title: An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.
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.
  
  
  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.
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Salter
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Acharya
authors.forename: Kelli S
authors.initials: KS
authors.lastname: Walters
authors.forename: Richard
authors.initials: R
authors.lastname: Redman
authors.forename: Ariel
authors.initials: A
authors.lastname: Anguiano
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Garman
authors.forename: Carey K
authors.initials: CK
authors.lastname: Anders
authors.forename: Sayan
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Holly K
authors.initials: HK
authors.lastname: Dressman
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Marcom
authors.forename: John
authors.initials: J
authors.lastname: Olson
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nevins
authors.forename: Anil
authors.initials: A
authors.lastname: Potti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008495:Medical Oncology / Q000379:methods; D035683:MicroRNAs / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil