Phase II Genomics Study of Ixabepilone as Neoadjuvant Treatment for Breast Cancer

Authors:
  • MZMilvia Zambetti
    Milvia Zambetti
  • ALAntoni Llombart-Cussac
    Antoni Llombart-Cussac
  • GMGeorgy Manikhas
    Georgy Manikhas
  • EKErnst Kubista
    Ernst Kubista
  • GSGünther G. Steger
    Günther G. Steger
  • AMAnatoly Makhson
    Anatoly Makhson
  • STSergei Tjulandin
    Sergei Tjulandin
  • HLHeinz Ludwig
    Heinz Ludwig
  • MVMark Verrill
    Mark Verrill
  • SESuzanne Egyhazi
    Suzanne Egyhazi
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Abstract
Purpose: 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. Patients and Methods: Patients with invasive breast cancer ≥ 3 cm were eligible. Ixabepilone 40 mg/m2 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 ≤ 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.

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