Publications by authors named "Thomas M Suter"

45 Publications

Trastuzumab Emtansine Plus Non-Pegylated Liposomal Doxorubicin in HER2-Positive Metastatic Breast Cancer (Thelma): A Single-Arm, Multicenter, Phase Ib Trial.

Cancers (Basel) 2020 Nov 25;12(12). Epub 2020 Nov 25.

Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ 07450, USA.

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.
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http://dx.doi.org/10.3390/cancers12123509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760511PMC
November 2020

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

N Engl J Med 2021 01 13;384(2):105-116. Epub 2020 Nov 13.

From the Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco (J.R.T.), Amgen, Thousand Oaks (L.S., J.C.L., N.H., S.A.A., C.E.K.), and Cytokinetics, South San Francisco (F.I.M.) - all in California; Estudios Clínicos Latino América, Rosario, Argentina (R.D.); the Division of Cardiology, Duke University School of Medicine and Duke Clinical Research Institute, Durham (G.M.F.), and the University of North Carolina, Chapel Hill (K.F.A.) - both in North Carolina; the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics and Clinical Trials, Institute of Health and Wellbeing (J.G.F.C.), University of Glasgow, Glasgow, and the National Heart and Lung Institute, Imperial College, London (J.G.F.C.) - both in the United Kingdom; Cardiology, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy (M.M.); the Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (S.D.S.); the University of Minnesota, Minneapolis (I.A.); Instituto Nacional de Cardiología, Mexico City (A.A.-M.); the Department of Cardiology, Herlev and Gentofte Hospital, and the Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (T.B.-S.); Saarland University, Universitätsklinikum des Saarlandes, Homburg, Germany (M.B.); Medical University of Vienna, Vienna (D.B.); Pontificia Universidad Católica de Chile, Santiago (R.C.); Complexo Hospitalario Universitario A Coruña, Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares, Instituto de Investigación Biomédica de A Coruña, Universidade da Coruña, A Coruña, Spain (M.G.C.-L.); the Departments of Cardiology and Health, Medicine and Caring Sciences, Linkoping University, Linkoping, Sweden (U.D.); Fundación Cardiovascular de Colombia, Floridablanca, Colombia (L.E.E.); University of Utah, Salt Lake City (J.C.F.); National and Kapodistrian University of Athens, Attikon University Hospital, Athens (G.F.); Hospital S. Francisco Xavier, Centro Hospitalar Lisboa Ocidental, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal (C.F.); Commenius University, Bratislava, Slovakia (E.G.); the Department of Cardiology, Queen Giovanna University Hospital and Medical University, Sofia, Bulgaria (A.R.G.); Libin Cardiovascular Institute and Cumming School of Medicine, University of Calgary, Calgary, AB (J.G.H.), and Montreal Heart Institute and Université de Montréal, Montreal (E.O.) - both in Canada; the Heart and Vascular Institute, Henry Ford Hospital, Detroit (D.E.L.); the National Clinical Research Center for Cardiovascular Diseases, National Health Commission Key Laboratory of Clinical Research for Cardiovascular Medications, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (J.L.); Middlemore Hospital, Otahuhu, Auckland, New Zealand (M.L.); St. Vincent's Hospital Sydney, Darlinghurst, NSW, Australia (P.M.); University Clinic of Lomonosov, Moscow State University, Moscow (V.M.); Saitama Citizens Medical Center, Saitama, Japan (S.M.); Institute of Cardiology, Kyiv, Ukraine (A.P.); Wroclaw Medical University, Wroclaw, Poland (P.P.); Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo (F.J.A.R.); Vilnius University, Vilnius, Lithuania (P.S.); the University of Cape Town, Cape Town, South Africa (K.S.); the Internal Cardiology Department, St. Ann Hospital and Masaryk University Brno, Brno, Czech Republic (J.S.); the Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (T.M.S.); St. John of God Hospital, Budapest, Hungary (J.T.); AZ Sint-Lucas, Ghent, Belgium (H.V.); the University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital, Bucharest, Romania (D.V.); the University of Groningen, Groningen, the Netherlands (A.A.V.); Dokuz Eylul University, Izmir, Turkey (M.B.Y.); and Université de Lorraine, INSERM Investigation Network Initiative Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Régional Universitaire de Nancy, Nancy (F.Z.), and Servier, Suresnes (C.V.) - both in France.

