bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the Tyrer-Cuzick Model in Women with Atypical Hyperplasia.
Authors: Boughey J. , Hartmann L. , Anderson S. , Degnim A. , Vierkant R. , Frost M. , Reynolds C. , Pankratz V. 
Published: December 2010

Abstract
Background: Risk prediction models are important clinical tools for counseling and decision making for women with an elevated risk of breast cancer, such as women with atypical lobular or ductal hyperplasia (atypia). The Gail model has been shown to underestimate the risk of breast cancer in women with atypia. We sought to evaluate the performance of the Tyrer-Cuzick model in a well-defined cohort of women with atypia.Methods: The Mayo Benign Breast Disease (BBD) Cohort includes 9,376 women aged 18 to 85 who had an open breast biopsy with benign pathological findings between 1967 and 1991. The subset of women with atypia was identified by our study pathologists. Risk factor data required by the Tyrer-Cuzick model were collated for each woman, and the model was used to predict each woman's risk of developing invasive breast cancer within ten years. The predicted numbers of breast cancers were compared to the observed numbers to assess overall model calibration, and the concordance between breast cancer outcomes and predicted probabilities was used to measure the accuracy of the model on the individual level. Subset analysis of women with strong family history was performed. Strong family history was defined as: at least one first-degree relative with breast cancer before the age of 50 years or two or more relatives with breast cancer, at least one being a first degree relative.Results: Three hundred and thirty one women with atypia were identified. Over a mean follow up of 13.7 years, 62 (19%) women have developed invasive breast cancer. Thirty one women developed invasive cancer in the first ten years after biopsy. The Tyrer-Cuzick model predicted that 64.6 invasive breast cancers would occur in the first ten years after biopsy. Thus, the predicted to observed ratio was 2.08 [95% CI: 1.47 – 2.96], p &lt; 0.001).The concordance statistic was 0.51, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who were diagnosed with invasive breast cancer within ten years of biopsy and those who were not.Performance was somewhat better in the subset of 68 women with a strong family history of breast cancer. The model predicted 12.3 invasive breast cancers, and 7 were observed, for a predicted to observed ratio of 1.76 [95% CI: 0.84 – 3.70]. The concordance statistic was 0.57.Conclusion: The Tyrer-Cuzick model significantly overestimated the risk of breast cancer in the first ten years after biopsy for this group of women with atypia. Individual risk estimates showed poor concordance. Performance was slightly improved in women with a strong family history of breast cancer. Physicians should be cautious when using the Tyrer-Cuzick model to predict ten-year risk in patients with atypia.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6063.
Microtubule Associated Protein Tau Expression as a Predictive and Prognostic Marker in a Trial Assessing Sequential Docetaxel as Adjuvant Chemotherapy for Early Breast Cancer (TACT).
Authors: Tutt A. , Gillett C. , Pinder S. , A'Hern R. , Dowsett M. , Ellis I. , Bartlett J. , Bliss J. , Johnston S. , Ellis P. , TACT Trial Trialists . 
Published: December 2010

Abstract
Objective: TACT, which compared sequential anthracycline-taxane (FEC-D) adjuvant chemotherapy with an anthracycline regimen of similar duration (Lancet 2009:373, 1681-1692) provides an opportunity to correlate tau expression levels with disease-free survival (DFS) and to explore the interaction between tau expression and docetaxel benefit. Patients and Methods: 4162 patients were randomized to FE60C (fluorouracil, epirubicin and cyclophosphamide,- 4 cycles) followed by docetaxel (4 cycles) or control. Control, determined by local centres, was FE60C (8 cycles) or epirubicin (4 cycles) followed by classical CMF (cyclophosphamide, methotrexate and fluorouracil - 4 cycles). Patients with hormone receptor positive tumours also received adjuvant endocrine treatment. Tissue blocks were obtained for 3610 TACT patients (87 % of total) to create tissue microarrays (TMA). Tau protein expression was assessed by immunohistochemistry (IHC). Tau was successfully scored by 2 observers (blinded to treatment allocation and clinical outcome), scoring 2 cores from separate TMAs for each of 2977 patients. Intensity (negative, weak, moderate or strong) and the proportion of tumour cells stained (in 5% increments) were recorded. Results: A very strong association was observed between level of intensity and proportion of staining (p&lt;0.001), subsequent analysis used tau intensity only. Fifty one percent of tumors were tau-positive defined as demonstrating weak or greater intensity of staining. Tau expression was positively correlated with ER status (p&lt;0.001), negatively correlated with grade (p&lt;0.001) and negatively correlated with HER2 status (p&lt;0.001). In absence of overall treatment benefit for docetaxel, significant factors predicting DFS on univariate analysis were tau, ER and HER-2 expression in addition to nodal status, grade, tumour size and age. With the exception of age these variables were also significant on multivariate analysis. No significant interaction between tau expression and efficacy of docetaxel was observed in all patients or in patients within the ER+HER2-ve, HER2 +ve and ER -ve HER2 –ve subsets. Exploratory analyses to assess interactions using tau intensity and proportion IHC staining as continuous variables are underway and will be reported. Conclusion: Tau expression was associated with improved DFS but there was no evidence of an interaction between tau and docetaxel benefit. These results are similar to NSABP-B28, which evaluated addition of paclitaxel to doxorubicin/cyclophosphamide.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 607.
Increased Radiation Resistance of Breast Cancer Cells by Endocrine Disrupting Chemical Bisphenol A.
Authors: Kil W. , Camphausen K. 
Published: December 2010

