bluuebunny/crossref_metadata_2025_split huggingface dataset:
A QPCR-Based Circulating Tumor Cell Detection Platform Predicts Survival in 776 Early Stage Breast Cancer Patients.
Authors: Molloy T. , Bosma A. , Baumbusch L. , Borgen E. , van't Veer L. , Naume B. 
Published: December 2010

Abstract
The detection of circulating tumor cells (CTCs) in the blood of cancer patients is a promising tool for risk stratification, treatment tailoring, and monitoring of the disease state. We previously developed a QPCR-based platform for the detection of CTCs in peripheral blood, which proved to be prognostic in a cohort of metastatic breast cancer patients.In the current study, we aimed to build on this work by determining the prognostic value of our CTC assay in an independent, prospectively collected, retrospective patient series of 776 non-metastatic, stage I-III breast cancer patients (median follow-up 7.3 years). Assay positivity was observed in 83 patients (10.7%), while maintaining 96% specificity in a group of 25 healthy female controls (however a second blood sample from the healthy control that gave a positive result was found to be negative). CTC positivity as determined by our assay corresponded to a significantly poorer relapse-free survival (RFS) (HR = 1.9, 95% CI = 1.3-2.9, p = 0.02) and overall survival (HR = 1.8, 95% CI = 1.1-2.8, p = 0.02) in this group. This platform demonstrated similar prognostic power to the pan-anticytokeratin (AE1/AE3) immunohistochemistry-based detection of disseminated tumor cells (DTCs) in the bone marrow of these patients (RFS HR = 1.9, 95% CI = 1.3-2.7, p = 0.02). Importantly, multivariate analyses including tumor size, histological grade, lymph node status, and hormone receptor status, both CTC and DTC status remained significant, independent predictors of RFS (CTC status HR = 1.6, 95% CI = 1.0-2.6, p = 0.037; DTC status HR = 1.6; 95% CI = 1.1-2.5, p = 0.023). However, CTC status was prognostic in both lymph node negative patients (HR = 2.0, p = 0.04) and lymph node positive patients (HR = 1.7, p = 0.043), whereas DTC status was only prognostic in lymph node positive patients (HR = 2.0, p = 0.002).This CTC detection platform represents an objective assay with both high specificity and prognostic power, and could be an effective clinical tool for outcome prediction in breast cancer patients.This work was supported by the Sixth Framework Program of the European Commission as part of the international DISMAL collaboration for research into disseminated epithelial malignancies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3002.
Multiple Biomarker Expression in Circulating Tumor Cells (CTCs) from Metastatic Breast Cancer (MBC) Patients (Pts).
Authors: Somlo G. , Hsieh H. , Curry D. , Frankel P. , Krivacic R. , Lau S. , Lazarus N. , Baker N. , Swain-Cabriales S. , Bruce R. 
Published: December 2010

Abstract
Background: Numeration of CTCs from MBC pts is predictive of outcome. Quantitative changes in CTC-s are currently tested for their potential to monitor therapy (Rx). Biomarker characterization of CTCs may be a useful adjunctive guide for Rx selection. Method: At the COHCC between 5/1/2008 and 4/31/09, consecutively treated pts with newly diagnosed/or progressing MBC were accrued. Blood samples (10-40 ml) were procured prior to or during systemic Rx, and were sent to PARC for analysis. A novel high-speed scanning instrument located CTCs from cytokeratin (CK) labeling enabling high resolution images to be selectively acquired using digital microscopy. From these images, CTCs were identified by CK, DAPI (nuclear marker) and CD45, and protein expression levels were determined for HER2, ER, ERCC1 and EGFR. Cell lines with expression of each marker were used for normalization of the cell intensities, and a scoring system was used to account for relative number and expression levels of markers on the CTCs. Results: Of 21pts tested 81% were found to have detectable CTCs. CTCs were further analyzed from 13 such pts, some of whom had multiple specimens. Expression of EGFR and ERCC1 were detected in 77% and 92% of specimens tested. Expression of HER2 was detected in 47% and ER in 91% in samples tested. Discordance rates for the expression of the above 4 markers on the primary tumors vs. CTC were measured either before, during systemic treatment, or at progression on therapy. We observed significant discordance rates for all markers tested:ER 36%; ERCC1:20%; EGFR:60%; and HER2: 50%, respectively. Conclusions: Multiplex tumor marker testing of CTCs from pts with MBC is feasible. Following additional validation of expression patterns and the high discordance rates observed between CTCs and primary or metastatic tumor sites, prospective trials incorporating CTC expression into personalized treatment strategies may be justified.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3007.
Predictive Factors for Positive Non-Sentinel Nodes Following a Positive Sentinel Node Biopsy: NSABP B-32.
Authors: Julian T. , Anderson S. , Golesorkhi N. , Fourchotte V. , Zheng P. , Mamounas E. , Brown A. , Boudros E. , Bear H. , Costantino J. , Wolmark N. 
Published: December 2010