Background: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown.

Methods: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes.

Results: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups.

Conclusions: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).
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http://dx.doi.org/10.1056/NEJMoa2025797DOI Listing
January 2021

Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology.

Eur J Heart Fail 2020 11 20;22(11):1966-1983. Epub 2020 Oct 20.

Cardio-Oncology Service, Royal Brompton Hospital and Imperial College London, London, UK.

Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed.
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http://dx.doi.org/10.1002/ejhf.2017DOI Listing
November 2020

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials.

Eur J Heart Fail 2020 11 27;22(11):2160-2171. Epub 2020 Oct 27.

Amgen, Inc., Thousand Oaks, CA, USA.

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials.

Methods And Results: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594).

Conclusions: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.
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http://dx.doi.org/10.1002/ejhf.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756903PMC
November 2020

The cancer patient and cardiology.

Eur J Heart Fail 2020 12 2;22(12):2290-2309. Epub 2020 Oct 2.

Campus Bio-Medico University School of Medicine, Rome, Italy.

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and management, and long-term follow-up strategies for patients at risk of cancer therapy-related cardiotoxicities. Research to better define strategies for early identification, follow-up and management is highly necessary. Although the academic cardio-oncology community may be the best vehicle to foster awareness and research in this field, additional stakeholders (industry, government agencies and patient organizations) must be involved to facilitate cross-discipline interactions and help in the design and funding of cardio-oncology trials. The overarching goals of cardio-oncology are to assist clinicians in providing optimal care for patients with cancer and cancer survivors, to provide insight into future areas of research and to search for collaborations with industry, funding bodies and patient advocates. However, many unmet needs remain. This document is the product of brainstorming presentations and active discussions held at the Cardiovascular Round Table workshop organized in January 2020 by the European Society of Cardiology.
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http://dx.doi.org/10.1002/ejhf.1985DOI Listing
December 2020

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.

Eur J Heart Fail 2020 11 6;22(11):1945-1960. Epub 2020 Aug 6.

Cardio-Oncology Center of Excellence, Washington University in St Louis, St Louis, MO, USA.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.
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http://dx.doi.org/10.1002/ejhf.1920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019326PMC
November 2020

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids.

Front Mol Biosci 2020 14;7:14. Epub 2020 Feb 14.

Cardiology Department, DBMR MEM C812, Bern University Hospital, Bern, Switzerland.

Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions. Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR). Spheroids formed in hanging drops or in non-adhesive wells showed spontaneous contractions for at least 1 month with frequent media changes. SEM of mechanically opened spheroids revealed a dense inner structure and no signs of blebbing. TEM of co-culture spheroids at 1 month showed myofibrils, intercalated disc-like structures and mitochondria. Ultrastructural features were comparable to fetal human myocardium. We then assessed immunostained 2D cultures, cryosections of spheroids, and whole-mount preparations by confocal microscopy. CF in co-culture spheroids assumed a small size and shape similar to the situation in ventricular tissue. Spheroids made only of CF and cultured for 3 weeks showed no stress fibers and strongly reduced amounts of alpha smooth muscle actin compared to early spheroids and 2D cultures as shown by confocal microscopy, western blotting, and qPCR. The addition of CF to cardiac spheroids did not lead to arrhythmogenic effects as measured by sharp-electrode electrophysiology. Video motion analysis showed a faster spontaneous contraction rate in co-culture spheroids compared to pure hiPSC-CMs, but similar contraction amplitudes and kinetics. Spontaneous contraction rates were not dependent on spheroid size. Applying increasing pacing frequencies resulted in decreasing contraction amplitudes without positive staircase effect. Gene expression analysis of selected cytoskeleton and myofibrillar proteins showed more tissue-like expression patterns in co-culture spheroids than with cardiomyocytes alone or in 2D culture. We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.
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http://dx.doi.org/10.3389/fmolb.2020.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033479PMC
February 2020

Cardio-oncology in clinical studies and real life.