Abstract
Purpose: Bisphenol A (BPA) is used in the manufacture of plastics and belongs to a family of compounds called endocrine disrupting chemicals (EDCs). Because of extensive use of BPA in the manufacture of consumer goods and products, humans are exposed to levels of BPA which may cause adverse effects on endocrine-sensitive organs. Here, we evaluated the effects of BPA on the proliferation of breast cancer cells and the effect of BPA on tumor cell radioresponse.Materials/Methods: Proliferation was evaluated in estrogen-sensitive (MCF-7) and estrogen-insensitive (MDA-MB-231) human breast cancer lines that were treated for 72 hour with BPA (0.1µM; environmentally relevant concentration). The effect on radiation sensitivity was evaluated using clonogenic survival assays after exposure to various dose of BPA (0.1, 1, and 10 µM-) followed by irradiation (IR). DNA damage was evaluated using phosphorylated histone H2AX (γH2AX) and the neutral comet assay. BPA induced cell cycle changes were evaluated by staining of phosphor-H3 and flow cytomety. To investigate the mechanism of BPA±IR induced cell growth, we explored the activation of Akt and mitogen-activated protein kinase (MAPK) after treatments.Results: Exposure of BPA at low-dose (0.1µM) for 72 hour resulted in an increase survival rate in MCF-7 cancer cell (150 ± 19% of control) with more limited effects on MDA-MB-231 cancer cell (123 ± 17% of control). Exposure of MCF-7 to BPA for 72 hour before radiation resulted in an increase in radioresistance with dose-reduction factors at a surviving fraction of 0.1 of 1.23 and 1.31 with BPA 0.1µM, 10µM, respectively. BPA had no effect on the number of cells in each phase of the cell cycle nor on the activation of the G2 cell cycle checkpoint after IR. As a measure of DNA double strand breaks, γH2AX were determined as a function of time after the BPA±IR treatments. BPA also significantly decreased γH2AX expression at 24 hours after IR. Expression of phosphorylated Akt and phosphorylated mitogen-activated protein kinase (MAPK) increased with BPA± IR but decreased with IR alone at 24 hr.Conclusions: These results suggest that BPA can enhance phosphorylation of Akt and MAPK possibly leading to a resistance to radiation-induced cell death after IR. Further studies are needed to determine the clinical relevance of these findings.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6073.
The Impact of National Press Coverage on Early Phase Clinical Trial Recruitment and Enrollment.
Authors: Bates N. , Higgins D. , Childs J. , Boettcher M. , Salazar L. , Disis M. 
Published: December 2010

Abstract
The American Society of Clinical Oncologists reports that only 5% of cancer patients ultimately enroll in a clinical trial. According to the National Cancer Institute, one key barrier to participation is a lack of knowledge about clinical trials, both on behalf of oncologists and the patients themselves. Unfortunately, many investigator-initiated and academic clinical trials simply do not have budgets that permit implementation of large-scale recruitment efforts. Recent experience by our group demonstrates that press coverage by national media is a particularly effective tool for generating public interest in clinical research, as well as increasing trial enrollment.In the third quarter of 2008, our academic translational research group was featured on a national news program. In the week following the broadcast, our group's website, which had been listed in the broadcast and accompanying web story, received an unprecedented number of hits. Not only did the broadcast generate interest in our group's research; more specifically, it translated to substantial increases in potential clinical trial candidates, and subsequently, increased trial enrollment. In the month following the broadcast, our group received 125 new clinical trial inquiries as a result of the feature. That number represented a seven-fold increase in new inquiries during the same period in 2007. Of those 125 contacts, more than half of patients were potentially eligible for one of our clinical trials based on an initial screening. From November 2008 to the present, nearly one-third of all clinical trial enrollments can be attributed to the news story. Enrollment to the vaccine trial specifically described in the news feature increased four fold in comparison to the same 6-month period in 2008-2009, with half of all new enrollments attributable to the news feature.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6078.
Sucess of Brochure/One Page Universal Consent for Biospecimen Donation.
Authors: Singh B. , Singh B. , Roses D. , Roses D. , Guth A. , Guth A. , Schnabel F. , Schnabel F. , Shapiro R. , Shapiro R. , Axelrod D. , Axelrod D. , Ginsberg A. , Ziguridis N. 
Published: December 2010

Abstract
Background: Accrual of biospecimens to biorepositories is a challenge and has been recognized as a critical barrier for translational research. HIPAA mandates that patients sign a separate Informed ConsentForm (ICF) for donating biospecimens for research. This poses a significant challenge to the medical staff and may negatively impact accrual to biorepositoriesMaterials and Methods: At NYU Cancer Institute, the ten page ICF was reformatted as a tri-fold brochure and one page ICF in 2005. The brochure is given to patients during the office visit or at time of registration and the triplicate one-page ICF on the day of surgery. The brochure contains information regarding biospecimen banking.The triplicate, one page consent is signed by the patient on the day of surgery.Results: In a 3-year period (2003-2005), the 10-page ICF was used to consent 433 patients from Breast, Gynecologic Oncology and GI Oncology, with an average of 2.77 patients per week. After the implementation of the novel brochure and single page ICF format, 1,426 patients were consented in the next 3- year period (2006-2008), with an average of 9.14 patients per week (10)Patients in the Breast Surgical Oncology Clinic at NYUCI were initially targeted. This was done in close cooperation with the breast surgical oncologists, nurses and operating room staff. The brochure/1-page ICF method doubled the accrual of patients from 141 to 304 patients in the first year (2005-6). However, the number of patients who consented did not increase in the next two years in spite of a significant increase in the total number of patients in the breast surgical oncology service.A root cause analysis was performed and it was determined that either the patients were not approached in the physician's office or the consenting process was not followed. It was concluded that a dedicated consenting professional was required to overcome these hurdles, who will primarily works in the operating room, where patients with diagnosis of cancer are targeted. This has yielded a significant increase in number of patients consenting for biospecimen donation. shows a significant increase in accrual since her recruitment in February 2009.Conclusions: A novel consenting mechanism with a brochure and one page consent has been successfully implemented at NYU Cancer Institute and has resulted in a significant increase in patients consenting for biospecimen donation. The process is being replicated institute wide for accrual to all biorepositories at NYULMC. This novel method can be widely employed to accrue specimens for clinical trials.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6081.
Phase II Trial with Gemcitabine, Paclitaxel and Bevacizumab for the First Line Treatment of Metastatic Breast Cancer.
Authors: Guardino A. , Chen M. , Levy M. , Chen C. 
Published: December 2010

Abstract
Background: Both gemcitabine and paclitaxel in combination, and paclitaxel and bevacizumab in combination, have shown higher response rates and improved time to progression (TTP) over single agent paclitaxel for the first line treatment of metastatic breast cancer. This phase II study was initiated to evaluate the efficacy and tolerability of combination gemcitabine, paclitaxel and bevacizumab as first line treatment for HER2 negative metastatic breast cancer.Methods: Women with HER2 negative metastatic breast cancer who have not received prior chemotherapy for metastatic disease are eligible for the study. The primary end point is time to progression (TTP). Secondary endpoints include duration of response, objective response rate and toxicities. Patients receive gemcitabine 1000 mg/m2 IV on days 1, 8, & 15, paclitaxel 80 mg/m2 IV on days 1, 8, & 15, and bevacizumab 10 mg/kg on days 1 & 15, on an every four week cycle. Patients are evaluated with imaging studies including CT and bone scan at baseline and every 3 months. Response to treatment is evaluated using RECIST methods. Treatment continues until disease progression or unacceptable toxicities and at which point the drug thought to cause the toxicity will be discontinued.Results: As of January 2009, 21 patients with a median age of 54 years (range: 30-76) have been enrolled. Estrogen and progesterone receptor was positive in 16 and 10 patients, respectively and 4 patients were negative for both. Among 17 evaluable patients, the clinical benefit rate (CR+PR+SD ≥ 24 weeks) is 88%. 10 patients have reached the study endpoint with a median TTP of 12 months (mean TTP of 13.3 months). In addition, the combination treatment with bevacizumab has been well tolerated without clinically significant bleeding and with less than 10% of patients experiencing grade 3 peripheral neuropathy, grade 3 hypertension and less than 5% experiencing grade 3 proteinuria. 4 patients experienced a thrombotic event, of which 2 were catheter-related. The primary toxicities were hematological which were expected. 16 patients experienced grade 3/4 hematological toxicities and responded to dose reductions. 9 patients remain on treatment.Discussion: The addition of bevacizumab to combination chemotherapy with gemcitabine and paclitaxel is well tolerated for first line therapy of HER2 negative metastatic breast cancer. Clinical activity has been observed and phase II enrollment is ongoing.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6089.
Phase II Study of the Novel Epothilone Sagopilone (ZK-EPO) in Patients with Progressive Metastatic Breast Cancer.
Authors: Campone M. , Dittrich C. , Cufer T. , Dudov A. , Dao Phan P. , Schmelter T. , Giurescu M. , Martin M. 
Published: December 2010

Abstract
Background: Sagopilone, a microtubule-stabilizing agent, is a novel, fully synthetic epothilone undergoing clinical development in a variety of tumor types. Proof-of-concept has been demonstrated in Phase II trials of platinum-resistant and -sensitive ovarian cancer, prostate cancer, and melanoma. Sagopilone has shown significant preclinical activity in taxane-resistant breast cancer cell lines, and preliminary clinical activity in patients (pts) with taxane-sensitive and -resistant disease in Phase I. This Phase II study assessed the efficacy, safety, and tolerability of sagopilone in metastatic breast cancer (MBC).Methods: Pts with progressive MBC who received a maximum of 2 previous chemotherapies not containing taxanes or vinca alkaloids were randomized to either i.v. sagopilone 12, 16, or 22 mg/m2 over 3 h or 22 mg/m2 over 0.5 h, every 21 days, for up to 6 cycles. The primary endpoint was the proportion of pts with a complete response (CR) or partial response (PR) as best overall response. A Simon's 2-stage design was used: 15 pts were to be initially accrued per arm; a further 12 pts were recruited per arm if ≥5/15 pts showed a response. The study was to be considered successful if an objective response (CR or PR) was observed in ≥10/27 pts.Results: Eighty-two female pts (median age 59 years) were randomized to treatment. The median number of treatment cycles was 3 (range 1-9). Of 77 pts evaluable for best response (per protocol set), 11 (14%) had PR, 32 (42%) stable disease (SD), 30 (39%) progressive disease (PD), and 4 (5%) unknown (Table 1).Table 1. Number of pts (%) with best overall responseSagopilone12 mg/m² 3 h16 mg/m² 3 h22 mg/m² 3 h22 mg/m² 0.5 hTotalNo. of pts14 (100.0)26 (100.0)16 (100.0)21 (100.0)77 (100.0)PR0 (0.0)3 (11.5)3 (18.8)5 (23.8)11 (14.3)SD5 (35.7)10 (38.5)8 (50.0)9 (42.9)32 (41.6)PD9 (64.3)11 (42.3)4 (25.0)6 (28.6)30 (39.0)Unknown0 (0.0)2 (7.7)1 (6.3)1 (4.8)4 (5.2) The study outcome was not considered successful for any of the 4 regimens tested. All 82 pts were evaluable for safety. Thirty-six pts discontinued the study prior to cycle 6: 35 due to adverse events (AEs) and 1 due to consent withdrawal. Treatment-related AEs documented in ≥20% pts were: sensory neuropathy 60% (18% grade 3, 1% grade 4); asthenia 26% (6% grade 3); alopecia 23%, myalgia 20% (2% grade 3); fatigue 20%; and nausea 20% (1% grade 3).Conclusions: Sagopilone did not meet the primary endpoint in this pt population with progressive MBC. Treatment-related AEs appeared to be considerable but manageable at all dose levels.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6107.
Preliminary Phase II Data Suggest That Entinostat (SNDX275), a Class 1 Selective Histone Deacetylase Inhibitor (HDACi), May Resensitize Breast Cancer Patients Progressing on Aromataste Inhibitor (AI) Therapy to Their AI Therapy.
Authors: Wardley A. , McCaffrey J. , Crown J. , Stein R. , Malik Z. , Rea D. , Barrett-Lee P. , Lee G. 
Published: December 2010

