast cancer subtype was largely presented in patients aged less than 50 years old (58.8%) compared with the luminal A subtype (48.5%), basal-like subtype (52.6%) and Her-2/neu breast cancer subtypes (47.4%). The largest tumor size was basal-like breast cancer (28.1mm), followed by luminal B (25.8mm), Her-2/neu (25.7mm) and luminal A (23mm) (P = 0.003). The lymph node status did not vary among the four groups, however, the mean number of lymph nodes metastasis was significantly different with 3.2, 2.9, 5.7 and 4.9 for luminal A, luminal B, Her-2/neu and basal-like subtypes respectively (P = 0.005).Conclusions: The distribution of breast cancer subtypes in Northern Chinese women was similar to other ethnicities. The basal-like and Her-2/neu breast cancer subtypes were associated with unfavorable clinical features. Further studies will identify the difference in treatment response and prognosis among the four subtypes in this cohort.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3168.
Biomarker Discovery and Evaluation of Response to Anti-Cancer Therapeutics in Breast Cancer Using a Novel Nanofluidic Immunoassay Platform.
Authors: Iacovides D. , Johnson A. , Boge A. , Nguyen U. , Shah S. , Gentalen E. , Gray J. 
Published: December 2010

Abstract
Our research efforts focus on the identification and detection of fundamental molecular differences between normal and tumor cells in breast, as well as differences among distinct breast cancer subtypes, especially in terms of signal transduction pathways that control cell cycle, apoptosis and cell growth. Cancer subtype specific molecular variations dramatically affect patient responses to already existing treatments. For example, the phosphorylation status of many proteins that are involved in signal transduction pathways perturbed in cancer cells is extremely important in determining whether these cells are susceptible to killing by available cancer therapeutics. Therefore, differentially phosphorylated protein isoforms can be a particularly useful prognostic biomarker of drug response in the clinic. However, accurate detection and quantitative analysis of cancer-related phosphoproteins in tumors is limited by current technologies.Using a novel, fully automated nanocapillary electrophoresis technology (FireFlyTM) designed to separate protein molecules based on their isoelectric point (pI), we are currently developing highly sensitive assays for reliable assessment of the phosphorylation status of cancer-related phosphoproteins in tumors, before and during drug treatment. We have already developed and optimized assays measuring AKT1, AKT2, AKT3, ERK1 and ERK2, and their respective phosphoisoforms. Using these assays, we were able to measure levels of activated ERK1/2 and AKT1/2/3 in a breast cancer cell line panel developed in our lab, using protein extracted from as few as 125 cells. Based on RNA expression data, cell lines in this panel have previously been categorized in two distinct subtypes (Basal and Luminal) and their molecular phenotypes closely resemble the respective profiles of tumors obtained from breast cancer patients (CITATION). This cell line panel is extensively used to measure cellular responses to breast cancer therapeutics, including drugs that target MEK, ERK, PI3K and AKT. Using FireFly assays, we are currently measuring changes in the phosphorylation states of these targets during drug treatment, in order to completely characterize pharmacodynamic changes in these cells during treatment, and develop molecular profiles that predict response in breast cancer tumors. Since this technology enables accurate detection and quantification of protein isoforms and post-translational modifications from only very small amounts of tumor samples or serum, it promises to propel cancer biomarker discovery and enable the development of clinically useful prognostic and diagnostic assays that predict responses to drugs targeting cancer-specific molecular networks.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3172.
Breast Cancer Risk Estimation Using the OncoVue® Model Compared to Combined GWAS Single Nucleotide Polymorphisms.
Authors: Jupe E. , Pugh T. , Knowlton N. , Defreese D. 
