bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential changes in tissue biomarkers after bevacizumab (BEV) alone in a neoadjuvant study of BEV and chemotherapy in ER+ breast cancer (BC) versus triple-negative breast cancer (TNBC) patients (pts).
Authors: Boucher Yves , Martin John D. , Tolaney Sara M. , Ancukiewicz Marek , Seano Giorgio , Goel Shom , Yeh Eren , Meyer Jack E , Isakoff Steven J. , Duda Dan G. , Winer Eric P. , Krop Ian E. , Jain Rakesh K. 
Published: March 2020

1065 Background: The benefit of the anti-VEGF antibody BEV—despite its confirmed activity with chemotherapy—remains unclear in BC pts. This may reflect that its benefit is limited to an unknown subset of BC pts. Methods: We previously reported the outcome and circulating biomarker data of a phase II study of neoadjuvant BEV with chemotherapy in ER+ BC and TNBC pts (NCT00546156; ASCO 2012 abstr 1026). In the present study we evaluated tissue biomarkers after 1 run-in cycle of BEV treatment alone. Patients then received BEV with standard dose-dense doxorubicin/cyclophosphamide/paclitaxel. We analyzed the changes in tissue biomarkers in ER+ BC versus TNBC pts after BEV alone and their correlation with outcome at surgery. The primary endpoint was pathologic response, measured by the Miller-Payne (MP) score (MP5=pCR). Results: Mean MP score was 3.1 for ER+ BC pts versus 4 for TNBC pts (area under ROC=0.60, P<0.001). This supports the hypothesis that the activity of BEV with chemotherapy may depend on BC subtype. In TNBCs, BEV significantly decreased mean microvascular density (MVD) by 33% (p<0.05). MVD was inversely correlated with the fraction of tissue positive for the hypoxia marker CAIX post-BEV (p<0.01). Moreover, a high pre-treatment MVD correlated with an increase in CAIX+ fraction post-BEV (p<0.05). In addition, a drop in MVD associated with increased CAIX+ fraction post-BEV (p=0.05). Finally, high (>60%) pericyte coverage post-BEV—ie, more mature vessels—was inversely correlated with CAIX+ fraction (p<0.05). MP score was more favorable for TNBC pts with lower CAIX+ fraction at baseline (p=0.058) and post-BEV (p<0.05), and higher MVD at baseline (p<0.05) and post-BEV (p<0.05). In contrast, BEV reduced MVD non-significantly by 15% in ER+ BC (p=0.25). There was no correlation between MVD and CAIX+ fraction in ER+ BCs. In contradistinction to TNBC, in ER+ BCs the fraction of CAIX+ tumor was directly correlated with MP score (p<0.01). Conclusions: Our exploratory study suggests that vascular pruning post-BEV may reduce vascular function and increase hypoxia, and reduce the effectiveness of chemotherapy in TNBC. Clinical trial information: NCT00546156.
Development and validation of a model and web application to predict 5-year distant relapse-free survival in women receiving neoadjuvant chemotherapy.
Authors: Mohiuddin Jahan , Deal Allison Mary , Drobish Amy , Cheang Maggie Chon U. , Reeder-Hayes Katherine Elizabeth , Carey Lisa A. 
Published: March 2020

1077 Background: Response to neoadjuvant chemotherapy (NAC) is an increasingly recognized intermediate marker for prognosis, but we still lack validated prognostic tools that incorporate tumor factors and response. This study aimed to create a prognostic model and nomogram for 5-year distant relapse-free survival (DRFS) and to develop a web application for providers and patients to predict the probability of distant relapse within 5 years. Methods: The prognostic model was developed using data from patients treated with NAC in the UNC Neoadjuvant Database and the Cox proportional hazards method. Patients who received NA trastuzumab were included in model data, but patients who received NA endocrine therapy were not included. The model was internally validated with bootstrap resampling, and externally validated with an independent, public data set (n=411) (Cancer Res 2011;71(24 Suppl):Abs S5-2). A web tool was developed to calculate probability of 5-year DRFS. Results: Four-hundred and seven stage I-III patients, including 106 relapse events, were used for model development. The following factors were ultimately included in the model: RCB class, age, overall grade, HER2 status, hormone receptor (HR) status, and an interaction term between age and HR status. Validation showed agreement between predicted and observed outcomes in all patients and more specifically HR+/HER2- and HR-/HER2- patients (Table). There were an insufficient number of HER2+ patient in the validation data to reliably analyze that subgroup. Conclusions: An externally validated predictive modelincorporating patient, tumor, and response variables is accurate in predicting 5-year distant relapse risk for patients undergoing NAC. The model can be conveniently accessed as an online application at www.NeoadjuvantRelapse.info for precise risk prediction. [Table: see text]
Safety and tolerability of adjuvant dose dense chemotherapy in elderly patients with node-positive early breast cancer.
Authors: Karavasilis Vasilios , Pectasides Dimitrios G. , Papadimitriou Christos A. , Gogas Helen , Kouvatseas George , Christodoulou Christos , Koutras Angelos , Pentheroudakis George E. , Linardou Helena , Razis Evangelia , Aravantinos Gerasimos , Dimopoulos Meletios A. , Fountzilas George 
Published: March 2020

