Principal Investigator

Awardee Organization

Mayo Clinic Rochester
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

TrAstuzumab Cardiomyopathy Therapeutic Intervention with Carvedilol (TACTIC) Trial

Trastuzumab, a monoclonal directed against the human epidermal growth factor (EGF) receptor-2 (HER-2), revolutionized HER-2-positive breast cancer treatment, albeit, with the therapy-limiting side effect of cardiotoxicity. We found that 40% of patients experience a left ventricular ejection fraction (LVEF) decline >10% during trastuzumab therapy, and 4% develop heart failure (HF). In 25-50% of these cases, the LVEF decline is not fully reversible, even with cardiovascular therapy. Genetic contributors to cardiac vulnerability and the best cardiovascular management strategy are unknown. A critical need exists for cardio-preventive approaches in patients at risk of trastuzumab-induced cardiotoxicity. The current application’s objective is to evaluate cardio-protective approaches using carvedilol in curative-intent trastuzumab for HER-2-positive breast cancer. Our central hypotheses are that a pre-emptive preventive approach (cardiovascular therapy with the beta-blocker carvedilol started before trastuzumab therapy), or a reactive preventive approach (cardiovascular therapy started in response to early subclinical signs of cardiac dysfunction/ injury, i.e. cardiac troponin elevation or abnormal global longitudinal strain (GLS)) will reduce cardiotoxicity compared with a standard “wait-and-see” approach (carvedilol prescribed once cardiotoxicity has occured). We furthermore hypothesize that carvedilol extension beyond the active trastuzumab treatment leads to superior outcomes and that pharmacogenomics can predict cardiotoxicity non-responsive to cardiovascular therapy with carvedilol. This clinical trial will test these hypotheses, involving 450 adult breast cancer patients beginning a year of curative-intent trastuzumab therapy, randomized to either a preemptive, a reactive, or reference care approach. This study addresses three specific study aims: Aim 1: To compare the incidence of a) HF or asymptomatic decline in LVEF by >10% in those with LVEF ≥50% or ≥5% in those with LVEF decrease to a nadir of <50% (lead primary aim #1), and b) reversible LVEF decline to within 5% of baseline (secondary primary aim #1) with a pre-emptive, reactive, and “wait-and-see” approach of carvedilol initiation in breast cancer patients over the course of adjuvant trastuzumab therapy. This aim addresses the question of initiation of cardioprotective efforts for trastuzumab therapy. Aim 2: To compare the delta change in LVEF from completion to 1 year post-completion of trastuzumab therapy between a cardioprotective approach with carvedilol confined the duration of trastuzumab therapy or extended for 1 year thereafter. This aim addresses the question of duration of cardioprotective efforts for trastuzumab therapy. Aim 3: To test the association of predefined genetic variants with change in GLS and LVEF during and after trastuzumab therapy, adjusted for treatment arm. This aim is to identify genetic variants that predict trastuzumab cardiotoxicity in general as well as lack of response (primary prevention of drop in LVEF or secondary improvement of LVEF) to carvedilol. This trial’s completion will guide clinical care in seeking the best management strategy (“tactic”) for cardio-protection in breast cancer patients undergoing trastuzumab therapy in terms of efficacy, time of initiation, and duration of treatment with the beta-blocker carvedilol.


  • Zhang D, Guo W, Al-Hijji MA, El Sabbagh A, Lewis BR, Greason K, Sandhu GS, Eleid MF, Holmes DR, Herrmann J. Outcomes of Patients With Severe Symptomatic Aortic Valve Stenosis After Chest Radiation: Transcatheter Versus Surgical Aortic Valve Replacement. Journal of the American Heart Association. 2019 May 21;8(10):e012110. PMID: 31124737
  • Lestuzzi C, Stolfo D, De Paoli A, Banzato A, Buonadonna A, Bidoli E, Tartuferi L, Viel E, De Angelis G, Lonardi S, Innocente R, Berretta M, Bergamo F, Guglielmi A, Sinagra G, Herrmann J. Cardiotoxicity from Capecitabine Chemotherapy: Prospective Study of Incidence at Rest and During Physical Exercise. The oncologist. 2022 Mar 4;27(2):e158-e167. PMID: 35641220
  • Herrmann J, Guo W, Fan X, Rihal C, Lerman A. Reply: Cancer Patient Risk After Coronary Intervention: Words of Caution in Complicated Patients. JACC. Cardiovascular interventions. 2021 Aug 23;14(16):1849. PMID: 34412805
  • Lester SC, Taparra K, Petersen MM, Funk RK, Blanchard MJ, Young PM, Herrmann J, Hunzeker AE, Schultz HL, McCollough C, Tasson AM, Leng S, Martenson JA, Deisher AJ, Whitaker TJ, Williamson EE, Laack NN. Electrocardiogram-Gated Computed Tomography with Coronary Angiography for Cardiac Substructure Delineation and Sparing in Patients with Mediastinal Lymphomas Treated with Radiation Therapy. Practical radiation oncology. 2020 Mar-Apr;10(2):104-111. Epub 2019 Nov 26. PMID: 31783172
  • Butel-Simoes LE, Haw TJ, Williams T, Sritharan S, Gadre P, Herrmann SM, Herrmann J, Ngo DTM, Sverdlov AL. Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension-Mechanisms and Mitigation. Hypertension (Dallas, Tex. : 1979). 2023 Apr;80(4):685-710. Epub 2023 Feb 9. PMID: 36756872
  • Zhu M, Chen C, Foster NR, Hartley C, Mounajjed T, Salomao MA, Fruth BF, Beamer SE, Kim Y, Harrington SM, Pitot HC, Sanhueza CT, Feng Y, Herrmann J, McWilliams RR, Lucien F, Huang BQ, Ma WW, Bekaii-Saab TS, Dong H, Wigle D, Ahn DH, Hallemeier CL, Blackmon S, Yoon HH. Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction. Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jul 15;28(14):3021-3031. PMID: 35552651
  • Herrmann J. From trends to transformation: where cardio-oncology is to make a difference. European heart journal. 2019 Dec 21;40(48):3898-3900. PMID: 31761931
  • Toya T, Sara JD, Corban MT, Taher R, Godo S, Herrmann J, Lerman LO, Lerman A. Assessment of peripheral endothelial function predicts future risk of solid-tumor cancer. European journal of preventive cardiology. 2020 Apr;27(6):608-618. Epub 2019 Oct 31. PMID: 31668110
  • Herrmann J, López-Fernández T, Lyon AR. Year in cardiovascular medicine: cardio-oncology 2020-21. European heart journal. 2022 Jan 3. Epub 2022 Jan 3. PMID: 34974609
  • Guo W, Fan X, Lewis BR, Johnson MP, Rihal CS, Lerman A, Herrmann J. Cancer Patients Have a Higher Risk of Thrombotic and Ischemic Events After Percutaneous Coronary Intervention. JACC. Cardiovascular interventions. 2021 May 24;14(10):1094-1105. PMID: 34016406
  • Archibald WJ, Rabe KG, Kabat BF, Herrmann J, Ding W, Kay NE, Kenderian SS, Muchtar E, Leis JF, Wang Y, Chanan-Khan AA, Schwager SM, Koehler AB, Fonder AL, Slager SL, Shanafelt TD, Call TG, Parikh SA. Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes. Annals of hematology. 2021 Jan;100(1):143-155. Epub 2020 Jun 1. PMID: 32488603
  • Lenihan D, Carver J, Porter C, Liu JE, Dent S, Thavendiranathan P, Mitchell JD, Nohria A, Fradley MG, Pusic I, Stockerl-Goldstein K, Blaes A, Lyon AR, Ganatra S, López-Fernández T, O'Quinn R, Minotti G, Szmit S, Cardinale D, Alvarez-Cardona J, Curigliano G, Neilan TG, Herrmann J. Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement. CA: a cancer journal for clinicians. 2020 Nov;70(6):480-504. Epub 2020 Sep 10. PMID: 32910493
  • Balanescu DV, Donisan T, Dayah T, Palaskas N, Lopez-Mattei J, Kim P, Pinnix CC, Moudgil R, Balanescu SM, Herrmann J, Cilingiroglu M, Marmagkiolis K, Iliescu C. Refractory radiation-induced coronary artery disease: mapping the path and guiding treatment with optical coherence tomography. The international journal of cardiovascular imaging. 2019 May;35(5):759-760. Epub 2019 Feb 13. PMID: 30758691
  • Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nature reviews. Cardiology. 2020 Aug;17(8):474-502. Epub 2020 Mar 30. PMID: 32231332
  • Herrmann J, Lpez-Fernndez T, Lyon AR. The year in cardiovascular medicine 2022: the top 10 papers in cardio-oncology. European heart journal. 2023 Feb 1;44(5):348-350. PMID: 36587940
  • Herrmann J. Vascular toxic effects of cancer therapies. Nature reviews. Cardiology. 2020 Aug;17(8):503-522. Epub 2020 Mar 26. PMID: 32218531
  • Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, Herrmann J, Porter C, Lyon AR, Lancellotti P, Patel A, DeCara J, Mitchell J, Harrison E, Moslehi J, Witteles R, Calabro MG, Orecchia R, de Azambuja E, Zamorano JL, Krone R, Iakobishvili Z, Carver J, Armenian S, Ky B, Cardinale D, Cipolla CM, Dent S, Jordan K, ESMO Guidelines Committee. Electronic address: Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Annals of oncology : official journal of the European Society for Medical Oncology. 2020 Feb;31(2):171-190. PMID: 31959335
  • López-Fernández T, Lyon AR, Herrmann J. 2022 ESC Guidelines on cardio-oncology: how can we improve the cardiovascular health of patients with cancer and cancer survivors? European heart journal. Cardiovascular pharmacotherapy. 2022 Dec 15;9(1):4-5. PMID: 36107817
  • Goldman A, Maor E, Bomze D, Liu JE, Herrmann J, Fein J, Steingart RM, Mahmood SS, Schaffer WL, Perales MA, Shouval R. Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy. Journal of the American College of Cardiology. 2021 Nov 2;78(18):1800-1813. PMID: 34711339
  • Brown SA, Ray JC, Herrmann J. Precision Cardio-Oncology: a Systems-Based Perspective on Cardiotoxicity of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. Journal of cardiovascular translational research. 2020 Jun;13(3):402-416. Epub 2020 Apr 6. PMID: 32253744
  • Alvarez-Cardona JA, Ray J, Carver J, Zaha V, Cheng R, Yang E, Mitchell JD, Stockerl-Goldstein K, Kondapalli L, Dent S, Arnold A, Brown SA, Leja M, Barac A, Lenihan DJ, Herrmann J, Cardio-Oncology Leadership Council. Cardio-Oncology Education and Training: JACC Council Perspectives. Journal of the American College of Cardiology. 2020 Nov 10;76(19):2267-2281. PMID: 33153587
  • Manohar S, Ghamrawi R, Chengappa M, Goksu BNB, Kottschade L, Finnes H, Dronca R, Leventakos K, Herrmann J, Herrmann SM. Acute Interstitial Nephritis and Checkpoint Inhibitor Therapy: Single Center Experience of Management and Drug Rechallenge. Kidney360. 2020 Jan 7;1(1):16-24. doi: 10.34067/KID.0000152019. eCollection 2020 Jan 30. PMID: 35372854
  • Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors. International journal of cancer. 2020 Dec 1;147(11):3160-3167. Epub 2020 Jul 16. PMID: 32449208
  • Martinez DS, Noseworthy PA, Akbilgic O, Herrmann J, Ruddy KJ, Hamid A, Maddula R, Singh A, Davis R, Gunturkun F, Jefferies JL, Brown SA. Artificial intelligence opportunities in cardio-oncology: Overview with spotlight on electrocardiography. American heart journal plus : cardiology research and practice. 2022 Mar;15. Epub 2022 Apr 1. PMID: 35721662
