bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transforming Acidic Coiled-Coil-Containing Protein 2 (TACC2) in Human Breast Cancer, Expression Pattern and Clinical/Prognostic Relevance.
Authors: Cheng S. , Cheng S. , Douglas-Jones A. , Mansel R. , Jiang W. 
Published: December 2010

Abstract
BACKGROUND: TACC2 is a member of the transforming acidic coiled-coil-containing protein family and is associated with the centrosome-spindle apparatus during cell cycling. In vivo, the TACC2 gene is expressed in various splice forms predominantly in postmitotic tissues, including heart, muscle, kidney, and brain. Recent work has shown that members of this family, including TACC2, may be involved in the progression of certain solid tumours. The aim of the current study was to identify the role of TACC2 in breast cancer and to establish if a prognostic relevance exists.MATERIALS AND METHODS: Fresh frozen primary human breast cancer tissues (n = 120) and non-neoplastic mammary tissues (n = 32) were used. The distribution and location of TACC2 was assessed using immunohistochemical staining (IHC) and imaging analysis tools. The transcript levels of TACC2 were determined using quantitative real time-PCR. The results were analyzed against the clinical, pathological and follow-up (10 years) data. Statistical analysis was by Mann-Whitney U test and Kaplan-Meier method. Shown are median transcript level.RESULTS: TACC2 protein staining was seen in both normal epithelial cells and cancer cells in mammary tissues. Increased staining of TACC2 was seen in most of the breast tumours examined when compared with normal breast tissues. Quantitative analysis of the TACC2 transcript also revealed a higher level expression in tumours compared with normal tissues (p=0.027, tumours vs normal). TACC2 expression was significantly increased in higher grade tumours compared to those in lower grade tumours (grade-3 vs grade-1, p=0.046). Using the Nottingham Prognostic Index (NPI), TACC2 transcript was significantly higher in tumours from patients with a moderate prognosis than from those with a good prognosis (p = 0.019). The expression in samples from patients with poor clinical outcome (with metastasis, recurrence and breast cancer related death) was significantly higher than that from patients who remained disease free (median (IQR) 33.8 (3.0-110.2) copies vs 6 (1.6-28.9) copies, p=0.038). This was reflected by the shorter disease-free survival for patients with high TACC2 (107 (91-122.8, 95% CI) months compared with 137 (125-150.6) months for patients with low TACC2 transcripts (p=0.019).CONCLUSION: This study shows that increased expression of TACC2 correlates with poor prognosis in patients with breast cancer. This suggests that TACC2 mediates an oncogenic effect on breast cancer cells. The findings also suggest that TACC2 may be a potential therapeutic target.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3159.
Consistent Principal Components from Triple Negative Breast Cancer Expression Profiles Yields Agent Specific Predictors of Chemotherapy Response.
Authors: Li Q. , Eklund A. , Juul N. , Desmedt C. , Haibe-Kain B. , Haibe-Kain B. , Sotiriou C. , Symmans W. , Pusztai L. , Richardson A. , Szallasi Z. , Szallasi Z. 
Published: December 2010

Abstract
Genome scale expression profiling is likely to yield improved methods for optimizing therapy for individual breast cancer patients. Microarray based predictors of response to chemotherapy have been described for ER-positive tumors, but supervised methods haven't yielded highly accurate predictors of response in triple-negative breast cancer (TNBC). The problem of deriving predictive or prognostic classifiers is not trivial, and care must be taken to avoid pitfalls such as data set-specific noise and overfitting.To overcome these problems, we developed a two-stage unsupervised method to derive consistent metagenes from multiple data sets. In the first stage, we used principal component analysis to identify aspects of gene expression profiles that are consistently observed in multiple starting data sets. We then identified a subset of genes that best captured the information derived from these components. In the second stage, we factorized this subset of genes and derived metagenes applicable to any external data set. With this method, overfitting is eliminated by virtue of the unsupervised approach, and data set-specific noise is reduced by selecting only components presented in multiple data sets.We first applied our method to four TNBC data sets not obtained in a neoadjuvant setting and derived four metagenes. We then applied these metagenes to another four independent data sets annotated with response to various neoadjuvant therapies in order to assess their predictive performances. Two of the metagenes were associated with response: one predicted pathological complete response (pCR) in the two TFAC cohorts but not in the other two cohorts (Fig. a); the other was associated with pCR to TFAC, residual disease (RD) to epirubicin single agent, but not with response to FEC (Fig. b). Notably, these metagenes derived in an unsupervised manner were more strongly predictive than were classifiers derived using conventional supervised methods.As conclusion, we report and validate an unsupervised strategy as a robust and powerful alternative to supervised methods for deriving predictors for response to chemotherapy from microarray data. If confirmed in additional independent cohorts, these metagenes may lead to clinical tests to optimize therapy for individual TNBC patients.Figure 1. ROC curves indicate the association between two metagenes and agent-specific pathological complete response to neoadjuvant therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3163.
The Luminal B Marker NHERF1 Predicts Endocrine Resistance.
Authors: Rody A. , Karn T. , Solbach C. , Ruckhaeberle E. , Hanker L. , Mueller V. , Schmidt M. , Gaetje R. , Holtrich U. , Kaufmann M. 
Published: December 2010

