bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Topoisomerase IIa and HER2 Status in 126 Patients from the US Oncology 9735 Trial of Adjuvant Chemotherapy with Docetaxel/Cyclophosphamide (TC) vs Doxorubicin/Cyclophosphamide (AC) in Early Breast Cancer.
Authors: Aitelli C. , Aitelli C. , Saad R. , Mackey D. , Asmar L. , Jones S. , Jones S. , Jones S. , Pippen J. , Pippen J. , Pippen J. 
Published: December 2010

Abstract
Background: HER2/neu (HER2) positive breast cancers are associated with worse survival, resistance to cyclophosphamide/methotrexate/fluorouracil, and hypothesized to be sensitive to anthracyclines. It has been postulated that only a subset of HER2 positive breast cancers are sensitive to anthracyclines. Investigators have been working on how to identify this subset of patients, thus sparing patients from anthracyclines that have potential cardiac and bone marrow toxicities. Overexpression of the topoisomerase IIa gene (TOP2A) is the putative biomarker for sensitivity to anthracyclines. Testing tumors for overexpression of this gene may help identify patients who will not benefit from anthracylines. TOP2A is located in the same amplicon as the HER2 gene and can be assessed for overexpression by a FISH assay.Materials and Methods: Paraffin tissue blocks were obtained in 126 patients entered on US Oncology trial 9735 which recruited patients between 1997 and 2000. Data on HER2 status and outcome was previously reported (JCO 27:1177-1183, 2009). TOP2A status was then assessed by fluorescent in situ hybridization (FISH) using the LSI TOP2A Spectrum Orange Probe (Vysis). A total of 20 cells were counted and a gene ratio of greater than 2.0 was considered positive. Clinical data and outcome were available for statistical analysis.Results: We found that none of the 97 HER2 negative cases demonstrated overexpression of TOP2A by FISH analysis. TOP2A was overexpressed in 43% of the 29 HER2 positive cases. An analysis of outcome will be presented at the meeting, although the number of cases limits this observation.Discussion: Our study supports the observation that TOP2A is not overexpressed in HER2 negative disease and is only observed in a subset of cancers overexpressing HER2. Clinical correlation of outcome will be necessary to confirm whether or not TOP2A is a reliable biomarker of sensitivity to anthracyclines. The ongoing US Oncology trial of TC vs. TAC in HER2 negative breast cancer (USOR Trial 06-090) should provide that evidence.Supported in part by a grant from sanofi-aventis.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2134.
Biomarkers of Oxidative Stress in Breast Cancer.
Authors: Jassal R. , Talwar D. , Mcmillan D. , Tovey S. 
Published: December 2010

Abstract
INTRODUCTIONDespite significant improvements in cancer diagnosis and treatment, approximately one-quarter of breast cancer patients will die of their disease. Oxidative stress has been implicated as a contributory factor in the development of breast cancer. Reactive oxygen species can initiate lipid peroxidation, resulting in generation of reactive secondary products which can induce oxidative DNA damage and mutations in the p53 tumour suppressor gene, which is one of the most frequent mutations associated with breast cancer development. Oxidative stress has also been associated with activation of transcription factors and tamoxifen resistance. The aim of the present study was to identify the levels of lipid peroxdation products; malondialdehyde and 8-iso-Prostaglandin F2α (8-iso-PGF2α), in patients with primary operable breast cancer, and to correlate these levels with pathological factors of disease including tumour grade, ER and HER2 status and also Nottingham prognostic index (NPI) status.METHODS:89 patients with primary operable breast cancer and 10 healthy subjects were studied. Plasma levels of MDA (total and free) and 8-iso-PGF2α were measured.RESULTS:The majority of patients were over 50 years (87%), had grade II/III tumours (68%), were axillary lymph node positive (41%) and had ER-positive tumours (82%). Compared to the control, patients had higher levels of total MDA (p&lt;0.001), free MDA (p&lt;0.001), and 8-iso-PGF2α (p&lt;0.001). Both free (p&lt;0.05) and total MDA (p=0.001) were significantly correlated with increasing tumour grade. Furthermore, total MDA levels were also associated with increased tumour size (p&lt;0.05) and ER-negative tumours (p&lt;0.05). Taken together, both total (p&lt;0.001) and free (p &lt;0.05) MDA were significantly associated with higher NPI categories. 8-iso-PGF2α showed only a correlation with increasing age (p&lt;0.05)CONCLUSION:The present study shows that patients with breast cancer have evidence of increased levels of oxidative stress. Furthermore, MDA concentration was significantly associated with conventional markers of poor prognosis. This data suggests oxidative stress may be involved in tumour progression to a more aggressive phenotype. Thus MDA maybe a useful marker of tumour associated oxidative damage and may provide a promising marker for risk prediction and targets for preventative measures in breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2141.
Decreased Phosphorylation of RSK May Predict Response for Neoadjuvant Chemotherapy.
Authors: Yi J. , Yu J. , Yu J. , Ko E. , Ko E. , Han W. , Han W. , Noh D. , Noh D. 
Published: December 2010

Abstract
Neo-adjuvant chemotherapy is an essential part of the management of locally advanced breast cancer. The resistance in breast cancer towards chemotherapeutic agents makes chemotherapy an incommodious problem. Current clinical factors cannot predict therapy response sufficiently in the treated patients. Doxorubicin is an effective breast cancer drug but is hampered by a severe, dose-dependent toxicity. The resistance mechanisms responsible for doxorubicin-resistance of breast cancer have been the subject of numerous investigations. Identification of proteins that are associated with doxorubicin resistance is a first step toward better response prediction and tailored treatment of patients.In this study, we compared the expression of core proteins and their phosphorylated forms of several canonical pathways (MAPK signaling, Apoptosis, PI3K/Akt Signaling, Cell Cycle/Checkpoint and TGF-β/Smad signaling) in breast cancer tissues which were divided into two classes based on the type of response to doxorubicin therapy by immunoblotting. As a result, we found that the phosphorylated form of ribosomal protein S6 kinase (RSK) was low in doxorubicin-resistant breast cancer tissues compared with doxorubicin-sensitive breast cancer tissues.We also investigated RSK's phosphorylation rate and doxorubicin sensitivity of various breast cancer cell lines including MCF-7, MCF-7s (sphere form), MDA-MB-231, MDA-MB-231s, MDA-MB-436, MDA-MB-453, MDA-MB-468, ZR75-1, BT474, Hs578T, T47D and MCF-10A to determine the phosphorylation rate of RSK in relation to the drug sensitivity of the breast cancer cell lines. Expectedly, the phosphorylation of RSK was low in doxorubicin resistant breast cancer cell line such as MDA-MB-453, ZR75-1 and Hs578T. Additionally, MCF-7s and MDA-MB-231s showed decreased phosphorylation rates compared with MCF-7 and MDA-MB-231.In conclusion, decreased phosphorylation of RSK may predict response and further clinical studies should evaluate for molecular function of phosphorylated RSK during doxorubicin therapy. Furthermore, immunohistochemistry for the detection of RSK's phosphorylation rate in breast cancer tissues is being developed for the analysis of increased and independent group of patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2146.
Mouse Mammary Tumor Expressing MMTV-SmoM2 as a Tool To Study Lung Metastasis.
Authors: Moraes R. , Landua J. , Lewis M. 
Published: December 2010

Abstract
Background: The hedgehog signaling network regulates pattern formation, proliferation, cell fate and stem/progenitor cell self-renewal in many organs. Altered hedgehog signaling is implicated in 20-25% of all cancers, including breast cancer. We demonstrated previously that expression of activated human SMO (SmoM2) under the mouse mammary tumor virus (MMTV) promoter in transgenic mice leads to increased proliferation, altered differentiation, ductal dysplasias, and increase the proportion of mammosphere-forming cells, with reduction of stem cell pool, in virgin mice.Material and Methods: We isolated and established a tumor line from this mouse line (named TU505). To investigate the role of hedgehog signaling in mammary tumorigenesis and metastasis we transplanted TU505 fragments (1-2mm3) to a cleared fat pad of 3 week-old mice. After 10 days we removed the primary tumors and let the mice recover for another 3 weeks, which at that time the animals were sacrificed and the lungs removed under stereomicroscope. The lung metastases visible at naked eyes were snap frozen for RNA isolation, and the remaining lungs fixed in 4%PFA.Results: The TU505 is a tumor expressing MMTV-SmoM2, triple-negative (ER-, PR-, and HEB2-), hormone independent, highly metastatic to the lung, and with a robust expression of Ptch1, Ptch2, Smo, Gli2, and Gli3. The gene expression of primary tumor and metastasis are compared.Discussion: The hedgehog signaling networks has been associated with metastasis. The TU505 is a strong tool to study mammary gland tumorigenesis and metastasis.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2165.
Use of Bisphosphonates and Risk of Postmenopausal Breast Cancer.
Authors: Rennert G. , Pinchev M. , Rennert H. 
Published: December 2010

