title: TLE3 as a candidate biomarker of response to taxane therapy.
abstract: BACKGROUND
  The addition of taxanes (Ts) to chemotherapeutic regimens has not demonstrated a consistent benefit in early-stage breast cancer. To date, no clinically relevant biomarkers that predict T response have been identified.
  
  
  METHODS
  A dataset of immunohistochemistry stains in 411 patients was mined to identify potential markers of response. TLE3 emerged as a candidate marker for T response. To test the association with T sensitivity, an independent 'triple-negative' (TN) validation cohort was stained with anti-TLE3 antibody.
  
  
  RESULTS
  TLE3 staining was associated with improved 5-year disease-free interval (DFI) in the overall cohort (n = 441, P < 0.004), in patients treated with cyclophosphamide (C), methotrexate, and 5-fluorouracil (n = 72, P < 0.02), and in those treated with regimens containing doxorubicin (A) and a T (n = 65, P < 0.04). However, no association was shown with outcome in untreated patients (n = 203, P = 0.49) or those treated with a regimen containing A only (n = 66, P = 0.97). In the TN cohort, TLE3 staining was significantly associated with improved 5-year DFI in all patients (n = 81, P < 0.015), in patients treated with AC + T (n = 45, P < 0.02), but not in patients treated with AC (n = 17, P = 0.81). TLE3 was independent of tumor size, nodal status, and grade by bivariable analysis in both cohorts.
  
  
  CONCLUSIONS
  TLE3 staining is associated with improved DFI in T-treated patients in two independent cohorts. Since the validation study was performed in a TN cohort, TLE3 is not serving as a surrogate for estrogen receptor or HER2 expression. TLE3 should be studied in large clinical trial cohorts to establish its role in T chemotherapy selection.
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. swati.kulkarni@roswellpark.org
authors.forename: Swati A
authors.initials: SA
authors.lastname: Kulkarni
authors.forename: David G
authors.initials: DG
authors.lastname: Hicks
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Watroba
authors.forename: Christine
authors.initials: C
authors.lastname: Murekeyisoni
authors.forename: Helena
authors.initials: H
authors.lastname: Hwang
authors.forename: Thaer
authors.initials: T
authors.lastname: Khoury
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Beck
authors.forename: Brian Z
authors.initials: BZ
authors.lastname: Ring
authors.forename: Noel C
authors.initials: NC
authors.lastname: Estopinal
authors.forename: Marshall T
authors.initials: MT
authors.lastname: Schreeder
authors.forename: Robert S
authors.initials: RS
authors.lastname: Seitz
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Ross
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012097:Repressor Proteins; C116694:TLE2 protein, human