Semin Oncol 2019 12 18;46(6):421-425. Epub 2019 Nov 18.

University Campus Bio-Medico, Rome, Italy. Electronic address:

Session V of the Colloquium was chaired by Professors Teresa López-Fernández of Spain and Grzegorz Opolski of Poland. The 3 speakers addressed cardio-oncology issues as they relate to both clinical studies and real life situations. Professor Susan Dent discussed cardio-oncology networks for patients, emphasizing the importance of establishing a framework where the expertise of the cardiology consultant can supplement and reinforce the goals of optimal cancer therapy. Professor Thomas Suter moved the discussion further, sharing his insight into cardiac monitoring in clinical trials, emphasizing the lack of uniform criteria and lack of consensus regarding reversibility of cardiac events and long-term implications of modest declines in systolic function frequently found in clinical trials for which long-term follow-up may not be a component of the trial. Professor Giorgio Minotti added important considerations to the discussion of clinical trials. He emphasized that the usual reporting of cardiac systolic function omits important diastolic dysfunction data generated but often ignored during the routine cardiac exams. The inclusion of cardiac biomarker changes would also help to broaden the perspective of cardiac effects and events seen in patients enrolled in clinical trials.
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http://dx.doi.org/10.1053/j.seminoncol.2019.01.004DOI Listing
December 2019

Cardio-Oncology Services: rationale, organization, and implementation.

Eur Heart J 2019 06;40(22):1756-1763

Cardiologist in Practice, Corso Venezia 10, Turin, Italy.

Aims: Anticancer therapies have extended the lives of millions of patients with malignancies, but for some this benefit is tempered by adverse cardiovascular (CV) effects. Cardiotoxicity may occur early or late after treatment initiation or termination. The extent of this cardiotoxicity is variable, depending on the type of drug used, combination with other drugs, mediastinal radiotherapy, the presence of CV risk factors, and comorbidities. A recent position paper from the European Society of Cardiology addressed the management of CV monitoring and management of patients treated for cancer.

Methods And Results: The current document is focused on the basis of the Cardio-Oncology (C-O) Services, presenting their rationale, organization, and implementation. C-O Services address the spectrum of prevention, detection, monitoring, and treatment of cancer patients at risk of cardiotoxicity and/or with concomitant CV diseases. These services require a multidisciplinary approach, with the aims of promoting CV health and facilitating the most effective cancer therapy.

Conclusion: The expected growing volume of patients with cancer at risk of developing/worsening CV disease, the advent of new technological opportunities to refine diagnosis, and the necessity of early recognition of cancer therapy-related toxicity mandate an integrative multidisciplinary approach and care in a specialized environment. This document from the ESC Cardio-Oncology council proposes the grounds for creating C-O Services in Europe based on expert opinion.
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http://dx.doi.org/10.1093/eurheartj/ehy453DOI Listing
June 2019

Characterization of cytoskeleton features and maturation status of cultured human iPSC-derived cardiomyocytes.

Eur J Histochem 2017 Jun 21;61(2):2763. Epub 2017 Jun 21.

University Hospital Bern, Cardiology Department.

Recent innovations in stem cell technologies and the availability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have opened new possibilities for studies and drug testing on human cardiomyocytes in vitro. Still, there are concerns about the precise nature of such 'reprogrammed' cells. We have performed an investigation using immunocytochemistry and confocal microscopy on several cellular features using commercially available hiPSC-CMs. For some selected developmentally regulated or cardiac chamber-specific proteins, we have compared the results from hiPSC-derived cardiomyocytes with freshly isolated, ventricular cardiomyocytes from adult rats. The results show that all typical cardiac proteins are expressed in these hiPSC-CMs. Furthermore, intercalated disc-like structures, calcium cycling proteins, and myofibrils are present. However, some of these proteins are only known from early developmental stages of the ventricular myocardium or the diseased adult heart. A heterogeneous expression pattern in the cell population was noted for some muscle proteins, such as for myosin light chains, or incomplete organization in sarcomeres, such as for telethonin. These observations indicate that hiPSC-CMs can be considered genuine human cardiomyocytes of an early developmental state. The here described marker proteins of maturation may become instrumental in future studies attempting the improvement of cardiomyocyte in vitro models.
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http://dx.doi.org/10.4081/ejh.2017.2763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484009PMC
June 2017

Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy.

J Clin Oncol 2017 Mar 23;35(8):878-884. Epub 2016 Oct 23.

Dimitrios Zardavas, Breast International Group; Martine J. Piccart-Gebhart and Evandro de Azambuja, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Thomas M. Suter, Bern University Hospital, Bern; Jutta Steinseifer, Johannes Noe, Sabine Lauer, and Nedal Al-Sakaff, F. Hoffmann-La Roche, Basel, Switzerland; and Dirk J. Van Veldhuisen, University Medical Center Groningen, University of Groningen, The Netherlands.

Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers' increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.
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http://dx.doi.org/10.1200/JCO.2015.65.7916DOI Listing
March 2017

Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure.

Clin Cancer Res 2017 Jan 19;23(1):43-51. Epub 2016 Dec 19.

Stanford University School of Medicine, Stanford, California.

Purpose: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline.

Experimental Design: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE.

Results: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2).

Conclusions: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 23(1); 43-51. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215621PMC
January 2017

Cardiotoxicity of breast cancer treatment: no easy solution for an important long-term problem.

Eur Heart J 2016 06 7;37(21):1681-3. Epub 2016 Apr 7.

Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehw133DOI Listing
June 2016

Cardiovascular disease after cancer therapy.

EJC Suppl 2014 Jun 29;12(1):18-28. Epub 2014 May 29.

Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.

Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC). Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results. Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment.
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http://dx.doi.org/10.1016/j.ejcsup.2014.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250533PMC
June 2014

Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer.

J Clin Oncol 2015 Apr 23;33(10):1136-42. Epub 2015 Feb 23.

Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.

Purpose: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC).

Patients And Methods: Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety.

Results: Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days.

Conclusion: Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.
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http://dx.doi.org/10.1200/JCO.2014.58.7782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657012PMC
April 2015

Development and Characterization of a Scaffold-Free 3D Spheroid Model of Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes.

Tissue Eng Part C Methods 2015 Aug 16;21(8):852-61. Epub 2015 Mar 16.

1 Department of Clinical Research, Cardiology, Bern University Hospital , Bern, Switzerland .

Cardiomyocytes (CMs) are terminally differentiated cells in the adult heart, and ischemia and cardiotoxic compounds can lead to cell death and irreversible decline of cardiac function. As testing platforms, isolated organs and primary cells from rodents have been the standard in research and toxicology, but there is a need for better models that more faithfully recapitulate native human biology. Hence, a new in vitro model comprising the advantages of 3D cell culture and the availability of induced pluripotent stem cells (iPSCs) of human origin was developed and characterized. Human CMs derived from iPSCs were studied in standard 2D culture and as cardiac microtissues (MTs) formed in hanging drops. Two-dimensional cultures were examined using immunofluorescence microscopy and western blotting, while the cardiac MTs were subjected to immunofluorescence, contractility, and pharmacological investigations. iPSC-derived CMs in 2D culture showed well-formed myofibrils, cell-cell contacts positive for connexin-43, and other typical cardiac proteins. The cells reacted to prohypertrophic growth factors with a substantial increase in myofibrils and sarcomeric proteins. In hanging drop cultures, iPSC-derived CMs formed spheroidal MTs within 4 days, showing a homogeneous tissue structure with well-developed myofibrils extending throughout the whole spheroid without a necrotic core. MTs showed spontaneous contractions for more than 4 weeks that were recorded by optical motion tracking, sensitive to temperature and responsive to electrical pacing. Contractile pharmacology was tested with several agents known to modulate cardiac rate and viability. Calcium transients underlay the contractile activity and were also responsive to electrical stimulation, caffeine-induced Ca(2+) release, and extracellular calcium levels. A three-dimensional culture using iPSC-derived human CMs provides an organoid human-based cellular platform that is free of necrosis and recapitulates vital cardiac functionality, thereby providing a new and promising relevant model for the evaluation and development of new therapies and detection of cardiotoxicity.
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http://dx.doi.org/10.1089/ten.TEC.2014.0376DOI Listing
August 2015