Abstract
Background: Following a positive sentinel node biopsy (SNB), current guidelines recommend an axillary dissection (AD) regardless of SN metastatic tumor size. In the majority of clinically node negative patients the risk for positive non-sentinel axillary nodes (NSN) is low. Predictive factors for positive NSNs following a positive SNB are analyzed in NSABP B-32 with inclusion of SN metastatic tumor size.Materials and Methods: After stratification, women with operable invasive breast cancer and clinically negative nodes were randomized to Sentinel Node Resection (SNR) with immediate conventional Axillary Dissection (AD) [Group 1] or to SNR without AD [Group 2]. Group 2 patients with positive SNs underwent AD. A multivariate analysis of SN positive patients from both groups for whom both a SNR and an AD had been performed was used to assess the need for AD following SNB. Nodes were classified as either SNs or NSNs, defined as all axillary dissection nodes plus any intramammary or other nodes that were not resected as SNs.Results: Between May 1999 and February 2004, 5,611 patients were entered into NSABP Protocol B-32. There were a total of 1,361 SN positive patients with AD from both groups. Data from 1,166 patients were available for multivariate analysis which included SN metastatic tumor size in 735 patients: 424 patients with macrometastaes (&gt;2 mm) and 311 with micrometastases (&lt;2 mm). In 626 patients SN metastatic size was unknown.In patients with positive SNB, results from the final multivariate model based on 653 patients with known covariate values indicated clinical tumor size was a significant predictor for positive NSN (p=0.044, OR: 1.17). Lymphovascular invasion was a significant predictor for positive NSN (p=0.0004, OR: 1.85). SN metastatic tumor size (Macro vs Micro) was a highly significant predictor for positive NSN (p&lt;0.0001, OR: 3.42). Age at study entry, treatment type, proposed type of surgery, HER-2 status, and location of tumor were not significant multivariate predictors for positive NSN. Predictive modeling for positive NSN probability will be presented.Conclusion: Completion AD following a positive SNB, although helpful in prognosis and treatment planning, may not be required in patients with small tumors, absence of lymphovascular invasion, and micrometastases.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 301.
Implementation of a Composite Score System for Evaluation of Circulating Tumor Cells in Blood of Breast Cancer Patients.
Authors: de Albuquerque A. , Kaul S. , Breier G. , Krabisch P. , Stryzhevska N. , Bastert G. , Fersis N. 
Published: December 2010

Abstract
Background: We present a highly specific immunomagnetic separation technique in combination with an improved multimarker gene panel for molecular identification and characterization of circulating breast tumor cells in blood. Here we describe the creation of a new composite score in order to manage results and avoid false positives. Methods: Blood from breast cancer patients with primary or metastatic disease was drawn into two 10mL EDTA-tubes. The high affinity antibodies BM7 (MUC1) and VU1D9 (EpCAM) were used for immunomagnetic tumor cell enrichment. Separated cells were lysed and used for mRNA isolation and c-DNA synthesis (Qiagen®). A real-time quantitative RT-PCR approach using MESA FAST SYBR Assay (Eurogentec®) and primers selected from the UniversalProbeLibrary system (Roche AG®) for the epithelial markers cytokeratin 19 (CK19), mammaglobin 1 (MG1), epithelial cell adhesion molecule (EpCAM), baculoviral IAP repeat-containing 5 (Sur), immunosuppressive CD276 (CD276), carcinoembryonic antigen-related cell adhesion molecule 5 (CEA), HER-2, aldehyde dehydrogenase 1 family, member A1 (ALDH1), hypoxia inducible factor (HIF-1alpha) and CD44 molecule (CD44) was used for tumor cell identification and characterization. The ß-actin transcript was used for internal control and matched calibrator probes containing 2 or 10 tumor cells were used for quantitative expression analysis of tumor associated genes present in blood.Results: Positivity rate was based on a score that consists of 2 different characteristics: Marker detection (ranking according to the number of positive markers, varies from 0 – negative - to 1 – positive - for each marker) in combination with the marker expression level (ranking according to the C(t) values and varies from 0 – less then 2 tumor cells – to 1 – more then 2 tumor cells). This composite score is based on the expression of CK19, MG1, EpCAM, Sur and CD276 and has a ranking from 0 to 10. Negative cases are classified with score 0 and 1, cases ranked with score 2 need retesting and finally scores above 2 indicate clearly positive patients. The additional surrogate markers CEA, HER-2, ALDH, HIF and CD44 are analysed in positive patients in order to obtain further information. In our group of metastatic breast cancer patients, 53% were classified as positive, 42% of the patients were negative and in 5% a retesting is needed. Conclusion: The results of the composite score clearly show an increase of sensitivity and specificity for this assay. The implementation of this test in the routine monitoring of patients should help us to evaluate treatment response and create individualized treatment schedules.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3015.
Examination of TIMP-1 Levels and Relapse-Free Survival for Patients in NCIC CTG MA.14 Who Received Adjuvant Tamoxifen +/- Octreotide LAR.
Authors: Ali S. , Chapman J. , Lipton A. , Leitzel K. , Pritchard K. , Pu X. , Wilson C. , Carney W. , Shepherd L. , Pollak M. 
Published: December 2010

Abstract
Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have diverse multifunctional roles in tumorigenesis. AL/KL/SA postulated from first line metastatic endocrine therapy that elevated pre-treatment serum TIMP-1 required additional therapy. NCIC CTG MA.14 adjuvant endocrine trial permitted examination of whether TIMP-1 serum levels post-chemotherapy was associated with RFS. Methods: NCIC CTG MA.14 is a trial where 667 postmenopausal patients were randomized to receive adjuvant tamoxifen +/- octreotide LAR with a stratification factor of no, concurrent or sequential chemotherapy. For the purposes of this work, this was simplified to whether a patient had or had not received adjuvant chemotherapy prior to the serum draw. Serum TIMP-1 was assessed on &gt;90% of the trial patients. We examined the effect of baseline TIMP-1 levels on relapse-free survival (RFS) of 1) all types, 2) bone only, 3) all types of bone, and 4) non-bone, by timing of chemotherapy before the serum draw utilizing continuous TIMP (ng/ml) and categorical TIMP (&lt;454, &gt;454 ng/ml, based on 95% non-parametric cut-point for healthy post-menopausal females). Data were available on patient and tumour characteristics of age (years), pathologic tumour size (cm), pathologic lymph node status (# nodes), IGF-1, C-peptide, IGFBP-3. Step-wise forward Cox multivariate models were used where a factor was added if p&lt;=0.05, and interaction terms were added for TIMP-1 level and timing of chemotherapy. Results: High (categorical) TIMP-1 was significantly associated with longer RFS (p=0.04) in the non-bone RFS multivariate model in the subgroup of patients who had prior chemotherapy, but not in those who did not. The interaction between TIMP-1 and administration of chemotherapy before serum draw was significant (p=0.02). High (continuous) TIMP-1 was significantly associated with longer bone only RFS (p=0.04) in subgroup who had no chemotherapy before the serum draw, but not in those who may or may not have had it after. There was no significant interaction effect. Categorical and continuous TIMP-1 were not associated with any other type of RFS. Conclusions: We found a predictive benefit with the assessment of serum TIMP-1 in hormone receptor positive patients, that high TIMP-1 levels after adjuvant chemotherapy were predictive of a reduction in non-bone RFS.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3022.
Human Circulating Endorepellin LG3 Fragment and Breast Density: A Potential Combination with Screening Mammography in Women with Dense Breast.
Authors: Lee J. , Lee J. , Yang E. , Han W. , Han W. , Lee C. , Noh D. , Noh D. 
Published: December 2010

