Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer.
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.
Baselga
José
J
Vall d'Hebron University Hospital, Barcelona, Spain. jbaselga@vhebron.net
Zambetti
Milvia
M
Llombart-Cussac
Antoni
A
Manikhas
Georgy
G
Kubista
Ernst
E
Steger
Günther G
GG
Makhson
Anatoly
A
Tjulandin
Sergei
S
Ludwig
Heinz
H
Verrill
Mark
M
Ciruelos
Eva
E
Egyhazi
Suzanne
S
Xu
Li-An
LA
Zerba
Kim E
KE
Lee
Hyerim
H
Clark
Edwin
E
Galbraith
Susan
S
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
D000970:Antineoplastic Agents; D034261:Epothilones; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C430592:ixabepilone