Report on the international colloquium on cardio-oncology (rome, 12-14 march 2014).

Ecancermedicalscience 2014 29;8:433. Epub 2014 May 29.

Working Group of the International Colloquium on Cardio-Oncology (Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands).

Cardio-oncology is a relatively new discipline that focuses on the cardiovascular sequelae of anti-tumour drugs. As any other young adolescent discipline, cardio-oncology struggles to define its scientific boundaries and to identify best standards of care for cancer patients or survivors at risk of cardiovascular events. The International Colloquium on Cardio-Oncology was held in Rome, Italy, 12-14 March 2014, with the aim of illuminating controversial issues and unmet needs in modern cardio-oncology. This colloquium embraced contributions from different kind of disciplines (oncology and cardiology but also paediatrics, geriatrics, genetics, and translational research); in fact, cardio-oncology goes way beyond the merging of cardiology with oncology. Moreover, the colloquium programme did not review cardiovascular toxicity from one drug or the other, rather it looked at patients as we see them in their fight against cancer and eventually returning to everyday life. This represents the melting pot in which anti-cancer therapies, genetic backgrounds, and risk factors conspire in producing cardiovascular sequelae, and this calls for screening programmes and well-designed platforms of collaboration between one key professional figure and another. The International Colloquium on Cardio-Oncology was promoted by the Menarini International Foundation and co-chaired by Giorgio Minotti (Rome), Joseph R Carver (Philadelphia, Pennsylvania, United States), and Steven E Lipshultz (Detroit, Michigan, United States). The programme was split into five sessions of broad investigational and clinical relevance (what is cardiotoxicity?, cardiotoxicity in children, adolescents, and young adults, cardiotoxicity in adults, cardiotoxicity in special populations, and the future of cardio-oncology). Here, the colloquium chairs and all the session chairs briefly summarised what was said at the colloquium. Topics and controversies were reported on behalf of all members of the working group of the International Colloquium on Cardio-Oncology.
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http://dx.doi.org/10.3332/ecancer.2014.433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039411PMC
June 2014

Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events.

Eur J Cancer 2014 Aug 12;50(12):2162-70. Epub 2014 Jun 12.

Memorial Sloan-Kettering Cancer Center, New York, NY, United States.

Purpose: To define cardiovascular (CV) risk and reversibility of cardiac events in patients who received sunitinib versus comparator treatment (interferon-alfa or placebo).

Patients And Methods: We performed a retrospective adjudication of comprehensive CV adverse events (AEs) from two phase 3 trials. Components of the comprehensive CV AE end-point comprised hypertension, symptomatic and asymptomatic left ventricular ejection fraction decreases (SD-LVEF; AD-LVEF) and extent of reversibility, heart-failure symptoms, thromboembolic events, dysrhythmia and CV death. Three cardiologists and one oncologist, blinded to treatment allocation, adjudicated suspected CV AEs in the pooled trial database (N=1090).

Results: Incidence rates (IR) for sunitinib versus Interferon-alfa (IFN-α)/placebo were hypertension: 6.9 versus 2.6 (hazard ratio (HR), 3.1; 95% confidence interval (CI), 2.4-4.0); SD-LVEF: 0.4 versus 0.2 (HR, 2.5; 95% CI, 1.0-6.2); AD-LVEF: 1.1 versus 0.8 (HR, 2.1; 95% CI, 1.3-3.4); and composite CV AE end-point: 10.1 versus 4.8 (HR, 2.5; 95% CI, 2.0-3.1), however reversibility, not previously quantified, was found to be clinically meaningful.

