bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing the design and distribution of clinical trial information via handheld devices
Authors: Monaco V. , Arnold A. M. , Simon B. , McCarty K. S. , Jacobs S. A. 
Published: March 2020

6145 Background: The timely identification of available clinical trials by an oncologist for a patient represents a critical initial step in the research process. The challenges in supporting this step are threefold: (1) Large cancer centers may have more than 200 active clinical trials; (2) The accrual status of any particular clinical trial can change frequently; (3) Oncologists have limited time in their schedule to seek out clinical trial information. We hypothesized that delivering up-to-date clinical trial information directly to a handheld device would address the combination of these three challenges, and we utilized an iterative design process to refine the format and organization of this information. Methods: Web pages containing clinical trial information and optimized for a handheld display were created using an existing database and standard web development software. AvantGo software was utilized for transferring these web pages to handheld devices upon synchronization. Feedback on the initial design was obtained from four oncologists based in our community network locations. Two subsequent designs were developed based on both this feedback and encountered technical constraints. Results: Four major design changes emerged during our iterative design process. These changes included: (1) The organization of trial information based on network location; (2) The improvement of trial disease categories; (3) The shortening of trial titles; and (4) The inclusion of descriptive trial summaries for all trials. Conclusions: A demonstration of the handheld clinical trial information that is available to over 60 oncologists in our extended network will be provided. The merits of this approach as well as the lessons learned from our design process should be considered by other cancer centers seeking new methods for the distribution of clinical trial information. No significant financial relationships to disclose.
Circulating endothelial progenitor cells correlate to stage in patients with invasive breast cancer
Authors: Naik R. , Jin D. , Chuang E. , Gold E. , Tousimis E. , Christos P. , De Dalmas T. , Donovan D. , Rafii S. , Vahdat L. 
Published: March 2020

616 Background: Tumor growth and metastasis is dependent on neo-angiogenesis. Both pre-existing and circulating vascular cells have been shown to contribute to the assembly of tumor neo-vessels in specific tumors. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow constitutes a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be increased in certain malignant states. However, the role of circulating EPCs in breast cancer is largely unknown. Methods: We recruited twenty-five patients with biopsy-proven invasive breast cancer (BC) at Weill Cornell Breast Center to participate in a pilot study investigating the correlation of circulating EPCs to extent of disease and initiation of chemotherapy. For each patient, a baseline sample was drawn before systemic treatment, and for seventeen of those patients, a second sample was taken after the first round of chemotherapy. Levels of peripheral blood EPCs, as defined by co-expression of CD133 and VEGFR2, were quantified by flow cytometry. Results: BC patients with stage III & IV disease had statistically higher levels of circulating EPCs than did patients with stage I & II disease (median=165,000 EPCs/5×106MNCs vs. median=6,920 EPCs/5x106MNCs, respectively, p < 0.0001 by Wilcoxon rank-sum test). In addition, in late-stage patients, levels of EPCs demonstrated a statistically significant drop after initiation of chemotherapy (median=162,500 EPCs/5x106MNCs [pre] vs. median=117,500 EPCs/5x106MNCs [post], p = 0.01 by Wilcoxon signed-rank test). Conclusion: These results suggest that circulating EPCs may serve as a potential tumor biomarker in breast cancer and that EPCs may represent a plausible target for future therapeutic intervention. Supported in part by the Mentored Medical Student in Clinical Research Program (General Clinical Research Center/National Institutes of Health Grant M01RR00047), Madeline & Stephen Anbinder Clinical Scholar Award, and Anne Moore Breast Cancer Research Fund No significant financial relationships to disclose.
Simultaneous, quantitative detection of multiple biomarkers in human breast cancers using multicolor nanoparticles
Authors: Al-Hajj A. H. , Yezhelyev M. V. , Liu T. , O’Regan R. M. 
Published: March 2020