Abstract
(Background) In vitro studies have reported that the endorepellin LG3 fragment (ERLG3F), which is matrix-derived endogenous anti-angiogenic factor, can be a circulating biomarker candidate for breast cancer. This study examined the plasma ERLG3F levels in breast cancer patients and normal healthy controls, and evaluated its potential roles as a screening biomarker for breast cancer (Methods) ERLG3F levels were determined by competitive ELISA in the plasmas from prospectively constructed independent cohorts (train and test set) from July 2006 to September 2007 for the Biomarker Discovery Project (funded by 21C Frontier Functional Proteomics Program of South Korea). The Breast Cancer Cohort (BC) (n=366) has plasmas drawn preoperatively; the Healthy Control Cohort (HC) (n=305), drawn when volunteers visited our Healthcare Center for medical check-up. Circulating ERLG3F, mammography, and the combining marker (CM) of both were evaluated for their performance of identifying breast cancer in the train set and verified again in the test set. (Results) Decreased ERLG3F levels were observed in the individual plasmas from BC compared to the HC. The decrease was significantly prominent in patients without axillary lymph node metastasis (negative vs. positive), young age (&lt; 50 vs. ≥50 yr), and dense breast (mammographic density Gr 3 or 4 vs. 1 or 2). We used a cutoff level, which correspond to 2SD below the mean ERLG3F in total healthy controls. ERLG3F significantly improved the performance of mammography in distinguishing breast cancer cases from healthy controls, although it is less sensitive than mammography as a single marker. (Conclusion) We conclude that ERLG3F can be a useful diagnostic biomarker for breast cancer and its role can be even better when used for young women with dense breast for whom mammography is less helpful.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3026.
Inhibin A Is Downregulated during Chemotherapy in Patients with Early Breast Cancer.
Authors: Rack B. , Burkhardt N. , Jueckstock J. , Kuhn C. , Noeding S. , Hoenig A. , Friedrich M. , Schindlbeck C. , Sommer H. , Friese K. , Janni W. , Mylonas [. 
Published: December 2010

Abstract
Introduction: Inhibins are dimeric glycoproteins, composed of an alpha-subunit (INH-a) and one of two possible beta-subunits (ßA or ßB), with substantial roles in human reproduction and in endocrine-responsive tumours. In breast cancer tissue, the growth factor Inhibin A is involved in cell differentiation and proliferation, thus suggesting a possible role as tumor marker. Aims of this study were to determine the serological measurement of Inhibin A (a- bA) in breast cancer patients during chemotherapy.Material and Methods: A series of 28 high risk N0 and N+ breast cancer patients who underwent standardized chemotherapy (3 x FEC and 3 x Docetaxel) followed by two years of zoledronate in the German SUCCESS trial were prospectively evaluated before chemotherapeutic treatment as well as after chemotherapy and two years after chemotherapy for the serological expression of Inhibin A. For serological analysis the ultrasensitive Inhibin A ELISA (DSL – U.S.A.) was used according to manufactures instruction. For statistical analysis the Wilcoxon rang sum test was used for paired samples. Statistical significance was assumed at p&lt; 0.05.Results: The concentration of Inhibin A showed a significant decrease between data obtained before chemotherapy and after chemotherapy (p&lt;0.005) and two-year follow up (p&lt;0.001). Interestingly, there were seen no differences between the time point four weeks after chemoherapy and at two years (p=0.744).Discussion: Therefore, chemotherapy decreases significantly the Inhibin A concentration during chemotherapy. This might reflect a suppression of ovarian function and might be a marker for chemotherapy-induced amenorrhoea. Moreover, it has been suggested that Inhibin A might be a tumour marker for breast cancer, and therefore a sudden increase of its concentration might be indicative of breast cancer recurrence.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3028.
Paradoxical Relationship of Chromosomal Instability with Breast Cancer Outcome: Identification of a Good Prognostic ER Negative/HER2 Negative Breast Cancer Cohort with Extreme Chromosomal Instability.
Authors: Swanton C. , Swanton C. , Juul N. , Li Q. , Eklund A. , Richardson A. , Szallasi Z. , Szallasi Z. 
Published: December 2010