1093 Background: Intensive chemotherapy confers benefit to older and younger patients with early breast cancer (BC). We aim to characterize the feasibility and toxicity profile of adjuvant dose-dense chemotherapy (ADDC) in older women with early node positive (BC). Methods: Available data from women who received ADDC for BC within three randomized trials between 1997 and 2008 were retrieved from our electronic database. These trials included HE 10/97: epirubicin and cyclophosphamide, methotrexate and fluorouracil (CMF) with or without paclitaxel, HE 10/00: epirubicin and concurrent or sequential paclitaxel and CMF and HE 10/05: a sequential three arm study of epirubicin, paclitaxel and CMF compared with epirubin, CMF and either weekly paclitaxel or docetaxel. We identified women aged >65 years and we looked at differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome. Results: From a total of 2,640 patients with a median age of 52 years, who received ADDC, we identified 453 patients (17%) > 65 years, hormonal positive in 76%, all node negative. At least 90% of the planned doses were delivered in 37% of the elderly, compared to 49% of the younger patients (p < 0.0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients compared to 21% of younger (p < 0.0001). Febrile neutropenia occurred in 4.5% of elderly patients as opposed to 2% of younger (p < 0.002). Elderly patients experienced more frequently grade 3 and 4 fatigue, mucositis and sensory neuropathy, though the incidence of these toxicities was relatively low (all p < 0.0001). Relative dose intensities were significantly lower in elderly patients, mainly affected docetaxel and paclitaxel administration. Treatment discontinuation, regardless causality, was not different in both groups. At a median follow-up of 120 months, there was no significant difference in disease free survival. Conclusions: Elderly node positive BC patients treated with ADDC derive comparable clinical benefit as younger patients, mainly in the cost of increased risk of hematological toxicity. This should be taken into account in decision making and treatment individualization in high risk BC patients.
Prognostic impact of changes in circulating tumor cells (CTC) in metastatic breast cancer (MBC).
Authors: Wallwiener Markus , Hartkopf Andreas D. , Riethdorf Sabine , Sprick Martin , Domschke Christoph Wolfram , Schott Sarah , Baccelli Irene , Modugno Caroline , Schoenfisch Birgitt , Burwinkel Barbara , Marme Frederik , Heil Joerg , Sohn Christof , Pantel Klaus , Trumpp Andreas , Schneeweiss Andreas 
Published: March 2020

11012 Background: To prospectively assess the prognostic value of CTC counts at baseline and after one cycle of therapy and their kinetics for response, progression-free (PFS), and overall survival (OS) in MBC. Methods: MBC patients underwent CTC enumeration (CellSearch, Veridex) at baseline (CTCBL), after one cycle of a new line of therapy (CTC1C), and at progression (CTCPD). CTC status was classified as negative (neg (−)) or positive (pos (+)) for <5 and ≥5 CTC/7.5 ml peripheral blood, respectively. CTC kinetics (CTCKIN) from CTCBL to CTC1C were classified as favorable if CTCs remained neg (neg>neg) or became neg (pos>neg), or as unfavorable (neg>pos or pos>pos). Tumor response was assessed every 2–3 months using RECIST criteria. CTC status and kinetics were associated with outcome using log-rank and Fisher’s exact tests. Results: Of 326 patients enrolled (median age (range) at first diagnosis: 50 (23–81) years), 115/326 (35%) were CTCBL+, 51/162 (31%) were CTC1C+, and 39/108 (36%) were CTCPD+. Median follow-up was 15.9 months (mos). Median PFS and OS were significantly reduced in CTCBL+ compared to CTCBL− patients (PFS, 4.3 vs. 7.1 mos, p = .019; OS, 15.0 mos vs. not reached (nr), p <.001) and for CTC1C+ compared to CTC1C− patients (p <.001 for PFS and OS). CTCKIN were predictive of progressive disease as best response (neg>neg, 33%; pos>neg, 38%; pos>pos, 60%; neg>pos, 75%; p = .040). PFS and OS for patients with unfavorable CTCKIN were significantly shorter than for favorable CTCKIN (PFS, 3.7 vs. 6.8 mos, p <.001; OS, 7.8 mos vs. nr, p <.001). Conclusions: CTC at baseline, CTC after one cycle and CTC kinetics are highly predictive of outcome in MBC. Serial CTC enumeration could serve as a useful adjunct to standard diagnostic tests in tailoring therapy. Further details of CTCPD will be presented at the meeting. Clinical trial information: S-295/2009.
Elevated CSF-1 serum concentrations to predict lymph node metastasis and overall survival in women with early breast cancer.
Authors: Singer Christian F. , Aharinejad Seyedhossein , Salama Mohamed , Zins Karin , Paulus Patrick , Berger Andreas 
Published: March 2020