Published: December 2010

Abstract
Background: We have developed a new breast cancer risk assessment model (OncoVue) that integrates information from 22 single nucleotide polymorphisms (SNPs) and 5 personal risk factors. It has been shown to effectively stratify risk in three independent validation populations. Genome wide association studies (GWAS) have identified seven candidate SNPs independently associated with breast cancer risk. Using estimates of relative risks and allele frequencies derived from these studies, a theoretical examination of these SNPs has concluded that they have the potential to modestly improve clinical risk estimation. We have examined both the OncoVue model and these GWAS SNPs in the same case-control population to determine their utility in risk estimation.Materials and Methods: A randomly selected subset of participants (376 cases and 982 controls) that had enrolled in a larger case-control study conducted in six distinct geographic regions of the United States were examined. DNAs were genotyped for the 22 SNP variants in OncoVue and combined with personal factors to calculate the risk scores for the individual participants. DNAs were also genotyped for the following GWAS SNPs: rs2981582 (FGFR2), rs3817198 (LSP1), rs889312 (MAP3K), rs4415084 (MRPS30), rs13281615 (POU5F1P1), rs13387042 (TNP1), and rs3803662 (TOX3, formerly TNRCR9). Association of individual GWAS SNP genotypes with breast cancer risk was evaluated by calculating odds ratios (ORs). Assuming independent contribution of each SNP to risk, a combined GWAS risk score was calculated using a multiplicative model. Positive likelihood ratios (PLRs) were calculated using a risk threshold of 1.5-fold the control population mean risk to evaluate the proportion of individuals placed at elevated risk by OncoVue compared to the combined GWAS risk scores.Results: OncoVue exhibited significant ability to stratify risk at the 1.5-fold mean with a PLR of 2.2 and at a risk level of 2.5-fold mean the PLR increased to 5.0. In analyses of individual GWAS SNPs, statistically significant associations with breast cancer were identified for homozygous carriers of the rare allele for the FGFR2, MAP3K and TOX3 genes. However, the PLR for the combined GWAS risk scores at 1.5-fold mean was 1.0 indicating no ability to discriminate risk in this study population.Conclusions: In this case-control population OncoVue effectively stratified risk by accurately assigning elevated risk to breast cancer cases. In the same population, a combined risk score produced from seven GWAS SNPs did not effectively stratify risk. These results indicate that the OncoVue model has clinical utility for identifying elevated risk women who might benefit from additional screening and prevention.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3177.
Selective Tri-Nucleotide Spacers Modulate the Regulatory Potential of Estrogen Response Elements.
Authors: Kallen C. , Yang D. , Sidell N. 
Published: December 2010

Abstract
Estrogens bound to Estrogen Receptors (ERs) play critical roles in breast cancers through their binding to certain DNA motifs (i.e. estrogen response elements or EREs) in the promoters of target genes to regulate their transcriptional activity. The consensus ERE has the 15 base sequence AGGTCAnnnTGACCT where nnn are known as the tri-nucleotide spacer. The base specificity or sequence of this spacer is thought to be unimportant in terms of its effect on ERα-ERE binding affinity or transactivation efficiency. In the present experiments, whole genome sequence analysis of ERα-DNA binding sites was performed in MCF-7 breast cancer cells using CHIP-on-chip assays to determine frequency variations in EREs that bind ERα. Here, we present evidence that ERα binds to widely variant ERE sequences, both in terms of half-site specificity and tri-nucleotide spacer identity. Overall, our analysis indicated that whole genome ERα-ERE binding highly favored specific C(A/T)G enriched tri-nucleotide spacers, suggesting some evolutionary advantage to this three base configuration. To address this question in MCF-7 cells, we designed consensus EREs containing different nnn spacers (CTG, GCC, TTT) to test as binding probes in Electrophoretic Mobility Shift Assays and as enhancer elements in luciferase reporter vectors. Our results indicated differences in the ERα-ERE binding affinity depending on the nnn spacer sequence with the order of affinity being CTG &gt; GCC &gt; TTT. To determine the potential functional significance of the tri-nucleotide spacers, luciferase reporter assays in MCF-7 cells were performed. Results showed the same dependency on the sequence of the nnn spacer to induce luciferase activity in response to estrogen treatment (CTG&gt;GCC&gt;TTT). These experiments indicate that the identity of the three base spacer elements in the ERE are important for influencing ERα-ERE interactions and functional activity. These data support the results of the whole genome CHIP-on-chip analysis and suggest that increased frequency of ERα binding to ERE motifs with C(A/T)G spacers is due to preferential binding characteristics resulting in efficient transactivation of estrogen target genes.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3179.