Abstract
Background: Aromatase inhibitors (AI), reduce peripheral conversion of androgen to estrogen, and are standard treatment for ER+ breast cancer (BCA); however, despite initial benefit, the disease eventually progresses. Once patients become resistant to AI, cytotoxic chemotherapy is often used for palliation. Histone deacetylase inhibitors (HDACi) have been shown preclinically to reverse AI resistance and sensitize tumor to AI. Entinostat, an oral selective HDACi, reverses both de novo and acquired hormone resistance in BCA in cell lines and xenograph models and has been well-tolerated, in humans, as a single agent and in combination with other agents tested to date.Methods: Postmenopausal women with ER+ BCA progressing while receiving AI for &gt; 3 months were enrolled. Eligibility criteria included: measurable disease by RECIST criteria, PS 0 or 1, and ≤ 1 chemotherapy for metastatic disease. Exclusion criteria included: rapidly-progressing BCA, life-threatening metastases, chemotherapy within 3 months, and previous exposure to epigenetic modulating agents. Patients continued the AI therapy on which the cancer was progressing, with the addition of entinostat 5 mg weekly in 28-day cycles. Primary objective was to determine clinical benefit rate during the first 6 cycles, defined as the proportion of patients achieving CR, PR or SD lasting &gt; 6 months. Secondary objectives included ORR and PFS. Exploratory biomarkers for anti-tumor activities and entinostat pharmacology were also measured.Results: To date, 24 patients have been enrolled from October 2008 – May 2009. Interim results from 20 patients are described here. The median age is 69 yrs. Eight (40%) and 12 (60%) patients had ECOG scores of 0 and 1, respectively. Fifteen patients (80%) had received tamoxifen; 12 (60%) had prior chemotherapy or immunotherapy. Nine patients (45%) had visceral involvement (lung, pleura, and liver), and 10 had metastases to bone, 3 to breast, and 1 to skin. Among the 10 patients who have completed ≥ 2 cycles, preliminary analysis indicates that the longest durations of SD thus far are &gt; 6 months in 1 and &gt; 5 months in 2 patients. Preliminary analysis of biomarkers in paired samples from 6 patients indicates that HDAC inhibition correlates with changes in cellular molecular targets. Entinostat has been well-tolerated. The majority of AEs were mild to moderate in severity, and the character of AEs was generally consistent with that seen with AI therapy.Conclusion: Entinostat in combination with AI was well-tolerated in patients with progressive BCA. Disease stabilization in several patients was observed. At dose administered, expected pharmacological effects were achieved.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6111.
Synergistic Growth Inhibition with a PI3 Kinase/mTOR Inhibitor Plus Lapatinib.
Authors: Speicher T. , Hackl W. , Lipton A. 
Published: December 2010

Abstract
The mammalian target of rapamycin, mTOR, is a member of the phosphatidylinositol 3-kinase (PI3-K) /Akt family and plays a key role in cell growth and survival. The PI3-K/mTOR pathway is activated by many growth factor receptors in human tumor cells. In addition, the PI3-K pathway is constitutively activated by mutation in one-third of breast cancers. Therefore, blockade of the PI3-K/mTOR pathway may sensitize breast cancers to HER-2/neu inhibition. BEZ235 (Novartis Pharma AG) is a potent, oral, dual PI3-K/mTOR inhibitor currently in Phase I clinical trials. The purpose of this study was to assess the in vitro effects of combining a dual PI3-K/mTOR inhibitor (BEZ235, Novartis Pharma AG) and a lapatinib-like dual inhibitor of EGFR and HER-2/neu (GW2974) on the growth of HER-2/neu-transfected MCF-7 human breast cancer cells. Cells were exposed to the lapatinib-like compound [GW2974 (0.05-5.0µM)] or the dual PI3-K/mTOR inhibitor [BEZ235 (0.5-3nM)] alone or in combination for 3 days (12 different dose combinations were tested). Cell growth was determined using the colorimetric MTT tetrazolium dye assay. The Chou-Talalay method of isobologram analysis was performed to determine the inhibitory effect. Dose-dependent growth inhibition was observed in HER-2/neu-transfected MCF-7 cells after 3 days exposure to GW2974 (IC50: 5.0 mM) or BEZ235 (IC50: 2.2 nM). Exposure to the combination of GW2974 (0.05-0.50 mM) and BEZ235 (0.50-1.0 nM) resulted in synergistic growth inhibition in HER-2/neu-transfected MCF-7 human breast cancer cells. In summary, the combination of lapatinib plus PI3-K/mTOR warrants further investigation as a therapeutic strategy for breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6114.