Abstract
Background Bisphosphonates are commonly used for the treatment of osteoporosis and for prevention and treatment of skeletal lesions due to malignancy. However the association between the use of bisphosphonates and the risk of developing breast cancer has not been reported.Methods The Breast Cancer in Northern Israel Study (BCINIS) is a population-based case-control study in northern Israel of breast cancer cases and age/clinic/ethnic-group matched controls. Use of bisphosphonates for at least 5 years was assessed in 4,575 postmenopausal cases and controls using a structured interview. It was further validated by data from prescription records among participants for whom they were available.Results The self-reported long-term use of bisphosphonates prior to diagnosis was associated with a significantly reduced relative risk of breast cancer (Odds Ratio=0.66, 95% CI: 0.47-0.93). This association remained significant in a pharmacy records based analysis after adjustment for age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, BMI, use of calcium supplements, HRT use, number of pregnancies, months of breast feeding and age at first pregnancy (OR=0.71, 0.57-0.90). A significant dose response association between length of use of bisphosphonates and breast cancer risk was found. Breast tumors identified in bisphosphonates users were more often ER positive and less often poorly differentiated.Conclusions The use of bisphosphonates for more than 1 year was associated with a 29% relative reduction in the risk of postmenopausal breast cancer. Tumors developing under bisphosphonates treatment tended to have a favorable prognostic factors profile.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 27.
Transcriptomic Profiles and Circulating Tumor Cell Detection in Primary Breast Cancer.
Authors: Bidard F. , Reyal F. , Valet F. , Mathiot C. , Brain E. , André F. , Espié M. , Salmon R. , De Cremoux P. , Spyratos F. , Marty M. , Pierga J. 
Published: December 2010

Abstract
Background: We have previously demonstrated that circulating tumor cells (CTC) detection by the CellSearch system is strongly associated with metastatic outcome in non-metastatic breast cancer (BC) treated by neoadjuvant chemotherapy (NACT) [Pierga, Clin Cancer Res 2008]. Transcriptomic analysis of primary tumors may uncover molecular phenotypes associated with CTC detection.Methods: Both CTC detection in blood at diagnosis and transcriptomic analysis of the primary tumor have been performed prospectively in 58 non-metastatic BC patients (pts) treated by NACT in a phase II trial (REMAGUS02). We searched for an association between CTC detection and (i) intrinsic molecular subtypes, (ii) stemness signature, (iii) other published signatures, and (iv) expression of molecular markers involved in CTC detection. CTC-associated genes were also studied (v).Results: (i) CTC detection was not statistically associated with an intrinsic molecular subtype: 29% in basal-like (n=5/17pts), 33% in HER2+ (3/9pts), 13% in luminal A (2/13pts), 20% in luminal B (2/10pts) and 29% in normal-like (2/7pts) BC. (ii) No association was found between CTC detection and the stemness signature. (iv) CTC detection was also not related to the “stemness profile”; it was independent of EpCAM, CK8 and CK18 transcriptomic expression. Other results (iii, v) will be disclosed at the meeting.Conclusion: Our study is the first to compare tumor gene expression profiles and blood dissemination of cancer cells in early BC pts. In these pts, CTC detection by the CellSearch system does not depend on intrinsic molecular subtypes, contrary to a published report based on in vitro-grown cells lines [Sieuwerts, J Natl Cancer Inst 2009]. Being independent from molecular prognostic factors, CTC detection is likely to play a critical role in early BC management.Supported by PHRC AOM/2OO2/02117, Pfizer inc., Roche, sanofi-aventis.ISRCTN10059974
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3005.
Characterization of Metastatic Breast Cancer Patients with Non-Detectable Circulating Tumor Cells.
Authors: Mego M. , Mego M. , Mego M. , Dawood S. , De Giorgi U. , De Giorgi U. , Valero V. , Andreoupolou E. , Handy B. , Ueno N. , Reuben J. , Cristofanilli M. 
Published: December 2010

Abstract
Background: Circulating tumor cells (CTC) are independent predictor of progression free and overall survival in metastatic breast cancer patients, with superior prognosis for patients with CTC &lt;5 per 7.5mL of peripheral blood. However, 30-50% of patients have non-detectable CTC. The aim of this study was to assess the prognostic factors in MBC patients with non-detectable CTC.Methods: This retrospective study included 271 MBC patients evaluated between January 2004 and December 2007. Median age of patients was 56 years (range: 23-82 years). CTCs were enumerated before patients started a new line of treatment using the CellSearchTM. Overall survival (OS) was calculated from the date of CTC measurement, estimated by the Kaplan-Meier product limit method, and compared between groups with the log-rank test.Results: Median CTC count was 2 (range: 0-1780) per 7.5 mL. CTCs were not detected in 99 (36.5%) patients, while 112 (41.3%) patients had CTC ≥ 5. Median OS for patients with 0 CTC; 1-4 CTC and ≥ 5 CTC was 29.3; 26.4; and 19.4 months (p = 0.04), respectively. Patients with brain metastasis have the highest probability of non-detectable CTC (71.4% vs. 33.6%; p = 0.001), while patients with bone metastasis are more likely to have CTC ≥ 1 (48.2% vs. 31.8%; p = 0.01). There was no association between other tumor characteristics (ER, PR, HER2, number and localization of tumor metastasis) and non-detectable CTC status. Patients with CTC = 0 have non-significantly better OS compared to patients with CTC ≥ 1 (29.3 vs. 23.3 months; p = 0.09) and have superior survival in all but one analyzed subgroups; only inflammatory breast cancer (IBC) patients with CTC = 0 have inferior OS compared with patients with CTC ≥ 1 (26 vs. 37 months; p = 0.67). In a subgroup of patients with non-detectable CTC, triple negative MBC has the poorest survival (median OS = 18.8 months), while hormone receptor positive MBC, without visceral metastases and non-inflammatory breast cancer has the best survival (median OS = 36.9 months). In multivariate analysis, hormone receptor status and line of therapy were only independent prognostic factors for OS in patients with non-detectable CTC (Table 1).Conclusion: Patients with non-detectable CTC before start of new line of therapy comprise a heterogeneous group of patients with substantially different prognosis. Triple negative and IBC patients represent poor prognosis subgroups. These data suggest heterogeneity of microscopic disease in advanced cancer and indicate the need to investigate combining additional detection technologies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3006.
Circulating Tumor Cells (CTCs) and Epithelial Mesenchymal Transition (EMT) in Breast Cancer: Describing the Heterogeneity of Microscopic Disease.
Authors: Mego M. , Mego M. , Mego M. , Mani S. , Li C. , Andreoupolou E. , Tin S. , Jackson S. , Cohen E. , Gao H. , Cristofanilli M. , Reuben J. 
Published: December 2010