619 Background: Conventional methods of detecting breast cancer biomarkers are hampered by a lack of adequate quantification and/or an inability to detect multiple targets on small quantities of tissue. We have previously demonstrated that estrogen receptor (ER), progesterone receptor (PR) and HER2/neu (HER2) can be detected and quantified simultaneously using antibodies (Abs) directly conjugated to nanoparticles, called quantum dots (QDs), on single breast cancer sections (ASCO 2005). We have expanded our assay to use multicolored QDs conjugated directly to Abs (QD-Abs) to detect and quantify simultaneously ER, PR, and HER2, along with 3 putative biomarkers, epidermal growth factor receptor (EGFR), mammalian target of Rapamycin (mTOR), and insulin-like growth factor receptor (IGFR), in breast cancer cell lines and human breast cancers. Methods: We used multicolored QDs directly conjugated to primary Abs to detect the 6 proteins in breast cancer cell lines (MCF-7, BT474, MDA-231) and single sections of human breast cancers. The 6 proteins were quantified using spectral separation microscopy, and compared to Western blotting. Results: We detected all 6 proteins simultaneously using QD-Abs in breast cancer cell lines and breast tumors. Using hyper-spectral imaging and wavelength-resolved spectroscopy, we separated all 6 fluorescent signals, and quantified the expression of each protein detected using QD-Abs. Quantification of the biomarkers showed good correlation with Western blotting. Conclusions: These results are proof of principle that 6 proteins can be simultaneously quantified using QD-Abs in single breast cancer sections. The use of multiplex QDs offers a novel method of determining the proteome of an individual breast cancer on single breast cancer sections. With the expanding use of targeted therapies in breast cancer, the ability to detect multiple proteins on small breast cancer specimens using QD-Abs, could allow not only the accurate selection of therapy, but a unique method of determining the activity of specific targeted agents. No significant financial relationships to disclose.
Performance characteristics of common immunologic biomarkers used in clinical trials
Authors: Goodell V. , Macleod B. , Slota M. , Disis M. L. 
Published: March 2020

620 Background: Standardization of cell-based immunologic monitoring is becoming increasingly important as methods for measuring cellular immunity become more complex. We assessed the ability of 2 cell-based assays widely used in immune monitoring, the ELISPOT assay and a modified limiting dilution assay based on titrated thymidine incorporation, to predict T cell responses to a HER-2/neu protein vaccine in breast cancer patients. We also assessed the ability of these assays to predict T cell response to tetanus toxoid and CMV, and analyzed the correlation between results from the ELISPOT and modified limiting dilution assays. Methods: 27 Stage II, II, and IV HER-2/neu positive breast cancer patients were vaccinated against the HER-2/neu protein and tt. PBMC were collected before and after vaccination. Samples were analyzed by mLDA and ELISPOT for T cell response to HER-2/neu (a low level response), response to tt (moderate level) and T cell response to CMV (high level). Results: Correlation analysis indicates that there is a strong, significant association between results from the ELISPOT assay and the mLDA for HER-2/neu specific T cell response (Rs=0.547, p=0.02). ROC curves plotted to assess the diagnostic performance of the mLDA and ELISPOT assay indicate that T cell proliferation measurements are a significant indicator of T cell response to the HER-2/neu vaccine (p=0.05), as well as responses to tt (p=0.01) and CMV (p=0.016), respectively. Precursor frequency, as measured by ELISPOT, is a significant indicator of high level T cell response to CMV (p=0.03), but not of a moderate tt response (p=0.09), or HER-2/neu (p=0.09) T cell responses. Conclusion: The mLDA achieves greater assay accuracy in measuring low level T cell responses to HER-2/neu and moderate responses to tt than the ELISPOT assay. No significant financial relationships to disclose.
c-kit: Identification of co-regulated genes by gene expression profiling and clinical relevance of two breast cancer subtypes with stem cell like features
Authors: Rody A. , Holtrich U. , Müller V. , Gaetje R. , Diallo R. , Gehrmann M. , Von Minckwitz G. , Engels K. , Karn T. , Kaufmann M. 
Published: March 2020