  • Villarraga H, Herrmann J. Cardiotoxicity assessment in breast cancer patients: is it straining? European heart journal open. 2022 Aug 29;2(4):oeac020. doi: 10.1093/ehjopen/oeac020. eCollection 2022 Jul. PMID: 36117953
  • Herrmann J. Common Vascular Toxicities of Cancer Therapies. Cardiology clinics. 2019 Nov;37(4):365-384. Epub 2019 Aug 26. PMID: 31587779
  • Totzeck M, Michel L, Lin Y, Herrmann J, Rassaf T. Cardiotoxicity from chimeric antigen receptor-T cell therapy for advanced malignancies. European heart journal. 2022 May 21;43(20):1928-1940. PMID: 35257157
  • Rajai N, Ahmad A, Toya T, Sara JD, Herrmann J, Lerman LO, Lerman A. Coronary microvascular dysfunction is an independent predictor of developing cancer in patients with non-obstructive coronary artery disease. European journal of preventive cardiology. 2023 Feb 14;30(3):209-216. PMID: 35989450
  • Safdar A, Ahmed T, Liu VY, Addoumieh A, Agha AM, Giza DE, Balanescu DV, Donisan T, Dayah T, Lopez-Mattei JC, Kim PY, Hassan S, Karimzad K, Palaskas N, Tsai JY, Iliescu GD, Yang EH, Herrmann J, Marmagkiolis K, Angelini P, Iliescu CA. Trigger related outcomes of takotsubo syndrome in a cancer population. Frontiers in cardiovascular medicine. 2022 Oct 28;9:1019284. doi: 10.3389/fcvm.2022.1019284. eCollection 2022. PMID: 36386379
  • El-Harasis MA, Hefazi M, Julakanti R, Hogan WJ, Litzow MR, Patnaik MM, Herrmann J. Cardiovascular outcomes in patients receiving myeloablative vs. reduced intensity conditioning prior to allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. Bone marrow transplantation. 2021 Feb;56(2):508-510. Epub 2020 Aug 8. PMID: 32772045
  • Layoun ME, Yang EH, Herrmann J, Iliescu CA, Lopez-Mattei JC, Marmagkiolis K, Budoff MJ, Ferencik M. Applications of Cardiac Computed Tomography in the Cardio-Oncology Population. Current treatment options in oncology. 2019 May 6;20(6):47. PMID: 31056717
  • Ruddy KJ, Sangaralingham LR, Van Houten H, Nowsheen S, Sandhu N, Moslehi J, Neuman H, Jemal A, Haddad TC, Blaes AH, Villarraga HR, Thompson C, Shah ND, Herrmann J. Utilization of Cardiac Surveillance Tests in Survivors of Breast Cancer and Lymphoma After Anthracycline-Based Chemotherapy. Circulation. Cardiovascular quality and outcomes. 2020 Mar;13(3):e005984. Epub 2020 Feb 28. PMID: 32106704
  • Marell PS, Vierkant RA, Olson JE, Herrmann J, Larson N, LeBrasseur NK, D'Andre SD, Cheville AL, Barksdale T, Loprinzi CL, Couch F, Ruddy KJ. Factors Associated With Physical Activity Levels in Patients With Breast Cancer. The oncologist. 2022 Oct 1;27(10):e811-e814. PMID: 35946834
  • Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, Carver J, Dent S, Ky B, Lyon AR, López-Fernández T, Fradley MG, Ganatra S, Curigliano G, Mitchell JD, Minotti G, Lang NN, Liu JE, Neilan TG, Nohria A, O'Quinn R, Pusic I, Porter C, Reynolds KL, Ruddy KJ, Thavendiranathan P, Valent P. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. European heart journal. 2022 Jan 31;43(4):280-299. PMID: 34904661
  • Herrmann J, McCullough KB, Habermann TM. How I treat cardiovascular complications in patients with lymphoid malignancies. Blood. 2022 Mar 10;139(10):1501-1516. PMID: 34752600
  • Park JY, Guo W, Al-Hijji M, El Sabbagh A, Begna KH, Habermann TM, Witzig TE, Lewis BR, Lerman A, Herrmann J. Acute coronary syndromes in patients with active hematologic malignancies - Incidence, management, and outcomes. International journal of cardiology. 2019 Jan 15;275:6-12. Epub 2018 Oct 5. PMID: 30318297
  • Kim JW, Dayah TJ, Javaid A, Monlezun DJ, Balanescu DV, Donisan T, Karimzad K, Hakeem A, Boone DL, Palaskas N, Lopez-Mattei J, Kim PY, Durand JB, Song J, Balanescu SM, Yang EH, Herrmann J, Marmagkiolis K, Toutouzas K, Johnson NP, Iliescu CA. Reclassification of Treatment Strategy with Fractional Flow Reserve in Cancer Patients with Coronary Artery Disease. Medicina (Kaunas, Lithuania). 2022 Jul 1;58. (7). PMID: 35888603
  • Tehrani D, Wang X, Rafique AM, Hayek SS, Herrmann J, Neilan TG, Desai P, Morgans A, Lopez-Mattei J, Parikh RV, Yang EH. Impact of Cancer and Cardiovascular Disease on In-Hospital Outcomes of COVID-19 Patients: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry. Research square. 2021 Jun 11. PMID: 34127966
  • Lyon AR, Dent S, Stanway S, Earl H, Brezden-Masley C, Cohen-Solal A, Tocchetti CG, Moslehi JJ, Groarke JD, Bergler-Klein J, Khoo V, Tan LL, Anker MS, von Haehling S, Maack C, Pudil R, Barac A, Thavendiranathan P, Ky B, Neilan TG, Belenkov Y, Rosen SD, Iakobishvili Z, Sverdlov AL, Hajjar LA, Macedo AVS, Manisty C, Ciardiello F, Farmakis D, de Boer RA, Skouri H, Suter TM, Cardinale D, Witteles RM, Fradley MG, Herrmann J, Cornell RF, Wechelaker A, Mauro MJ, Milojkovic D, de Lavallade H, Ruschitzka F, Coats AJS, Seferovic PM, Chioncel O, Thum T, Bauersachs J, Andres MS, Wright DJ, López-Fernández T, Plummer C, Lenihan D. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. European journal of heart failure. 2020 Nov;22(11):1945-1960. Epub 2020 Aug 6. PMID: 32463967
  • Owoyemi I, Vaughan LE, Costello CM, Thongprayoon C, Markovic SN, Herrmann J, Otley CC, Taner T, Mangold AR, Leung N, Herrmann SM, Kukla A. Clinical outcomes of solid organ transplant recipients with metastatic cancers who are treated with immune checkpoint inhibitors: A single-center analysis. Cancer. 2020 Nov 1;126(21):4780-4787. Epub 2020 Aug 12. PMID: 32786022
  • Ezzeddine FM, Saliba AN, Jain V, Villarraga HR, Herrmann J, Asirvatham SJ, Cha YM. Outcomes of cardiac resynchronization therapy in patients with chemotherapy-induced cardiomyopathy. Pacing and clinical electrophysiology : PACE. 2021 Apr;44(4):625-632. Epub 2021 Mar 15. PMID: 33592678
  • Hedayati E, Papakonstantinou A, Gernaat SAM, Altena R, Brand JS, Alfredsson J, Bhoo-Pathy N, Herrmann J, Linde C, Dahlstrom U, Bergh J, Hubbert L. Outcome and presentation of heart failure in breast cancer patients: findings from a Swedish register-based study. European heart journal. Quality of care & clinical outcomes. 2020 Apr 1;6(2):147-155. PMID: 31328233
  • Imanishi M, Cheng H, Kotla S, Deswal A, Le NT, Chini E, Ko KA, Samanthapudi VSK, Lee LL, Herrmann J, Xu X, Reyes-Gibby C, Yeung SJ, Schadler KL, Yusuf SW, Liao Z, Nurieva R, Amir ED, Burks JK, Palaskas NL, Cooke JP, Lin SH, Kobayashi M, Yoshimoto M, Abe JI. Radiation therapy induces immunosenescence mediated by p90RSK. Frontiers in cardiovascular medicine. 2022 Nov 7;9:988713. doi: 10.3389/fcvm.2022.988713. eCollection 2022. PMID: 36426217
  • Patel SR, Herrmann J, Vierkant RA, Olson JE, Couch FJ, Hazim A, Sloan JA, Loprinzi CL, Ruddy KJ. N-Terminal Pro Brain Natriuretic Peptide, sST2, and Galectin-3 Levels in Breast Cancer Survivors. Journal of clinical medicine. 2021 Jul 27;10. (15). PMID: 34362097
  • Ruddy KJ, Patel SR, Higgins AS, Armenian SH, Herrmann J. Cardiovascular Health during and after Cancer Therapy. Cancers. 2020 Dec 11;12. (12). PMID: 33322622

Clinical Trials

Study Name Clinical Trial ID
TrAstuzumab Cardiomyopathy Therapeutic Intervention With Carvedilol NCT03879629