title: Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031.
abstract: OBJECTIVE
  Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations.
  
  
  METHODS
  Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis.
  
  
  RESULTS
  On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004).
  
  
  CONCLUSIONS
  Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.
authors.affiliation: Siteman Cancer Center, Washington University in St Louis, 660 South Euclid Avenue, St Louis, MO 63110, USA. mellis@dom.wustl.edu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Snider
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.forename: Katherine
authors.initials: K
authors.lastname: DeSchryver
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
authors.forename: Gary W
authors.initials: GW
authors.lastname: Unzeitig
authors.forename: Julie
authors.initials: J
authors.lastname: Margenthaler
authors.forename: Gildy V
authors.initials: GV
authors.lastname: Babiera
authors.forename: P Kelly
authors.initials: PK
authors.lastname: Marcom
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Guenther
authors.forename: Mark A
authors.initials: MA
authors.lastname: Watson
authors.forename: Marilyn
authors.initials: M
authors.lastname: Leitch
authors.forename: Kelly
authors.initials: K
authors.lastname: Hunt
authors.forename: John A
authors.initials: JA
authors.lastname: Olson
mesh_terms: D000077384:Anastrozole; D000730:Androstadienes / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D000077289:Letrozole; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009570:Nitriles / Q000627:therapeutic use; D017698:Postmenopause; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis*; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole; D000077289:Letrozole; C056516:exemestane