Conclusions: Hypertension and SD-LVEF/AD-LVEF were significantly higher with sunitinib versus IFN-α/placebo. Among patients who experienced a cardiac event, symptomatic and asymptomatic instances of decreased cardiac dysfunction were adjudicated as reversible in 47 of 83 (56%) and 17 of 30 (57%), respectively. Among sunitinib-treated patients, many were able to resume sunitinib dosing following resolution of events, a finding that is important for clinical care. In comparator groups, symptomatic and asymptomatic instances were adjudicated as reversible in 4 of 6 (66.7%) and 11 of 21 (52%), respectively. Thromboembolic, dysrhythmic and/or CV deaths were not significantly higher in sunitinib-treated patients.
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http://dx.doi.org/10.1016/j.ejca.2014.05.013DOI Listing
August 2014

Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01).

J Clin Oncol 2014 Jul 9;32(20):2159-65. Epub 2014 Jun 9.

Evandro de Azambuja and Martine J. Piccart-Genhart, Institut Jules Bordet; Evandro de Azambuja, Breast European Adjuvant Study Team; Martine J. Piccart-Gebhart, Université Libre de Bruxelles, Brussels, Belgium; Marion J. Procter and Dominique Agbor-Tarh, Frontier Science Scotland, Kincraig, Kingussie; David A. Cameron, University of Edinburgh and Western General Hospital, Edinburgh; Ian E. Smith, Royal Marsden Hospital and the Institute of Cancer Research; Mitch Dowsett, the Royal Marsden National Health Service Trust, London, United Kingdom; Dirk J. van Veldhuisen, University of Groningen, Groningen, the Netherlands; Otto Metzger-Filho and Richard D. Gelber, Dana-Farber Cancer Institute, Boston, MA; Jutta Steinseifer, F. Hoffmann-La Roche, Basel; Thomas M. Suter, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, Bern, Switzerland; Michael Untch, HELIOS Klinikum Berlin, Buch; Christian Jackisch, Klinikum Offenbach, Offenbach, Germany; Luca Gianni, San Raffaele Institute, Milan, Italy; Jose Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; Richard Bell, Andrew Love Cancer Centre, Geelong Hospital, Geelong, Australia; and Brian Leyland-Jones, Edith Sanford Breast Cancer Research Institute, Sioux Falls, SD.

Purpose: To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy.

Patients And Methods: The Herceptin Adjuvant (HERA) trial is a three-arm, randomized trial comparing 2 years or 1 year of trastuzumab with observation in 5,102 patients with human epidermal growth factor receptor 2 (HER2) -positive early-stage breast cancer. Cardiac function was closely monitored. Eligible patients had left ventricular ejection fraction (LVEF) ≥ 55% at study entry following neoadjuvant chemotherapy with or without radiotherapy. This 8-year median follow-up analysis considered patients randomly assigned to 2 years or 1 year of trastuzumab or observation.

Results: The as-treated safety population for 2 years of trastuzumab (n = 1,673), 1 year of trastuzumab (n = 1,682), and observation (n = 1,744) is reported. Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4% of patients in the 2-year arm and 5.2% of patients in the 1-year arm. Cardiac death, severe congestive heart failure (CHF), and confirmed significant LVEF decrease remained low in all three arms. The incidence of severe CHF (0.8%, 0.8%, and 0.0%, respectively) and confirmed significant LVEF decrease (7.2%, 4.1%, and 0.9%, respectively) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm. Severe CHF was the same for 2-year and 1-year trastuzumab. Of patients with confirmed LVEF decrease receiving 2-year trastuzumab, 87.5% reached acute recovery. Of patients with confirmed LVEF decrease receiving 1-year trastuzumab, 81.2% reached acute recovery.