Systemic MiRNA Levels as Novel Breast Cancer Biomarkers.
Authors: Heneghan H. , Miller N. , Newell J. , Kerin M. 
Published: December 2010

Abstract
Background: The development of clinically validated biomarkers for breast cancer has remained an insurmountable task despite other advances in the field of molecular biology. Mi(cro)RNAs have many characteristics of an ideal biomarker most notably their inherent stability, resilience, and ease of detection. Recent blood based miRNA profiling studies, reporting their presence in serum and plasma, have generated the concept that circulating miRNAs hold much potential as novel non-invasive biomarkers for cancer and other disease processes. The objective of this study was to investigate the potential of circulating microRNAs as novel breast cancer biomarkers.Materials and Methods: Using a real-time quantitative PCR approach, expression levels of a panel of 7 oncogenic miRNAs were quantified in tissue and blood specimens of 148 patients with breast cancer and 24 age-matched disease free control individuals. Advanced QBase Plus software and SPSS were used for biostatistical analysis of the data, and correlation with clinicopathological variables.Results: Cancer specific miRNAs were detected and significantly altered in the circulation of breast cancer patients preoperatively, most notably miR-195 (12 fold increase) and let-7a (5-fold increase), (p &lt; 0.001 and p&lt;0.001 respectively). Increased systemic miR-195 levels in breast cancer patients were also reflected in breast tumors. Systemic let-7a levels varied inversely with disease stage, being highest in carcinoma in-situ patients and getting progressively lower through to stage IV invasive disease. Furthermore we identified that circulating levels of miR-195 and let-7a decreased in cancer patients post-operatively following curative tumor resection (p&lt;0.001 and p&lt;0.001 respectively). Finally we found that specific circulating miRNAs correlated with certain clinicopathological variables, namely nodal status and estrogen receptor statusDiscussion/Conclusion: Our results demonstrates the novel finding that miRNAs are detectable in the circulation of breast cancer patients, that expression profiles differ between patients and controls, and that the circulating miRNA expression profile correlates with various biopathologic parameters of breast cancer. Also, systemic miRNA levels revert to normal levels following tumour resection. In this, lies the expectation that systemic miRNAs will be clinically useful as a novel minimally invasive tool to aid in the early diagnosis and perioperative management of breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 32.
Adjuvant Tamoxifen Treatment Outcome According to Cytochrome P450 2D6 (CYP2D6) Phenotype in Early Stage Breast Cancer: Findings from the International Tamoxifen Pharmacogenomics Consortium.
