title: Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response.
abstract: BACKGROUND
  The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL.
  
  
  METHODS
  Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 - T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software.
  
  
  RESULTS
  When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 - T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS - T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS.
  
  
  CONCLUSIONS
  Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. mark.magbanua@ucsf.edu.|Division of Hematology/Oncology, University of California San Francisco, Box 1387, 2340 Sutter Street, San Francisco, CA, 94115, USA. mark.magbanua@ucsf.edu.
authors.forename: Mark Jesus M
authors.initials: MJ
authors.lastname: Magbanua
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. denise.wolf@ucsf.edu.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Wolf
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. cyau@buckinstitute.org.|Department of Surgery, University of California San Francisco, San Francisco, CA, USA. cyau@buckinstitute.org.|Buck Institute for Research on Aging, Novato, CA, USA. cyau@buckinstitute.org.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. sedavis4@gmail.com.|Department of Surgery, University of California San Francisco, San Francisco, CA, USA. sedavis4@gmail.com.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Davis
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. julia.r.crothers@kp.org.|Division of Hematology/Oncology, University of California San Francisco, Box 1387, 2340 Sutter Street, San Francisco, CA, 94115, USA. julia.r.crothers@kp.org.
authors.forename: Julia
authors.initials: J
authors.lastname: Crothers
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. alfred.au@ucsf.edu.|Department of Surgery, University of California San Francisco, San Francisco, CA, USA. alfred.au@ucsf.edu.
authors.forename: Alfred
authors.initials: A
authors.lastname: Au
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, CA, USA. chaqq@atarabio.com.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Haqq
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. cal@med.unc.edu.
authors.forename: Chad
authors.initials: C
authors.lastname: Livasy
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. hope.rugo@ucsf.edu.|Division of Hematology/Oncology, University of California San Francisco, Box 1387, 2340 Sutter Street, San Francisco, CA, 94115, USA. hope.rugo@ucsf.edu.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. laura.esserman@ucsf.edu.|Department of Surgery, University of California San Francisco, San Francisco, CA, USA. laura.esserman@ucsf.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Esserman
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. john.park@ucsf.edu.|Division of Hematology/Oncology, University of California San Francisco, Box 1387, 2340 Sutter Street, San Francisco, CA, 94115, USA. john.park@ucsf.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. laura.vantveer@ucsf.edu.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA. laura.vantveer@ucsf.edu.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van 't Veer
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D015398:Signal Transduction; D013997:Time Factors; D059467:Transcriptome; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen