title: Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity.
abstract: Purpose The primary toxicity of trastuzumab therapy for human epidermal growth factor receptor 2-overexpressing (HER2-positive) breast cancer is dose-independent cardiac dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. We hypothesized that angiotensin-converting enzyme inhibitors and β-blockers could prevent trastuzumab-related cardiotoxicity. Patients and Methods In this double-blinded, placebo-controlled trial, patients with HER2-positive early breast cancer were randomly assigned to receive treatment with perindopril, bisoprolol, or placebo (1:1:1) for the duration of trastuzumab adjuvant therapy. Patients underwent cardiac magnetic resonance imaging at baseline and post-cycle 17 for the determination of left ventricular volumes and left ventricular ejection fraction (LVEF). Cardiotoxicity was evaluated as the change in indexed left ventricular end diastolic volume and LVEF. Results Thirty-three patients received perindopril, 31 received bisoprolol, and 30 received placebo. Baseline demographic, cancer, and cardiovascular profiles were similar between groups. Study drugs were well tolerated with no serious adverse events. After 17 cycles of trastuzumab, indexed left ventricular end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36). In secondary analyses, trastuzumab-mediated decline in LVEF was attenuated in bisoprolol-treated patients (-1 ± 5%) relative to the perindopril (-3 ± 4%) and placebo (-5 ± 5%) groups ( P = .001). Perindopril and bisoprolol use were independent predictors of maintained LVEF on multivariable analysis. Conclusion Perindopril and bisoprolol were well tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy-related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling-the primary outcome-was not prevented by these pharmacotherapies.
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Pituskin
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Sheri
authors.initials: S
authors.lastname: Koshman
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Davinder
authors.initials: D
authors.lastname: Jassal
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Marshall
authors.initials: M
authors.lastname: Pitz
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Haykowsky
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Pagano
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Chow
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Thompson
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Larissa J
authors.initials: LJ
authors.lastname: Vos
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Ezekowitz
authors.affiliation: Edith Pituskin John R. Mackey, Sheri Koshman, Mark J. Haykowsky, Joseph J. Pagano, Kelvin Chow, Richard B. Thompson, Larissa J. Vos, Sunita Ghosh, Gavin Y. Oudit, Justin A. Ezekowitz, and D. Ian Paterson, University of Alberta, Edmonton, Alberta; and Davinder Jassal and Marshall Pitz, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: D Ian
authors.initials: DI
authors.lastname: Paterson
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D017298:Bisoprolol / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D066126:Cardiotoxicity / Q000000981:diagnostic imaging / Q000209:etiology* / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D020913:Perindopril / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases; D013318:Stroke Volume / Q000187:drug effects; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D017298:Bisoprolol; D020913:Perindopril; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human