622 Background: Expression of the proto-oncogene c-kit has been found in malignant tissue including a subset of breast cancers. c-Kit is also expressed in normal breast tissue and several authors found a loss of c-kit expression in breast carcinoma suggesting it might be involved in the growth control of mammary epithelium. Until now, only a few markers were described to be co-regulated with c-kit. To elucidate the possible role of c-kit in malignant transformation, we analyzed gene expression data of breast cancer patients. Methods: Tumor tissue of n=171 breast cancer patients were analyzed by gene expression profiling using Affymetrix Hg U133 Arrays (22,500 genes) and bioinformatic analyses. Tumor samples with high stromal and low epithelial cell content by gene expression profiling were excluded for further analysis. Validation was performed with n=100 independent samples. Results: A total of 10.5% of the tumors showed strong c-kit expression (2.5 fold above median). A careful dissection of global expression data revealed strong correlations of c-kit with the expression of a large cluster of genes containing several for whom c-kit coexpression was already described (HER1, CK-5/-17, PDGFR) as well as several members of the wnt signalling pathway, providing a possible novel link to mammary epithelial differentiation. Analysis of n=171 breast cancer samples according to this gene set allows the identification of putative “stem cell like” tumors (SCL) characterized by expression of several known stem cell markers. Surprisingly, a tight link of ER status and proliferation is restricted only to these SCL tumors but lost among non-SCL tumors. The clinical implications of our findings will be presented. Conclusions: For the first time these data bring together the description of two breast cancer subtypes identified by gene expression profiling with the actual stem cell model of the development of breast cancer. No significant financial relationships to disclose.
Postoperative adjuvant therapy with tamoxifen, tegafur-uracil (UFT), or both in women with node-negative breast cancer: A pooled analysis of six randomized controlled trials (relapse-free survival data)
Authors: Nakamura S. , Abe O. 
Published: March 2020

633 Background: In Japan, 6 randomized controlled trials of the oral 5-fluorouracil derivative tegafur-uracil (UFT) and tamoxifen (TAM), given alone or in combination, have been simultaneously performed in women with node-negative breast cancer. We performed a pooled analysis, based on the intention to treat, of individual patient data from these 6 trials (involving 2934 patients). Data on overall survival, the primary endpoint, have been reported previously (Noguchi et al., Journal of Clinical Oncology, 2005). We now report data on relapse-free survival (median follow-up, 6.2 years). Methods: Three 3-arm randomized controlled trials (surgery alone vs. surgery plus TAM vs. surgery plus UFT) and three 4-arm randomized controlled trials (surgery alone vs. surgery plus TAM vs. surgery plus UFT vs. surgery plus TAM and UFT) were performed in women with node-negative breast cancer. The results underwent a pooled analysis. Results: The 5-year relapse-free survival rate was 87.9% with surgery alone (n = 860; risk ratio [RR], 1), 90.5% with surgery plus TAM (n = 865; RR, 0.81; confidential interval [CI], 0.60–1.11; P = 0.21), 89.9% with surgery plus UFT (n = 860; RR, 0.83; CI, 0.66–1.21; P = 0.46), and 92.7% with surgery plus UFT and TAM (n = 349; RR, 0.63; CI, 0.39–0.99; P = 0.046). Subset analysis showed that combination therapy with UFT and TAM was not effective for women with estrogen-receptor-negative breast cancer (RR, 0.90; CI, 0.46–1.75; P = 0.75), but was very effective for women with estrogen-receptor-positive breast cancer (RR, 0.39; CI, 0.19–0.79; P = 0.009). Conclusions: Our results suggest that the effectiveness of oral fluoropyrimidine derivatives is enhanced by concurrent treatment with TAM in women with node-negative breast cancer. This contrasts with the results of previous studies showing that the response to anthracycline-based chemotherapy is attenuated in patients concurrently receiving TAM. No significant financial relationships to disclose.
Premenopausal breast cancer and the association between estrogen receptor status, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin
Authors: Eng-Wong J. , Chang S. , Hursting S. , Perkins S. N. , Núñez N. , Hill H. L. , Bondy M. , Li D. , Singletary S. E. 
Published: March 2020

640 Background: The IGF pathway and leptin are associated with breast cancer risk in premenopausal women. These proteins are implicated in breast carcinogenesis through their interactions with the estrogen pathway, potentially resulting in specific breast cancer histopathologic subtypes. Methods: Pretreatment serum IGF-I, IGFBP-3 and leptin levels were examined in newly diagnosed premenopausal breast cancer cases to determine whether an association with tumor estrogen receptor status exists. Odds ratios were determined by logistic regression analysis. Likelihood ratio tests for interaction with BMI were conducted. Results: One hundred and eight women were evaluated (mean age 42); 82 were ER positive and 26 were ER negative. 62 were normal weight (BMI<25) and 46 were overweight and obese (BMI≥25). Mean IGF-I, IGFBP-3 and leptin levels did not differ between the ER positive and ER negative tumors. No associations were found between IGF-I, IGFBP-3 or leptin and ER status of tumors overall or by subset analysis in normal weight versus overweight and obese individuals. A suggestion that elevated IGFBP-3 was associated with ER-negative disease did not reach statistical significance. Additionally, normal-weight women with ER-negative disease had higher leptin levels than their normal-weight ER-positive counterparts, although we lacked statistical power to detect an effect of BMI on the association between leptin levels and tumor hormone receptor status. Conclusions: This is the first report examining the IGF pathway and leptin in relation to ER status in premenopausal women with newly diagnosed breast cancer. Our small number of cases suggests a number of intriguing findings that should be evaluated in larger studies. Determining links between ER status and IGFBP-3 and leptin may help better define risk factors and potentially appropriate interventions for ER-negative versus ER-positive breast cancer. No significant financial relationships to disclose.
Prognostic significance of HER-2/neu over-expression on the incidence of brain metastasis in newly diagnosed breast cancer
Authors: Abdulkarim B. S. , Gabos Z. , Sinha R. , Hanson J. , Chauhan N. , Hugh J. , Mackey J. 
Published: March 2020

649 Background: As systemic therapy improves, brain metastases (BM) from breast cancer are becoming increasingly evident. An increased risk of BM in HER-2/neu over-expressing metastatic breast cancer patients has been suggested. However, the relationship between HER-2/neu over-expression and the risk of BM in newly diagnosed breast cancer patients is unknown. Methods: To determine incidence of BM in HER-2/neu over-expressing breast cancer patients, a cohort of patients between 01/1998 and 12/2003 with uniform HER-2/neu testing were identified from a cancer registry. A total of 460 patients with HER-2/neu over-expression and 500 patients with HER-2/neu negative disease were reviewed. Patients were excluded if there was breast cancer diagnosed before 01/1998 or others cancer. A total of 301 HER-2/neu over-expressing and 363 HER-2/neu negative patients were included for this analysis. The association between histological features and the occurrence of BM were evaluated with univariate and multivariate analyses. Results: BM were identified in 8% (24 patients) of HER-2/neu over-expressing breast cancer patients compared to only 1.7% (6 patients) in the HER-2/neu negative patients (hazard ratio 5.15 [2.079–12.78], p=0.0001). In patients with recurrent disease, the proportion of BM for HER-2/neu over-expressing patients was 24% compared to 10% in HER-2/neu negative patients. HER-2/neu over-expression, tumor size >2cm, ≥ 4 nodes positive and grade 2/3 were predictors of BM in univariate analysis. In multivariate analysis, HER-2/neu over-expression and tumor size>2cm were an independent prognostic factors for the development of BM, while hormone receptors expressions was protective (p=0.02). Conclusions: Our population based study show that newly diagnosed HER-2/neu over-expressing breast cancer patients are at significantly increased risk for BM. As most BM occur in HER-2/neu over-expressing patients with systemic metastatic disease, these findings could prompt consideration of brain prophylaxis strategies and/or serial radiologic screening to detect asymptomatic BM. No significant financial relationships to disclose.
Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study
Authors: Druker B. J. , Guilhot F. , O’Brien S. , Larson R. A. 
Published: March 2020