Abstract
Background: Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer (BC) patients. CTC are readily detected by CellSearch System based on their expression of EpCAM. Epithelial-mesenchymal transition (EMT) gives rise to cells with stem cell-like properties with increased chemotherapy resistance. Human mammary epithelial cells (HMEC) transformed by the EMT transcription factor TWIST1 and spiked into normal peripheral blood (PB) are not detected by EpCAM enrichment based conventional detection methods compared to non-transformed HMECs. We hypothesize that CTCs undergoing EMT and resultant loss of epithelial markers may escape detection by conventional detection methods. The aim of this study was to detect CTCs based on expression of EMT genes in breast cancer patient's peripheral blood.Methods: This prospective ongoing study of breast cancer patients consisted of 16 (57.1%) patients with metastatic disease, 19 (67.9%) patients with inflammatory breast cancer (IBC) and 12 (42.9%) patients with primary, non-IBC breast cancer, respectively. Isolated peripheral blood mononuclear cells (PBMC) were depleted of cells of hematopoietic origin (CD45+) using anti-CD45 coated magnetic beads. RNA extracted from CD45-depleted (CD45-) PBMC were interrogated for expression of TWIST1, SNAIL1, SLUG, ZEB1, FOXC2 and EpCAM gene transcripts by quantitative reverse transcription-PCR. Expressions of gene transcripts in CD45- PBMC from patients were compared to those of CD45- PBMC of healthy donors (HD). Expression of one or more gene transcripts was considered a positive result. Concurrently, a 7.5 mL PB sample was collected for determination of CTC by CellSearch.Results: Median age was 54 year (range: 34-72 years). Overall, the median CTC count by CellSearch was 2 (range; 0-750) per 7.5 mL of PB. TWIST1, SNAIL1, SLUG, ZEB1 and FOXC2 were overexpressed in CD45- PBMC in 7%, 4 %, 4%, 0% and 14 % of patients, respectively. At least one of the EMT genes was overexpressed in 6 (21%) of patients. TWIST1 and SLUG were overexpressed only in IBC patients (10.5% and 5.3% of patients, respectively). Patients with triple negative breast cancer more commonly overexpressed EMT genes compared to non-triple negative patients (30.8% vs. 13.3%). There was no correlation between expression of EMT genes, EpCAM expression or CTC count measured by CellSearch, respectively.Conclusions: These data suggest that EMT genes may be involved in the dissemination of CTCs. Loss of epithelial antigen on CTC due to EMT, triggered by high expression of these genes, may be responsible for their undetection by conventional methods in a fraction of patients with early or advanced breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3011.
Effect of Trastuzumab and Chemotherapy on Circulating Tumor Cells in Patients with Poor Prognosis Metastatic Breast Cancer.
Authors: De Giorgi U. , De Giorgi U. , Mego M. , Ueno N. , Handy B. , Jackson S. , Reuben J. , Valero V. , Cristofanilli M. 
Published: December 2010

Abstract
Background. Trastuzumab has significant activity in HER2 neu amplified metastatic breast cancer (MBC). We hypothesized that it may selectively act against circulating tumor cells (CTC) in HER2-positiveMBC. We assessed the effect of trastuzumab-based regimens on CTC in HER2-positive MBC with poor prognosis (≥ 5 CTC).Patients and Methods. We retrospectively evaluated patients with poor prognosis MBC (baseline ≥ 5 CTC) treated with a first-line regimen consisting of trastuzumab+antimitotic agents in 11 HER2-positive patients not previously pretreated with trastuzumab, chemotherapy with antimitotic agents in 24 HER2-normal patients, and other chemotherapeutic drugs (mainly capecitabine) in other 16 HER2-normal patients. CTC were detected and enumerated using the CellSearch system (Veridex LLC, Warren NJ, USA). We evaluated the effect on CTC counts and on progression-free survival (PFS) and overall survival (OS).Results. At a median follow-up of 16 months (range, 4 to 48), 24 patients (47%) died. All 11 HER2-positive patients treated with trastuzumab+antimitotic agents had &lt;5 CTC during the treatment. Only 16 (67%) with HER2-normal MBC had &lt;5 CTC with antimitotic agents (p = 0.037), and 28 (70%) with other chemotherapeutic regimens (p = 0.048). No statistically significant difference was observed between patients treated with antimitotic agents and those treated with other chemotherapeutic agents (p = 0.73). There was no difference between patients receiving polychemotherapy and monochemotherapy (p = 0.73). The median PFS was 12 months in HER2-positive patients treated with trastuzumab+antimitotic agents compared with 7 months for those with HER2-normal (p = 0.09). The median OS was not reached (&gt;20 months) and 19 months (p = 0.034), respectively. The median PFS was 8 months in HER2-normal patients with ≥5 CTC and 4 months in those with &lt;5 CTC (p = 0.01). The median OS was not reached (&gt;17 months) and 9 months (p = 0.01), respectively.Conclusions. Trastuzumab is highly effective in patients with HER2-positive MBC with poor prognosis (≥ 5 CTC). Antimitotic agents and other chemotherapy agents did not show a similar effect in HER2-normal MBC. CTC might be useful in the monitoring of poor prognosis MBC patients undergoing therapy with trastuzumab.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3014.