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Breast Cancer Research and Treatment

, Volume 164, Issue 3, pp 649–658 | Cite as

TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer

  • Denise A. YardleyEmail author
  • Edward R. Arrowsmith
  • Brooke R. Daniel
  • Janice Eakle
  • Adam Brufsky
  • David R. Drosick
  • Fred Kudrik
  • Linda D. Bosserman
  • Mark R. Keaton
  • Sharon A. Goble
  • Jeffrey A. Bubis
  • Victor M. Priego
  • Kelly Pendergrass
  • Yvonne Manalo
  • Martin Bury
  • Donald S. Gravenor
  • Gladys I. Rodriguez
  • Roger C. Inhorn
  • Robyn R. Young
  • William N. Harwin
  • Caryn Silver
  • John D. Hainsworth
  • Howard A. BurrisIII
Clinical Trial

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Triple-negative breast cancer Doxorubicin Cyclophosphamide Ixabepilone 

Notes

Funding

Supported in part by a grant from Bristol-Myer Squibb.

Authors contribution

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

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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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Denise A. Yardley
    • 1
    • 2
    Email author
  • Edward R. Arrowsmith
    • 1
    • 3
  • Brooke R. Daniel
    • 1
    • 3
  • Janice Eakle
    • 1
    • 4
  • Adam Brufsky
    • 5
  • David R. Drosick
    • 1
    • 6
  • Fred Kudrik
    • 1
    • 7
  • Linda D. Bosserman
    • 8
  • Mark R. Keaton
    • 9
  • Sharon A. Goble
    • 10
  • Jeffrey A. Bubis
    • 11
  • Victor M. Priego
    • 12
  • Kelly Pendergrass
    • 13
  • Yvonne Manalo
    • 14
  • Martin Bury
    • 15
  • Donald S. Gravenor
    • 16
  • Gladys I. Rodriguez
    • 17
  • Roger C. Inhorn
    • 18
  • Robyn R. Young
    • 1
    • 19
  • William N. Harwin
    • 1
    • 4
  • Caryn Silver
    • 1
    • 4
  • John D. Hainsworth
    • 1
    • 2
  • Howard A. BurrisIII
    • 1
    • 2
  1. 1.Sarah Cannon Research InstituteNashvilleUSA
  2. 2.Tennessee OncologyNashvilleUSA
  3. 3.Tennessee OncologyChattanoogaUSA
  4. 4.Florida Cancer SpecialistsFort MeyersUSA
  5. 5.University of Pittsburgh Medical CenterPittsburghUSA
  6. 6.Oncology Hematology CareCincinnatiUSA
  7. 7.South Carolina Oncology AssociatesColumbiaUSA
  8. 8.Wilshire Oncology Medical GroupLa VerneUSA
  9. 9.Augusta Oncology AssociatesAugustaUSA
  10. 10.Virginia Cancer InstituteRichmondUSA
  11. 11.ICON/Cancer Specialists of North FloridaJacksonvilleUSA
  12. 12.Center for Cancer and Blood DisorderBethesdaUSA
  13. 13.Kansas City Cancer CenterOverland ParkUSA
  14. 14.Costal Bend Cancer CenterCorpus ChristiUSA
  15. 15.Cancer Research Consortium of West MichiganGrand RapidsUSA
  16. 16.Family Cancer CenterMemphisUSA
  17. 17.South Texas Oncology HematologySan AntonioUSA
  18. 18.Mercy HospitalPortlandUSA
  19. 19.The Center for Cancer and Blood DisordersFt WorthUSA

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