6506 Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed patients (pts) with CML-CP (O’ Brien et al, NEJM 2003). 1,106 pts were randomized between June 2000 and Jan 2001 to either IM 400 mg or IFN+Ara-C with 553 pts to each treatment. This abstract is based on data collected up to 54 months after last patient had been recruited on IM. 60-months (5-year) data will be available for presentation. Methods: Evaluations included complete hematologic response (CHR), complete/partial cytogenetic response (CCyR/PCyR - defined as 0% / 1–35% Ph+ metaphases respectively), major cytogenetic response (MCyR=CCyR+ PCyR), major molecular response (MMR) - defined as ≥ 3 log reduction of BCR-ABL transcript levels from the standardized baseline, time to progression - defined as loss of CHR/MCyR, evolution to accelerated phase/blast crisis (AP/BC), or death due to any cause during treatment, and overall survival. Results: With a median follow-up of 54-months, 72% of the 553 randomized pts remain on initial IM treatment (5% of pts discontinued due to adverse events, 9.5% due to unsatisfactory therapeutic effect and 11% due to other reasons another 2.5% crossed over to IFN+Ara-C). Overall, the cumulative best response rates of CHR, MCyR and CCyR are 97%, 88% and 82%, respectively. The overall estimated survival was 90% (93% when censored at bone marrow transplant). An estimated 84% of pts have not progressed on treatment and 93% of pts were free from progression to AP/BC. The annual rate of progression to AP/BC of < 1% in the fourth year was lower than each of the first three years (1.5, 2.8, and 1.6%, respectively). Of the pts with MCyR at 12 months (n=436), an estimated 96% were free of progression to AP/BC at 54 months whereas it was only 81% for the 73 pts who did not achieve a MCyR at 12 months (p< 0.001). No patient with a MMR within 12 months progressed to AP/BC within 54 months. Conclusions: This analysis confirms the high rates and durability of responses to IM. Encouragingly, the rate of progression in the fourth year was lower than in each of the preceding three years. Results further demonstrate the beneficial effect of cytogenetic and molecular responses on long-term outcomes. [Table: see text]
Phase II clinical trial of ixabepilone in metastatic breast cancer (MBC) patients previously untreated with taxanes
Authors: Denduluri N. , Lee J. J. , Walshe J. M. , Yang S. X. , Vatas U. , Chow C. K. , Steinberg S. M. , Cox M. C. , Low J. A. , Swain S. M. 
Published: March 2020

651 Background: Ixabepilone, an epothilone B analog, stabilizes microtubules by binding to tubulin. The response rate (RR) in taxane-pretreated patients at our institution was 22%. Methods: Patients (pts) were eligible if they had MBC previously untreated with taxanes and measurable disease by RECIST criteria. Ixabepilone was given at 6mg/m2/d intravenously days 1–5 every 3 weeks until unacceptable toxicity or disease progression. Primary objectives included RR and toxicity. Pts underwent pre and/or post treatment tumor biopsies for correlative studies. Acetylated α-tubulin, Tau-1, and p53 were stained with anti-acetylated α-tubulin, anti-Tau-1, and anti-p53 antibodies in samples from 13 pts. Staining was scored quantitatively using the Automated Cellular Imaging System. Results: Twenty-three pts received 197 cycles (C). Median of 7C (range 2–22) per pt were administered. Median age was 55 (range 22–79). Seven pts received 1 prior metastatic chemotherapy regimen. Ten of 23 or 43% (exact 95% confidence interval: 23.2% to 65.5%) pts had partial responses (PR), 9 (39%) stable disease (SD) (2 unconfirmed PRs), and 4 (17%) progressive disease (PD). Median time to progression was 5.3 months; median duration of response was 5.4 months from date of best response. Four pts required dose reductions for neutropenia, neuropathy or fatigue. Grade 3/4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), infection without neutropenia (9%), motor neuropathy (4%), and muscle weakness (4%). No grade 3/4 sensory neuropathy was seen, but 35% and 13% of pts had grades 1 and 2 neuropathy respectively. Median acetylated α-tubulin at baseline was 0.2 in responders and 17.6 in non-responders (p=0.069). There were no differences in response according to Tau-1 or p53 expression at baseline. Conclusion: Ixabepilone is an effective treatment for MBC with a 43% RR in 23 pts previously untreated with taxanes. There was minimal hematologic toxicity and no grade 3 sensory neuropathy. The use of baseline level of acetylated α-tubulin to predict response may warrant further study. No significant financial relationships to disclose.