Abstract
Background:Tumors of the luminal B subtype of ER postive breast cancer are characterized by high proliferation as compared to the luminal A subtype. The luminal B have a worse prognosis. We aimed to identify genes specifically expressed in the luminal B subtype of breast cancers and analyze the prognostic impact of these genes and their relationship to endocrine therapy.Methods:121 genes overexpressed in LumB tumors were identified in a test set of 171 Breast cancer samples and reproducibly obtained in four independent validation datasets. The scaffold protein NHERF1 was analyzed in a large scale meta-analysis of microarray datasets encompassing n=3030 breast cancer samples.Results:NHERF1 is an ER regulated gene located on chromosome 17 coding for a scaffold protein involved in growth factor signal transduction. NHERF1 expression among ER positive tumors is associated with larger tumor size, higher histolocigal grading, and HER2 expression. A prognostic value of NHERF1 was observed among ER positive tumors (univariate HR 1.49, 95% CI 1.23-1.80, P&lt;0.001) but not among ER negative samples. NHERF1 remained significant in multivariate analysis (HR 1.37, 95% CI 1.05-1.79, P=0.020) and is not a surrogate marker for high proliferation. A benefit of endocrine treatment seems to be restricted to NHERF1 negative tumors.Conclusions:Markers like NHERF1 specific for the luminal B subtype of breast cancer correlate with poor prognosis and seem to be predictive for endocrine treatment response.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3164.
High Resolution Comparative Genomic Hybridization (CGH) Indicates That Genomic Profiles Are Very Heterogeneous for HER2 and TOP2A in FISH-Amplified Human Breast Cancer Specimens.
Authors: McArthur H. , Brogi E. , Patil S. , Wigler M. , Norton L. , Hicks J. , Hudis C. 
Published: December 2010

Abstract
Background: Clinical studies relating TOP2A and HER2 status by FISH and response to specific drug therapies, including anthracyclines, have yielded inconsistent results. The discordance across studies appears to reflect, in part, the well-documented limitations of FISH testing, including the use of large FISH probes to evaluate the relatively small genes of interest. However, it is also likely that the dichotomization of gene status into “amplified” or “non-amplified” categories inadequately describes complex changes across the gene areas of interest. Identification and delineation of specific amplification-deletion patterns in this region may be of significant clinical interest and could provide deeper insight into mechanisms of drug resistance. Consequently, we selected a subset of HER2 and TOP2A amplified specimens (by FISH) from an ongoing study of CGH, and examined individual amplification-deletion patterns by CGH.Methods: 471 consecutive, archived, formalin-fixed paraffin-embedded, &gt;1cm, HER2 2+ and 3+ by immunohistochemistry primary breast cancer specimens diagnosed between January 2000 and 2006 were selected. HER2 status was evaluated by FISH at MSKCC and CGH at Cold Spring Harbor Laboratory (CSHL) for all 471 specimens in a double-blinded experiment and clinical correlates evaluated. TOP2A status was also evaluated by FISH at MSKCC and CGH at CSHL in the subset of 64 HER2 2+ by IHC, HER2 FISH-positive specimens. Individual genome profiles by CGH were examined for 20 HER2 and TOP2A FISH co-amplified specimens.Results: 45 specimens had results available for analysis, 20 of which were amplified for both HER2 and TOP2A by FISH. By CGH: 6/20 (30%) were not amplified for HER2 or TOP2A; 4/20 (20%) had homogeneous amplification of HER2 and TOP2A; 8/20 (40%) had HER2 &gt; TOP2A amplification; and 2/20 (10%) had TOP2A &gt; HER2 amplification. Individual genome profiles around HER and TOP2A were examined by CGH. Marked heterogeneity was observed across specimens.Conclusions: CGH at the genome level suggests that current dichotomization strategies for classifying HER2 and TOP2A status appear to incompletely describe and represent the heterogeneity of genomic lability in these regions. The dichotomization of gene amplification results by FISH may contribute to the discordance demonstrated in reported some clinical studies. Studies exploring clinical correlates are underway.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3165.
Evolution of Genomic Diversity in the Breast Cancer Cell Line MCF-7.
Authors: den Hollander P. , Osadchey I. , Hampton O. , Hampton O. , Coarfa C. , Milosavljevic A. , Milosavljevic A. , Lee A. 
Published: December 2010

