title: Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer.
abstract: OBJECTIVE
  This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations.
  
  
  METHODS
  Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles.
  
  
  RESULTS
  One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in <or= 3% of patients. Reversible peripheral neuropathy was experienced by 3% of patients. CONCLUSION ER, microtubule-associated protein tau, and a 10-gene PLR model that included ER were identified as predictors of ixabepilone-induced pCR.
  
  
  RESULTS
  indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain. jbaselga@vhebron.net
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Milvia
authors.initials: M
authors.lastname: Zambetti
authors.forename: Antoni
authors.initials: A
authors.lastname: Llombart-Cussac
authors.forename: Georgy
authors.initials: G
authors.lastname: Manikhas
authors.forename: Ernst
authors.initials: E
authors.lastname: Kubista
authors.forename: Günther G
authors.initials: GG
authors.lastname: Steger
authors.forename: Anatoly
authors.initials: A
authors.lastname: Makhson
authors.forename: Sergei
authors.initials: S
authors.lastname: Tjulandin
authors.forename: Heinz
authors.initials: H
authors.lastname: Ludwig
authors.forename: Mark
authors.initials: M
authors.lastname: Verrill
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.forename: Suzanne
authors.initials: S
authors.lastname: Egyhazi
authors.forename: Li-An
authors.initials: LA
authors.lastname: Xu
authors.forename: Kim E
authors.initials: KE
authors.lastname: Zerba
authors.forename: Hyerim
authors.initials: H
authors.lastname: Lee
authors.forename: Edwin
authors.initials: E
authors.lastname: Clark
authors.forename: Susan
authors.initials: S
authors.lastname: Galbraith
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D034261:Epothilones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D020360:Neoadjuvant Therapy; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C430592:ixabepilone