11032 Background: Colony-stimulating factor-1 (CSF1) is a key modulator of tissue macrophages and contributes to the physiological function of the mammary gland. It has, however, also been associated with breast cancer since expression of its receptor CSF-1R is a strong predictor of poor outcome in early breast cancer and results in tumor cell invasiveness and pro-metastatic behavior in vitro. Methods: We have prospectively measured circulating CSF-1 with ELISA in 572 women with early breast cancer and in 688 women with benign breast lesions; and correlated these values with overall survival, nodal status and other clinical and histological parameters. Results: Serum CSF-1 concentrations were significantly elevated in patients with early breast cancer when compared to those with benign tumors (p<0.0001). Within breast cancer patients, CSF-1 was higher in women with involved axillary lymph nodes (p=0.04). CSF-1 concentrations were correlated with tumor size (p=0.002), age (p<0.001), and Ki67 expression (p=0.006). Log CSF-1 serum concentrations were predictive of poor survival in both univariate (HR: 3.77, CI: 1.65-8.65, p=0.002) and multivariate analyses (HR: 3.1, CI: 1.03-9.33, p=0.04). Post- but not premenopausal women with CSF-1 serum concentrations >873 pg/ml experienced a significantly poorer outcome (p=0.004 log rank test). Conclusions: CSF1 serum concentrations are elevated in women with malignant breast tumors. In early breast cancer, elevated serum CSF-1 is associated with nodal involvement, and in postmenopausal women also with poor overall survival.
Effect of nonmalignant accessory cells from the metastatic microenvironment on breast cancer cell resistance to antiestrogens.
Authors: Dhimolea Eugen , Mitsiades Constantine S. 
Published: March 2020

11039 Background: To address the role of the local metastatic microenvironment in the antiestrogen (AE) resistance exhibited by disseminated breast cancer (BrCa), we assembled heterotypic in vitro three-dimensional (3D) tissue cultures comprised of estrogen receptor-positive (ER+) BrCa cells and non-malignant accessory cells from organs frequently targeted by metastatic disease, to model the composition and architecture of metastatic lesions. Methods: MCF7 cells expressing luciferase, cultured alone or with accessory cells, were exposed to dose-ranges of hydroxytamoxifen (4-OHT), fulvestrant or raloxifene. MCF7 cells were also injected s.c. in nude mice either alone or with HS-5 bone marrow stromal cells (BMSCs). Tumor spheroid viability or xenograft growth were measured by bioluminescence. Results: MCF7 response to AEs in 3D conditions (collagen type I and/or Matrigel) was marked by acinar differentiation of tumor spheroids that resembles normal breast epithelium. Co-culture of MCF7 and immortalized accessory cells from the bone (BMSCs; HOBIT and hFOB osteoblasts), brain (SVGp12 astrocytes), liver (THLE3 hepatocytes), and lung (MRC9 fibroblasts) in 3D (but not 2D) conditions, conferred resistance to 4-OHT, raloxifene, and fulvestrant at clinically relevant doses. Heterotypic xenografts (MCF7 + BMSCs) had reduced response to tamoxifen compared with monotypic xenografts (MCF7 alone). BMSCs induced in MCF7 cells downregulation of TGFβ2; upregulation of a transcriptional signature enriched for genes associated with high-grade tumors, including genes involved in interferon response, signaling through EGFR superfamily members, NFkB and other antiapoptotic pathways; and elevated c-Myc protein levels. Exogenous TGFβ2 or neutralizing antibodies against INFγ partially re-sensitized MCF7 cells to 4-OHT in co-cultures. Conclusions: Our results indicate that accessory cells representing the microenvironment of metastatic sites confer AE resistance to BrCa cells in 3D tissue cultures and xenograft models. The mechanisms of stroma-induced AE resistance may reveal new therapeutic targets for refractory BrCa patients with metastatic disease.
Circulating tumor cells as a prognostic marker in metastatic non-small-cell lung cancer patients receiving chemotherapy.
Authors: Sakamori Yuichi , Kim Young Hak , Yoshioka Hiroshige , Hirabayashi Masataka , Onaru Koichi , Fukui Motonari , Hirata Toshiki , Mishima Michiaki 
Published: March 2020