Abstract
Background: Tumors arise from an accumulation of genetic changes via a multi-step process. Genetic rearrangements can potentially lead to fusions with consequent deregulation of a gene, or the generation of new genes (through the fusion of two genes) that maybe functionally important in tumor development and progression. Our knowledge of rearrangements in solid tumors is limited and it is likely that solid tumors are defined by fusion genes that are not yet discovered. We recently reported 157 genomic breakpoints that were identified in a BAC library generated from MCF-7 cells (termed MCF-7/BAC), and could be confirmed by PCR across breakpoint joins as likely somatic mutations. To gain insight into the heterogeneity of genomic breakpoints in breast cancer cell lines, we studied these 157 validated breakpoints in a two common MCF-7 sublines.Methods: DNA was isolated from MCF-7/ATCC and MCF-7/B and genomic breakpoints were amplified by PCR and visualized by gel electrophoresis. Breakpoints were called present or absent based upon amplification of a product at the predicted size. By mapping the breakpoints to specific stages in the evolution of MCF-7 we reconstructed the sequence of chromosomal rearrangement events in the cancer genomesResults: MCF-7/B harbored only 91 of the breakpoints from the original 157 identified from MCF-7/BAC, and MCF-7/ATCC only shared 40. MCF-7 had 3 breakpoints that were found in MCF-7/BAC but not in MCF-7/B. Thus, of the original 157 breakpoints, 37 (23.6%) were shared all three sublines. MCF-7/ATCC contained the least breakpoints, which might indicate that MCF-7/ATCC is ancestral to MCF-7/B and MCF-7/BAC. Consistent with this, of the 157 genomic breakpoints in MCF-7/BAC, 50.3% contained genes, while this was enriched in the MCF-7/ATCC to 72.5%. Interestingly, two breakpoints involving genes in double strand break repair are retained in all three sublines, indicating that these breakpoints might originate from an ancestral cell line, and that deficient double strand break repair might be the underlying cause of genomic instability in these cell lines.Discussion: These preliminary results imply that MCF-7/ATCC maybe ancestral to other MCF-7 sublines. We are now expanding our data set with six other MCF-7 sublines to reconstruct the phylogeny of this breast cancer cell lines. With this information we may get a better understanding of the evolution and heterogeneity of genomic instability and rearrangements in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3171.
Childbirth Following Breast Cancer: An Evaluation of the 'Healthy Mothers' Excess Mortality Risk.
Authors: Hartman M. , Hartman M. , Lim G. , Czene K. , Bhalla V. , Chow K. , Yap K. , Chia K. , Chia K. , Verkooijen H. , Verkooijen H. , Verkooijen H. 
Published: December 2010

Abstract
Background: The favorable outcome of mothers giving birth after breast cancer compared to those who do not, has been attributed to a healthy mother effect. Mainly former breast cancer patients with excellent health status and outlook proceed to having children after their disease. This study evaluates the excess mortality risk among these 'healthy mothers' and factors modifying this risk.Methods: By linking the Singapore Birth Registry (319'437 individuals) and Swedish Multi-Generation Cohort (11 million women) with the respective national cancer registries we identified all 509 women who gave birth &gt;12 months after a breast cancer diagnosis. We calculated excess absolute mortality risks and Standardized Mortality Ratios (SMRs). We used Poisson regression analysis to calculate relative risks of death by country, period of follow up and interval between cancer diagnosis and subsequent birth.Results: The overall 15-year cumulative mortality was 18.2% (95% CI: 13.3 – 20.7%) which is substantially higher than that of the background population (SMR 13.3, 95%CI: 10.4-16.9). Excess mortality risks remained constant over follow up time and were comparable between Sweden and Singapore. Mortality risks decreased significantly with increasing interval between diagnosis and subsequent birth.Conclusion: Despite being 'healthy mothers', women who give birth after a diagnosis of breast cancer have a substantially higher risk of death than the background population. This information may be useful in a woman's decision whether to have a(another) child after breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3173.
Bone Health in Postmenopausal Women Treated with Adjuvant Aromatase Inhibitors for Early Breast Cancer: 12 Months Follow-Up.
Authors: Nogués X. , Servitja S. , Peña M. , Martinez M. , Nadal R. , Garrigos L. , Diez Perez A. , Albanell J. , Tusquets I. 
Published: December 2010

