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An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer. Acharya, CR Anders, CK Anguiano, A Barry, WT Dressman, HK Garman, Katherine S Marcom, Kelly Mukherjee, Sayan Nevins, JR Olson, J Potti, A Redman, R Salter, KH Walters, KS
dc.coverage.spatial United States 2011-06-21T17:31:23Z 2008-04-02
dc.description.abstract BACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.
dc.language eng
dc.language.iso en_US
dc.relation.ispartof PLoS One
dc.relation.isversionof 10.1371/journal.pone.0001908
dc.subject Antineoplastic Agents
dc.subject Antineoplastic Combined Chemotherapy Protocols
dc.subject Breast Neoplasms
dc.subject Cell Line, Tumor
dc.subject Cyclophosphamide
dc.subject Doxorubicin
dc.subject Drug Screening Assays, Antitumor
dc.subject Fluorouracil
dc.subject Humans
dc.subject Medical Oncology
dc.subject MicroRNAs
dc.subject Paclitaxel
dc.subject RNA, Messenger
dc.subject Treatment Outcome
dc.title An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.
dc.type Journal article
dc.description.version Version of Record 2008-4-2
duke.description.issue 4
duke.description.volume 3
dc.relation.journal Plos One
pubs.begin-page e1908
pubs.issue 4
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Faculty
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Gastroenterology
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group School of Medicine
pubs.publication-status Published online
pubs.volume 3
dc.identifier.eissn 1932-6203

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