11041 Background: Radiographic response remains the gold standard for assessment of the chemotherapy effect and has been used as a surrogate endpoint in clinical trials. Recently, circulating tumor cells (CTC) have emerged as a novel prognostic marker in many types of cancer; however, their significance has not been fully examined in patients with non-small-cell lung cancer (NSCLC). Methods: We conducted a prospective study to evaluate the clinical significance of CTC in metastatic NSCLC patients treated with chemotherapy. Peripheral blood samples were collected for CTC analysis before chemotherapy, after 1 cycle of chemotherapy, and after 2 cycles of chemotherapy. CTC analysis was performed using CellSearch (Veridex). Results: One hundred and forty-eight patients wereenrolledbetween August 2009 and January 2012, and 121 patients were eligible for the analysis. CTC was positive (CTC ≥1) in 30.6% (37/121) before chemotherapy, in 21.0% (26/118) after 1 cycle of chemotherapy, and in 21.6% (24/111) after 2 cycles of chemotherapy, respectively. CTC counts were higher in patients with N3 lymph node metastases (vs. N0-2, p = 0.0001), M1b status (vs. M1a, p = 0.0081) or ≥2 metastasis sites (vs. 1 metastasis site, p = 0.0342). Although not statistically significant, a positive trend was observed between the radiographic response and the dynamic change of CTC counts (p = 0.0734). In multivariate analysis, including the radiographic response (responder vs. non-responder), baseline CTC was a significant negative predictive factor for PFS (HR = 1.867; p = 0.0080) and OS (HR = 2.753; p = 0.0006). Considering pre- and post-treatment time points (before and after 2 cycles of chemotherapy) together, CTC-positive patients at either time point experienced significantly worse PFS (HR = 1.747; p = 0.0143) and OS (HR = 2.031; p = 0.0123) than those who were CTC negative at both time points. Conclusions: CTC was an independent prognostic factor in patients with metastatic NSCLC who was treated with chemotherapy.
Sequential monitoring of androgen receptor expression and copy number variation in castration-resistant prostate cancer (CRPC).
Authors: Gross Mitchell E. , Agus David B. , Dorff Tanya B. , Pinski Jacek K. , Quinn David I. , Dago Angel E , Stepansky Asya , Carlsson Anders , Felch Natalie , Luttgen Madelyn , Kolatkar Anand , Hicks James B , Kuhn Peter 
Published: March 2020

11047 Background: The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to identify and characterize CTCs. Here, we utilized the HD-CTC assay to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential samples obtained from patients with CRPC treated with abiraterone acetate (AA). Methods: Patients were approached for participation in a study to provide peripheral blood at baseline, at 2-5 weeks, and at 9-12 weeks (or at progression). In each sample, 106cells (defined with a DAPI-intact nucleus) were quantitatively examined for the presence of cytokeratin and AR (CTCs) and CD45 (leukocytes). Initial results are available from 9 subjects treated with AA as standard of care. Results: At baseline, the median (range) CTC was 7.8 (1.1-57.2) cells/ml. Using a definition of AR positive (AR+) as >6 standard deviations over mean signal observed in leukocytes, the median (range) of AR+ and total CTCs observed at baseline were 3.1(0-33.8) and 7.8 (1.1-57.2) cells/ml, respectively. Detailed single-nucleus CNV analysis was performed in sequential samples in a single subject (Table). Complex genomic rearrangements were observed including AR amplification and 8p deletion in both AR+ and AR- negative (AR-) cells at baseline. During AA treatment, the frequency of AR+ CTCs decreased along with changes in the CNV pattern including loss of AR amplification. At 10 weeks, disease progression occurred coincident with re-emergence of an AR+ CTC population exhibiting AR amplification and a novel CNV pattern only distantly related to that of the baseline CTCs. While multiple complex abnormalities were noted, MYC amplification was observed at higher frequency in cells present at progression. Conclusions: Overall, our results demonstrate the feasibility of monitoring of CTCs for treatment emergent changes in protein which may be used to better monitoring and predict therapeutic responses in patients with metastatic cancer. [Table: see text]
Detection and genomic interrogation of invasive circulating tumor cells (iCTCs) derived from men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Friedlander Terence W. , Weinberg Vivian K. , Roy Ritu , Ngo Vy , Dong Huang , Doty Shaun , Zhao Qiang , Premasekharan Gayatri , Gilbert Elizabeth , Ryan Charles J. , Chen Wen-Tien , Paris Pamela 
Published: March 2020