Conclusion: Long-term assessment at 8-year median follow-up confirms the low incidence of cardiac events for trastuzumab given sequentially after chemotherapy and radiotherapy, and cardiac events were reversible in the vast majority of patients.
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http://dx.doi.org/10.1200/JCO.2013.53.9288DOI Listing
July 2014

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial.

Lancet Oncol 2013 Sep 7;14(10):933-42. Epub 2013 Aug 7.

University of Edinburgh and Cancer Services, NHS Lothian, Edinburgh, UK.

Background: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer.

Methods: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567.

Findings: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]).

Interpretation: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.
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http://dx.doi.org/10.1016/S1470-2045(13)70335-8DOI Listing
September 2013

2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.

Lancet 2013 Sep 18;382(9897):1021-8. Epub 2013 Jul 18.

Department of Medicine, European Institute of Oncology, Milan, Italy.

Background: Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial.

Methods: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0-10) is also reported. This study is registered with ClinicalTrials.gov, number NCT00045032.

Findings: We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio [HR] 0·99, 95% CI 0·85-1·14, p=0·86). Grade 3-4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20·4%] vs 275 [16·3%] grade 3-4 adverse events, and 120 [7·2%] vs 69 [4·1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67-0·86, p<0·0001) for disease-free survival and 0·76 (0·65-0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy.

Interpretation: 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care.

Funding: F Hoffmann-La Roche (Roche).
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http://dx.doi.org/10.1016/S0140-6736(13)61094-6DOI Listing
September 2013

Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes.

Cell Tissue Res 2012 Nov 4;350(2):361-72. Epub 2012 Aug 4.

Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital and University of Bern, Bern, Switzerland.

The clinical use of anthracyclines in cancer therapy is limited by dose-dependent cardiotoxicity that involves cardiomyocyte injury and death. We have tested the hypothesis that anthracyclines affect protein degradation pathways in adult cardiomyocytes. To this aim, we assessed the effects of doxorubicin (Doxo) on apoptosis, autophagy and the proteasome/ubiquitin system in long-term cultured adult rat cardiomyocytes. Accumulation of poly-ubiquitinated proteins, increase of cathepsin-D-positive lysosomes and myofibrillar degradation were observed in Doxo-treated cardiomyocytes. Chymotrypsin-like activity of the proteasome was initially increased and then inhibited by Doxo over a time-course of 48 h. Proteasome 20S proteins were down-regulated by higher doses of Doxo. The expression of MURF-1, an ubiquitin-ligase specifically targeting myofibrillar proteins, was suppressed by Doxo at all concentrations measured. Microtubule-associated protein 1 light chain 3B (LC3)-positive punctae and both LC3-I and -II proteins were induced by Doxo in a dose-dependent manner, as confirmed by using lentiviral expression of green fluorescence protein bound to LC3 and live imaging. The lysosomotropic drug chloroquine led to autophagosome accumulation, which increased with concomitant Doxo treatment indicating enhanced autophagic flux. We conclude that Doxo causes a downregulation of the protein degradation machinery of cardiomyocytes with a resulting accumulation of poly-ubiquitinated proteins and autophagosomes. Although autophagy is initially stimulated as a compensatory response to cytotoxic stress, it is followed by apoptosis and necrosis at higher doses and longer exposure times. This mechanism might contribute to the late cardiotoxicity of anthracyclines by accelerated aging of the postmitotic adult cardiomyocytes and to the susceptibility of the aging heart to anthracycline cancer therapy.
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http://dx.doi.org/10.1007/s00441-012-1475-8DOI Listing
November 2012

Cancer drugs and the heart: importance and management.

Eur Heart J 2013 Apr 12;34(15):1102-11. Epub 2012 Jul 12.

Department of Cardiology, Bern University Hospital, 3010 Bern, Switzerland.

