Annelies H Boekhout1, Jourik A Gietema2, Bojana Milojkovic Kerklaan1, Erik D van Werkhoven3, Renske Altena2, Aafke Honkoop4, Maartje Los5, Willem M Smit6, Peter Nieboer7, Carolien H Smorenburg8, Caroline M P W Mandigers9, Agnes J van der Wouw10, Lonneke Kessels11, Annette W G van der Velden12, Petronella B Ottevanger13, Tineke Smilde14, Jaap de Boer15, Dirk J van Veldhuisen16, Ido P Kema17, Elisabeth G E de Vries2, Jan H M Schellens18. 1. Division of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands. 2. Department of Medical Oncology University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 3. Biometrics Department, Netherlands Cancer Institute, Amsterdam, the Netherlands. 4. Department of Internal Medicine, Isala Clinics, Zwolle, the Netherlands. 5. Department of Internal Medicine, Antonius Hospital, Nieuwegein, the Netherlands. 6. Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands. 7. Department of Internal Medicine, Wilhelmina Hospital, Assen, the Netherlands. 8. Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, the Netherlands. 9. Department of Internal Medicine, Canisius Wilhemina Hospital, Nijmegen, the Netherlands. 10. Department of Internal Medicine, VieCuri Medical Center Noord-Limburg, Venlo, the Netherlands. 11. Department of Internal Medicine, Deventer Hospital, Deventer, the Netherlands. 12. Department of Internal Medicine, Martini Hospital, Groningen, the Netherlands. 13. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. 14. Department of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, the Netherlands. 15. Department of Internal Medicine, Hospital de Tjongerschans, Heerenveen, the Netherlands. 16. Department of Cardiology, University Medical Center Groningen, the Netherlands. 17. Department of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 18. Division of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands18Department of Pharmaceutical Sciences, Science Faculty Utrecht University, Utrecht, the Netherlands.
Abstract
IMPORTANCE: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%. DESIGN: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab. INTERVENTIONS: A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS: A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003). CONCLUSIONS AND RELEVANCE: The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00459771.
RCT Entities:
IMPORTANCE: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%. DESIGN: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for humanepidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab. INTERVENTIONS: A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS: A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003). CONCLUSIONS AND RELEVANCE: The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00459771.
Authors: Filipa Lynce; Ana Barac; Ming T Tan; Federico M Asch; Karen L Smith; Chau Dang; Claudine Isaacs; Sandra M Swain Journal: Oncologist Date: 2017-03-17
Authors: Kelly C Gast; Paul V Viscuse; Somaira Nowsheen; Tufia C Haddad; Robert W Mutter; Andrea E Wahner Hendrickson; Fergus J Couch; Kathryn J Ruddy Journal: Curr Treat Options Cardiovasc Med Date: 2018-03-01