Dataset Information

A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

ABSTRACT: Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs.

SUBMITTER: Blau CA

PROVIDER: S-EPMC4970582 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

Blau C Anthony CA Ramirez Arturo B AB Blau Sibel S Pritchard Colin C CC Dorschner Michael O MO Schmechel Stephen C SC Martins Timothy J TJ Mahen Elisabeth M EM Burton Kimberly A KA Komashko Vitalina M VM Radenbaugh Amie J AJ Dougherty Katy K Thomas Anju A Miller Christopher P CP Annis James J Fromm Jonathan R JR Song Chaozhong C Chang Elizabeth E Howard Kellie K Austin Sharon S Schmidt Rodney A RA Linenberger Michael L ML Becker Pamela S PS Senecal Francis M FM Mecham Brigham H BH Lee Su-In SI Madan Anup A Ronen Roy R Dutkowski Janusz J Heimfeld Shelly S Wood Brent L BL Stilwell Jackie L JL Kaldjian Eric P EP Haussler David D Zhu Jingchun J

Journal of the National Comprehensive Cancer Network : JNCCN 20160101 1

Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifi ...[more]

PMID: 26733551

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Project description:A novel, highly selective biomarker is urgently needed to predict and monitor triple-negative breast cancer (TNBC) because targeting molecules are not currently available. Although associated with various malignant tumors, the role of toll-like receptor 5 (TLR5) in TNBC remains uncertain. We aimed to define the effects of TLR5 in TNBC to determine whether it could serve as a prognostic and monitoring indicator for TNBC. We established TNBC cell line 4T1 with low TLR5 expression (GFP tag; TLR5- 4T1) and with normal TLR5 expression (GFP tag; TLR5+ 4T1) using lentivirus-shRNA-TLR5 knockdown transfection and negative lentivirus transfection, respectively. Detected by western blot and qPCR, we found knockdown of TLR5 resulted in decreased expression of TLR5 and E-cadherin and increased expression of N-cadherin, vimentin, fibronectin, TRAF6, SOX2, and Twist1, which were related to EMT (epithelial-mesenchymal transition). In addition, downregulation of TLR5 increased the invasion and migration of 4T1 cells in vitro, which were investigated by CCK-8 and wound healing, as well as transwell assay and colony formation. Furthermore, the metastatic ability of TLR5- 4T1 cells to the lungs was also increased compared to TLR5+ 4T1 cells in vivo. To verify the effect of TLR5 as a monitor indicator, mice bearing TLR5+ and TLR5- 4T1 tumors injected with 125I-anti-TLR5 mAb or isotype 125I-IgG were assessed by whole body phosphor-autoradiography and fluorescence imaging in vivo. Phosphor-autoradiography of model mice revealed early tumors at 6 days after inoculation with TLR5+ 4T1, but not TLR5- 4T1 cells. Intratumoral accumulation of radioactivity positively correlated with TLR5 expression, and fluorescence imaging in vivo revealed both TLR5+ and TLR5- 4T1 tumors. Our results suggested that downregulation of TLR5 in TNBC increased tumor invasiveness and EMT expression via TRAF6 and SOX2 pathway and TLR5 could serve as a prognostic and monitoring indicator for TLR5-positive tumors.

Project description:BACKGROUND:Chemotherapy resistance is a great obstacle in effective treatment for metastatic triple negative breast cancer (TNBC). The ability to predict chemotherapy response would allow chemotherapy administration to be directed toward only those patients who would benefit, thus maximizing treatment efficiency. Differentially expressed plasma proteins may serve as putative biomarkers for predicting chemotherapy outcomes. PATIENTS AND METHODS:In this study, 26 plasma samples (10 samples with partial response (S) and 16 samples with progression disease (R)) from patients with metastatic TNBC were measured by Tandem Mass Tag (TMT)-based proteomics analysis to identify differentially expressed proteins between the S and R group. Potential proteinswere validated with enzyme-linked immunosorbent assay (ELISA) in another 67 plasma samples. RESULTS:A total of 320 plasma proteins were identified, and statistical analysis showed that 108 proteins were significantly dysregulated between R and S groups in the screening stage. Bioinformatics revealed relevant pathways and regulatory networks of the differentially expressed proteins. Three differentially expressed proteins were validated by ELISA with 67 samples from TNBC patients. The R group had significantly higher plasma CAMK2A level than the S group (P=0.0074). The ROC curve analysis showed an AUC of 0.708, with sensitivity 48.4% and specificity 86.1%. In multivariate logistic regression analysis, the level of plasma CAMK2A was also significant for chemotherapeutic response (P=0.009, OR=0.152). Furthermore, the patients with higher CAMK2A level had shorter OS than those with lower CAMK2A level, which amounted to 13.9 and 28.9 months, respectively (P=0.034). In the multivariate Cox regression analysis, CAMK2A level still had significant effect on OS (P=0.031, HR=1.865). CONCLUSION:TMT-based proteomic analysis was able to identify potential biomarkers in plasma that predicted chemotherapy resistance in the metastatic TNBC. The plasma of CAMK2A level may serve as apotential predictive and prognostic biomarker for chemotherapy in metastatic TNBC.

Dataset Information

A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

Publications

A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

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