Abstract
Chromosomal Instability (CIN) is widely held to be associated with poor prognosis in solid tumours, including breast cancer, that may be related to enhanced clonal evolutionary capacity and the rapid acquisition of multi-drug resistance. Paradoxically, CIN is also associated with tumour suppression in animal models that may result from excessive genomic instability leading to autonomous cell lethality, a phenomenon analogous to "mutational meltdown" in model systems.We addressed whether such a phenomenon could be identified in breast cancer through a meta-analysis of CIN frequency in 1850 breast cancer patients. We assessed the distribution of CIN across breast cancer subtypes and its relationship with clinical outcome and prognosis using a surrogate of CIN, the CIN70 expression signature that correlates robustly with CIN in breast cancers quantified by DNA image cytometry. Increasing degrees of CIN predicted for poor outcome in multivariate analysis of 1850 patients and occurred more frequently in younger patients. Furthermore, CIN was more common in higher risk disease subtypes, including basal-like breast cancer, consistent with this pattern of genomic instability being a major determinant of breast cancer outcome.However, in agreement with previous evidence documenting a role for CIN in mediating cell lethality and tumour suppression in animal models, we demonstrate that a subset of tumours with extremes of CIN, that occur predominantly within the ER negative and HER2 negative subgroup, are associated with unexpected good prognosis in untreated breast cancer patients.We define a threshold of CIN beyond which clinical outcome improves and the relationship between CIN and proliferation is uncoupled. This evidence defines a paradoxical role for CIN in limiting tumour cell viability in vivo and suggests therapeutic strategies to tilt the balance toward CIN-mediated lethality in high-risk breast cancer subtypes in order to improve patient outcome.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3030.
High Expression of Cyclin E Increases the Risk for Breast Cancer Death by 2-3 Fold in Node Negative Breast Cancer Patients.
Authors: Lundgren C. , Holmqvist M. , Holmberg L. , Holmberg L. , Blomqvist C. , Fjällskog M. 
Published: December 2010

Abstract
Background: A large proportion of women with lymph node negative breast cancer treated with chemotherapy do not benefit from such treatment. Several studies have suggested that proliferation markers can identify patients at increased risk for recurrence. However, current international guidelines do not recommend proliferation markers for clinical use due to lack of well-powered studies and standardization of methodology. We wanted to investigate the prognostic value of cyclin E1 in a large population-based study on node negative breast cancer patients.Study Design: In a population-based, case-control study, 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio (OR) of 2.5 with a power of 90% at a significance level of 0.05. Tumor tissue was immunostained for cyclin E1 with a commercial antibody. Statistical analyses were performed for 200 (cyclin E 200) and 500 cells (cyclin E 500) counted, respectively.Results: Cyclin E1 was highly correlated to histologic grade, Ki-67 and cyclins A/B (rs= 0.5-0.6; p&lt;0.001) and inversely correlated to hormone receptors (rs=-0.2--0.3; p&lt;0.001). There was a statistically significant association between cyclin E1 and breast cancer death both in uni- and multivariate (adjusted for tumor size and age) analyses with OR 2.6 -2.7 for cyclin E 200 and OR 2.1-1.9 for cyclin E 500.Conclusions: We found that cyclin E1 is a prognostic factor for breast cancer death in a population-based node negative patient cohort. Patients with tumors expressing high levels of cyclin E have a 2-3 fold increased risk for breast cancer death.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3033.
Expression and Prognostic Value of L1-CAM in Breast Cancer.
Authors: Milde-Langosch K. , Schröder C. , Mueller V. , Schumacher U. , Wirtz R. , Altevogt P. , Krenkel S. , Jaenicke F. 
Published: December 2010

Abstract
Background: The L1 cell adhesion molecule (L1-CAM) has been shown to be involved in cell motility, invasion, chemoresistance and tumor growth in various experimental models, and is associated with impaired prognosis in melanoma, colon and ovarian cancer. However, limited information about its expression in breast cancer is available.Methods: To analyse its role and possible prognostic value in primary breast cancers, L1-CAM mRNA and protein expression using microarray analysis (n=167) and Western Blotting (n=106) was performed. Its cellular distribution was demonstrated by immunohistochemistry. The results were correlated with classical histological data, biologically relevant disease markers and clinical data including disease outcome.Results: L1-CAM mRNA overexpression and protein expression was observed in 14-15% of the carcinomas and its expression was confirmed by immunohistochemical staining. Generally tumour cells at the tumour stroma interface were L1-positive. High L1-CAM expression was associated with nodal involvement, high grading, human epidermal growth receptor 2 (Her-2), plasminogen activator inhibitor 1 (PAI-1) and vascular endothelial growth factor (VEGF) expression and a negative estrogen receptor (ER) status, but not with neuroendocrine markers. High L1-CAM mRNA expression in primary breast cancers was associated with a significantly shorter disease-free (p=0.011) and overall survival (p=0.005).Conclusions Our results indicate that L1-CAM is highly expressed in a relatively agressive subgroup of breast cancers. Given the emerging functional role of L1-CAM in promoting tumor growth and metastasis our results suggest that L1 may have this function in breast cancer as well. Thus, L1-CAM might be a suitable target for specific immunotherapies in selected high-risk breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3044.