11048 Background: Isolation, enumeration, and genomic profiling of CRPC CTCs offers the potential to discover genetic changes that occur in advanced disease. The Vitatex VitaCap platform captures CTCs based on their ability to invade a collagenous matrix (CAM), allows for capture of invasive CTCs (iCTCs) independent of EpCAM status, and yields viable cells suitable for comprehensive genomic study. Here we sought to compare CTC yields between the CAM and CellSearch platforms, to determine the utility of prostate-specific membrane antigen (PSMA) as an iCTC biomarker, to identify iCTC clusters and iCTCs expressing stem-like markers, and to explore the feasibility of iCTC epigenomic analysis. Methods: CTCs were isolated and enumerated simultaneously using the CellSearch and CAM platforms in 23 men with mCRPC. CAM-isolated iCTCs were defined as EpCAM+PSMA+ and were enumerated immunocytochemically (ICC) and by flow cytometry. iCTC clusters were enumerated by ICC. The Illumina Infinium HumanMethylation27 BeadChip was used to determine whole genome methylation status for CAM isolated cells. Results: 35 samples were collected for CAM analysis. A median of 27 (range 0-800) and 23 (range 2-390) iCTCs/ml were detected by ICC and flow respectively. In a subset of 20 samples, a median of 7 CTCs/ml (range 0-85) were detected by the CellSearch platform. CTCs were detectable by either CAM or CellSearch in >95% of samples. iCTC clusters were observed in 23% of samples with a median 7 clusters/ml (range 1-200). iCTCs expressing stem-like markers CD44 and Seprase were detected in 70% and 97% of samples by ICC and flow respectively, with a median of 9/ml (range 1-264) by flow. The iCTC methylation profile highly resembled mCRPC. Conclusions: The CAM and CellSearch platforms yield comparable CTC counts. iCTC clusters and iCTCs expressing stem-like markers are detectable using the CAM platform, and the iCTC methylome closely resembles that of mCRPC. Correlation with clinical data may yield further insight into the functional significance of these findings.
Clinical significance of BIM deletion polymorphism in non-small cell lung cancer with epidermal growth factor receptor mutation.
Authors: Isobe Kazutoshi , Hata Yoshinobu , Kaburaki Kyohei , Kobayashi Hiroshi , Sugino Keishi , Sakamoto Susumu , Tochigi Naobumi , Takai Yujiro , Shibuya Kazutoshi , Takagi Keigo , Homma Sakae 
Published: March 2020

11052 Background: Germ line alterations in the proapoptotic protein BCL2-like 11 (BIM) can have a crucial role in how a tumor responds to treatment. To clarify the clinical usefulness of detecting BIM deletion polymorphism in non-small cell lung cancer (NSCLC) with positive epidermal growth factor receptor (EGFR) mutation we examined the prognosis in patients with or without the BIM changes. Methods: Seventy NSCLC patients with positive EGFR mutation treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) between January 2008 and January 2013 were enrolled in this study. BIM deletion polymorphism was analyzed by PCR in 58 peripheral blood samples, 24 formalin-fixed paraffin-embedded (FFPE) slides of surgical specimens (lung tissue in 20, brain tissue in 4), and 12 samples that included both blood and tissue specimens. We performed retrospective analyses on clinical characteristics, response rate and toxicity of EGFR-TKI, and estimated the prognosis in patients with or without BIM deletion polymorphism. Results: BIM deletion polymorphism was present in 13 of 70 patients (18.6%) with homozygous deletion in 1 and heterozygous deletion in 12. There was no discordance between the two types of samples among the 12 patients. There were no significant differences between patients with or without BIM deletion polymorphism on clinical characteristics, response rate to EGFR-TKI and incidence of EGFR-TKI toxicity. Patients with BIM deletion polymorphism showed significantly shorter PFS that in patients without BIM deletion polymorphism (median: 216 days vs. 430 days, p < 0.001). There was no significant difference in OS. In multivariate analyses using the Cox regression model, BIM deletion polymorphism (hazard ratio = 4.2, p< 0.001, 95% CI = 2.026-8.777) was identified as an independent factor for shorter PFS. Conclusions: BIM deletion polymorphism could be detected by PCR on peripheral blood samples and FFPE slides of surgical specimens. BIM deletion polymorphism has emerged as an independent prognostic factor for shorter PFS. Therefore, new treatment strategies should be established for patients with BIM deletion polymorphism.