Authors: Goetz M. , Berry D. , Klein T. ,   International Tamoxifen Pharmacogenomics Consortium
Published: December 2010

Abstract
Background: An estimated 1.3 million women worldwide will be diagnosed this year with early stage breast cancer. The majority of women have estrogen receptor (ER) positive breast cancer and are candidates for endocrine therapy. Tamoxifen remains the most commonly employed agent worldwide and substantially reduces recurrence and mortality. Tamoxifen is a pro-drug. CYP2D6 converts tamoxifen to endoxifen, which is primarily responsible for inhibition of estrogen-stimulated breast cancer growth in vitro. There have been conflicting reports regarding the relationship between CYP2D6 genotype/phenotype and tamoxifen clinical outcome. The ITPC was established to collect the worldwide experience relating to genetic variation in CYP2D6 and the outcomes of women with ER positive breast cancer treated with adjuvant tamoxifen. Establishment of the predictive value of CYP2D6 would enable the a priori identification of patients that could be spared ineffective therapy.Methods: Individual patient data including tumor characteristics, genotype, medication data, and recurrence information were requested from all published and non-published reports of clinical outcomes related to CYP2D6 and deposited at PharmGKB. CYP2D6 genotype was available for the following null (*3, 4, 5 and 6) and IM (*10, 17 and 41) alleles. CYP2D6 inhibiting medication data was requested for weak and potent CYP2D6 inhibitors. The primary analysis was to determine the association of CYP2D6 phenotype (combined genotype and medication) with breast cancer recurrence in tamoxifen treated early stage, ER positive invasive breast cancer.Results: At this time, the ITPC has received patient data on 3432 patients from the U.S., Sweden, UK, Germany, Belgium, and Japan. Median age at diagnosis was 62 years. CYP2D6 genotype was available in 3,392 (99%). The allele frequency for CYP2D6*4, the most common allele associated with the CYP2D6 poor metabolizer phenotype, was q=0.23. A total of 1152 recurrences representing first events (either local, regional, distant, or contralateral breast cancer) were recorded. At the time of abstract submission, patient and genotype data from an additional 1300 tamoxifen treated patients were pending submission.Conclusions: The ITPC represents the largest collection of individual patient data in regard to the potential importance of CYP2D6 phenotype in adjuvant tamoxifen therapy. The findings from this consortium are expected to substantially improve the global understanding of CYP2D6 and tamoxifen clinical outcome. Final results will be presented at the meeting
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 33.
Breast MRI Screening of Women with a Prior High-Risk Lesion: Preliminary Results.
Authors: Brennan S. , Liberman L. , Dershaw D. , Morris E. 
Published: December 2010

Abstract
Purpose: To determine the frequency of breast cancer detection in women at increased risk due to a prior high-risk lesion.Materials and methods: An IRB approved retrospective review was performed of the records of 2184 breast MRIs starting from 1999, to identify patients who commenced screening breast MRI who had a history of a prior high risk lesion. Eighty-three women were identified who had a prior biopsy demonstrating a high-risk lesion such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS). History, imaging, and pathologic findings were reviewed.Results: Histologies of prior high-risk lesions in these 83 women were ADH in 24, LCIS in 54 and ALH in 5. The median length of MRI follow-up was four (range, 1-9) years. Biopsies were recommended based on MRI findings in 39 (47%) of 83 women, yielding cancer in seven (8%) women (four of whom also had benign biopsies), and benign findings only in 32 (39%) women. Six of the seven women who developed a breast cancer also had a family history of breast cancer. Histologic findings in these seven cancers were ductal carcinoma in situ (DCIS) in 4 (57%) and invasive cancer in three (43%). Invasive cancer histologies (n=3) were ductal in one and lobular in two; maximal histologic size was 2.0 cm. This large invasive cancer had a mammographic, sonographic, and palpable correlate, and was node-positive; the other cancers were identified by MRI only. Among these seven cancers, two (29%) were detected in screening year 1, two (29%) in screening year 2, two (29%) in screening year 3 and one in screening year 4 (14%). Three (43%) of the seven cancers were in the contralateral breast. In these 83 women, the likelihood of detecting cancer by MRI was higher in those with, rather than without, a family history of breast cancer (6/54=11% vs. 1/29=3%) and in women with prior LCIS rather than prior ADH (6/54=11% vs. 1/24=4%).Conclusion: Breast MRI detected cancer in 7 (8%) of 83 women with a prior high-risk lesion, six (86%) of whom also had a family history of breast cancer. Among these cancers, all were detected during the first four years of screening and less than half were invasive (43%). Further work with more patients is needed to determine the utility of breast MRI screening in women with specific prior high-risk lesions, with and without additional risk factors.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4002.