TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer
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Ixabepilone is a microtubule stabilizer with activity in taxane-refractory metastatic breast cancer and low susceptibility to taxane-resistance mechanisms including multidrug-resistant phenotypes and high β-III tubulin expression. Since these resistance mechanisms are common in triple-negative breast cancer (TNBC), ixabepilone may have particular advantages in this patient population. This study evaluated the substitution of ixabepilone for paclitaxel following doxorubicin/cyclophosphamide (AC) in the adjuvant treatment of early-stage TNBC.
Patients with operable TNBC were eligible following definitive breast surgery. Patients were randomized (1:1) to receive four cycles of AC followed by either four cycles (12 weeks) of ixabepilone or 12 weekly doses of paclitaxel.
614 patients were randomized: 306 to AC/ixabepilone and 308 to AC/paclitaxel. At a median follow-up of 48 months, 59 patients had relapsed (AC/ixabepilone, 29; AC/paclitaxel, 30). The median time from diagnosis to relapse was 20.8 months. The 5-year disease-free survival (DFS) rates of the two groups were similar [HR 0.92; ixabepilone 87.1% (95% CI 82.6–90.5) vs. paclitaxel 84.7% (95% CI 79.7–88.6)]. The estimated 5-year overall survival (OS) rates were also similar [HR 1.1; ixabepilone 89.7% (95% CI 85.5–92.7) vs. paclitaxel 89.6% (95% CI 85.0–92.9)]. Peripheral neuropathy was the most common grade 3/4 event. Dose reductions and treatment discontinuations occurred more frequently during paclitaxel treatment.
Treatment with AC/ixabepilone provided similar DFS and OS in patients with operable TNBC when compared to treatment with AC/paclitaxel. The two regimens had similar toxicity, although treatment discontinuation, dose modifications, and overall peripheral neuropathy were more frequent with AC/paclitaxel. Trial registration: Clinical Trials.gov Identifier, NCT00789581.
KeywordsTriple-negative breast cancer Doxorubicin Cyclophosphamide Ixabepilone
Supported in part by a grant from Bristol-Myer Squibb.
Conception and design: DAY, LDB, JDH, and HAB III. Collection and assembly of data: ERA, BRD, JE, AB, DRD, FK, MRK, SAG, JAB, VMP, KP, YM, MB, GIR, RCI, RRY, WNH, CS, JDH, and HAB III. Data analysis and interpretation: ERA, BRD, DSG, JDH, and HAB III, Administrative support: HAB III. Provision of study materials or patients: DAY, ERA, BRD, JE, AB, LDB, VMP, KP, YM, MB, DSG, GIR, RCI, RRY, and HAB III. Manuscript writing: All authors, Final approval of manuscript (and agree to be accountable for manuscript): All authors.
Compliance with ethical standards
Conflict of interest
Denise A. Yardley is on the speaker bureau for Genentech, Eisai. Mark R. Keaton is a consultant for Biotheranostics, speaker bureau for Biotheranostics, and received travel, accommodations, expenses from Biotheranostics. Sharon A. Gobble received research funding from Bristol-Myers Squibb. Kelly Perdergrass received honoraria from Amgen, and speaker bureau of Amgen and also a consultant for AbbVie, received research funding from Amgen, and travel, accommodations, expenses from AbbVie, Amgen. Gladys I. Rodriguez received honoraria from Genentech and a speaker bureau for Genentech. All the other authors declared that they have no conflict of interest to disclose.
Research involving human and animal participants
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study. This study was conducting within the laws of the United States.
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