Abstract
Background:The use of aromatase inhibitors (AI) in the adjuvant setting for postmenopausal women with receptor-positive breast cancer is well established. The AI treatment has been associated with decline in bone mineral density (BMD), and increased bone turnover markers. We designed a prospective study to evaluate the effect of oral bisphosphonates (BP) on vertebral and non vertebral fractures (VF), bone turnover markers (bTM), BMD, and quality of life (QoL) in postmenopausal women receiving adjuvant AI for hormone receptor positive early breast cancer.Material and methods:Postmenopausal, receptor-positive breast cancer women treated with AI as initial therapy [Letrozol (LET)] or after 2 or 5 years of tamoxifen [switched to exemestane (EXE)] were included. Patients were stratified by lumbar spine, femoral neck and total hip BMD to receive open-label treatment with BP, alendronate or risedronate, (if osteoporosis [T-score&lt;-2,5] or osteopenia [T-score&lt;-2.0] and 1 major risk factor, defined as group of high risk of fracture) or calcium and vitamin D supplementation (if normal BMD or T-score&gt;-2.0 and no major risk factor). Levels of 25-OH vitamin D, N-telopeptide (NTx), bone alkaline phosphatase (bALP) and osteocalcin (OC) were measured at baseline, 3, 12 and 24 moths, and BMD and thoracic and lumbar spine X-rays were assesed at baseline, 1 and 2 years. QoL was evaluated by ECOS-16 questionnaire and a visual analogue scale used to evaluate arthralgia. Results:from 03/2006 to 03/2009, 261 patients have been included and 117 have completed &gt;12 month follow up. All the bTM increased after 12 months of AI treatment and a significant decrease on BMD was also observed (Table 1). This effect is reverted with oral BP treatment, maintaining the BMD level and reducing the bTM. With the AI introduction QoL of patients became worse, and the BP treatment did not improve neither arthralgia nor bone pain. Osteoporotic fractures were recorded at baseline in 12.3% of women (4.2% VF and 7.7% non VF).Conclusions:AI treatment increased bone turnover, decreased BMD and QoL. Of note, BP use decreased bone turnover, has neutral effect in BMD and does not improve QoL. This study suggests that the current recommendation of the use of BP should be revisited to consider including all postmenopausal women treated with adjuvant AI to avoid increased bone turnover and bone mass decrease.Table 1. BMD at baseline, 12 months and changes Without BP (n=76) With BP (n=41) BMD value (g/cm2)AIBasal12 month% change / pBasal12 month% change / pFemoral NeckLET0.7650.751- 1.96 / 0.020.6480.657+ 1.61 / NS EXE0.7560.749- 0.6 / NS0.6260.644+ 2.63 / 0.013Lumbar spineLET0.9900.969- 2.36 / 0.00010.8150.813- 0.17 / NS EXE0.9570.940- 1.57 / 0.0430.8110.814+ 0.86 / NS
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3175.
Beneficial Effect of Tamoxifen for Women with DCIS: Long-Term Results from the UK/ANZ DCIS Trial in Women with Locally Excised DCIS.
Authors: Cuzick J. , Sestak I. , Pinder S. , Ellis I. , Hackshaw A. , Bundred N. , Forbes J. , Bishop H. , Fentiman I. , George W. 
Published: December 2010

Abstract
Background: Initial results of the UK/ANZ DCIS trial found that adjuvant radiotherapy reduced the recurrence of ipsilateral invasive breast cancer (BC) and ductal carcinoma in situ (DCIS) by 55% and 64% respectively, but the effect of tamoxifen was smaller (Lancet 2003, 362: 95-102). Here, we report an updated analysis of this trial.Methods: 1701 women with completely locally excised DCIS were enrolled in a randomised 2x2 trial of radiotherapy, tamoxifen or both. Elective decision to withhold or provide one of the treatments was also permitted and long-term follow-up was performed by treating hospitals. Seven patients were excluded due to protocol violations leaving 1694 patients available for analysis.Results: After a median follow-up of 12.7 years, a total of 376 breast cancers were diagnosed; 162 invasive (122 ipsilateral; 39 contralateral) and 197 DCIS (173 ipsilateral; 17 contralateral). Radiotherapy continued to reduce the incidence of ipsilateral invasive disease (HR=0.32 (0.19-0.56), P&lt;0.0001) and ipsilateral DCIS (HR=0.38 (0.22-0.63), P&lt;0.0001), but had no significant effect on contralateral breast cancer (HR=0.84 (0.45-1.58)). Tamoxifen significantly reduced all recurrences by 29% (HR=0.71 (0.58-0.88), P=0.002) (Figure 1). This consisted of a 30% (HR=0.70 (0.51-0.86)) reduction in recurrent ipsilateral DCIS, a small 5% (HR=0.95 (0.66-1.38)) reduction in ipsilateral invasive disease, and a 56% (HR=0.44 (0.25-0.77)) reduction in contralateral tumours. Overall, women randomised to radiotherapy and not receiving tamoxifen had a 59% reduction in recurrence (HR=0.41 (0.30-0.57), P&lt;0.0001), whereas those randomised to tamoxifen and not receiving radiotherapy had an overall reduction of 29% (HR=0.71 (0.57-0.87), P=0.001).Conclusion: This updated analysis confirms the long-term benefit of radiotherapy in women with DCIS treated by complete local excision and also established a benefit for tamoxifen. Ongoing work will examine in detail which subsets of tumours (e.g. high grade, oestrogen receptor positive) will benefit most from these treatments.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 34.
Elevation of Serum NT-Pro BNP Correlates with Asymptomatic Cardiac Dysfunction Induced by Doxorubicin.
Authors: Kittiwarawut A. , Vorasatekarnkit Y. , Tanasanwimon S. , Manusnayakorn S. , Sriuranpong V. 
Published: December 2010

Abstract
Background: Cardiac dysfunction is one of the major limitations of anthracycline treatment in cancer patients. Current reliable investigation to detect early cardiac damage from anthracycline is not available. There are several serum cardiac markers useful in other types of cardiomyopathy including NT-pro BNP, Troponin-T, and CK-MB. We chose to investigate potential application of these serum biomarkers in the cancer patients receiving anthracycline.Patients and methods: We prospectively collected data from a cohort of 52 female breast cancer patients who receiving doxorubicin and cyclophosphamide (AC) regimen every 3 weeks for 4 cycles for preoperative or postoperative adjuvant treatment. Cardiac function evaluations by echocardiography were done at baseline and post 4th cycle chemotherapy. Patients' blood samplings were serially measured for cardiac biomarkers at baseline, after 1st cycle, and after 4th cycle chemotherapy.Results: All patients were in good performance status with ECOG scale 0-1.The mean cumulative dose of doxorubicin in this study was 236.69 mg/m2. There was no symptomatic heart failure detected during study period. However, there were significant asymptomatic reductions of left ventricular ejection fraction (LVEF) from 70.73 ± 5.97% at baseline to 66.96 ± 5.48% (p&lt;0.001). The severities of LVEF declination were 17.4% in grade1 and 3.8% in grade 2 by clinical toxicity criteria of NCI version 2. We found significant elevation of serum NT-proBNP (p = 0.044) following the first dose of chemotherapy when compared the measurements in patients who had reduction of LVEF to those with normal LVEF. Measurement of serum Troponin-T and CK-MB showed no significant correlation with changes in LVEF. Generalized-estimating-equations correlation analysis demonstrated that the reduction of fractional shortening (FS) was significantly associated with the elevation NT-pro BNP (r = -0.016, p = 0.014). At cutoff level 45 pg/mL, serum NT-proBNP had 100% sensitivity and 66.67% specificity for the detection of cardiotoxicity in patients under 50 year-old.Conclusion: Asymptomatic reductions in cardiac function are common in patients treated with doxorubicin. NT-pro BNP may serve as a potential convenient serum biomarker for early detection of cardiotoxicity induced by anthracycline.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4003.