Progress in the detection and treatment of cancer has led to an impressive reduction in both mortality and morbidity. Due to their mechanism of action, however, conventional chemotherapeutics and some of the newer anti-cancer signaling inhibitors carry a substantial risk of cardiovascular side effects that include cardiac dysfunction and heart failure, arterial hypertension, vasospastic and thromboembolic ischaemia, dysrhythmia, and QT prolongation. While some of these side effects are irreversible and cause progressive cardiovascular disease, others induce only temporary dysfunction with no apparent long-term sequelae for the patient. The challenge for the cardiovascular specialist is to balance the need for life-saving cancer treatment with the assessment of risk from cancer drug-associated cardiovascular side effects to prevent long-term damage. This review discusses concepts for timely diagnosis, intervention, and surveillance of cancer patients undergoing treatment, and provides approaches to clinical uncertainties.
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http://dx.doi.org/10.1093/eurheartj/ehs181DOI Listing
April 2013

Cancer therapy modulates VEGF signaling and viability in adult rat cardiac microvascular endothelial cells and cardiomyocytes.

J Mol Cell Cardiol 2012 May 3;52(5):1164-75. Epub 2012 Feb 3.

Bern University Hospital, Cardiology, CH-3010 Bern, Switzerland.

This work was motivated by the incomplete characterization of the role of vascular endothelial growth factor-A (VEGF-A) in the stressed heart in consideration of upcoming cancer treatment options challenging the natural VEGF balance in the myocardium. We tested, if the cytotoxic cancer therapy doxorubicin (Doxo) or the anti-angiogenic therapy sunitinib alters viability and VEGF signaling in primary cardiac microvascular endothelial cells (CMEC) and adult rat ventricular myocytes (ARVM). ARVM were isolated and cultured in serum-free medium. CMEC were isolated from the left ventricle and used in the second passage. Viability was measured by LDH-release and by MTT-assay, cellular respiration by high-resolution oxymetry. VEGF-A release was measured using a rat specific VEGF-A ELISA-kit. CMEC were characterized by marker proteins including CD31, von Willebrand factor, smooth muscle actin and desmin. Both Doxo and sunitinib led to a dose-dependent reduction of cell viability. Sunitinib treatment caused a significant reduction of complex I and II-dependent respiration in cardiomyocytes and the loss of mitochondrial membrane potential in CMEC. Endothelial cells up-regulated VEGF-A release after peroxide or Doxo treatment. Doxo induced HIF-1α stabilization and upregulation at clinically relevant concentrations of the cancer therapy. VEGF-A release was abrogated by the inhibition of the Erk1/2 or the MAPKp38 pathway. ARVM did not answer to Doxo-induced stress conditions by the release of VEGF-A as observed in CMEC. VEGF receptor 2 amounts were reduced by Doxo and by sunitinib in a dose-dependent manner in both CMEC and ARVM. In conclusion, these data suggest that cancer therapy with anthracyclines modulates VEGF-A release and its cellular receptors in CMEC and ARVM, and therefore alters paracrine signaling in the myocardium.
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http://dx.doi.org/10.1016/j.yjmcc.2012.01.022DOI Listing
May 2012

Cardiac dysfunction after cancer treatment.

Tex Heart Inst J 2011 ;38(3):248-52

Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Onco-cardiology is an evolving discipline that requires the consideration of cardiotoxicity in preclinical, clinical,and therapeutic aspects of protocol development,treatment, and surveillance of patients who have undergone interventions using cardiotoxic agents. Only then can we foster new ways to maximize survival while keeping cardiac damage within acceptable limits. It is to this end that our working together has brought us to our present understanding. In the future, we may expect onco-cardiology to play an even greater role in the care of cancer patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113132PMC
October 2011

Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology.

Eur J Heart Fail 2011 Jan;13(1):1-10

Department of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre-clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross-disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science.
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http://dx.doi.org/10.1093/eurjhf/hfq213DOI Listing
January 2011

Insights into cardiovascular side-effects of modern anticancer therapeutics.

Curr Opin Oncol 2010 Jul;22(4):312-7

Purpose Of Review: Modern anticancer therapeutics can be associated with significant cardiovascular side-effects. Detection, risk assessment, and treatment of these unwanted effects are an important task for treating physicians. The purpose of this review is to focus on approved novel cancer therapeutics and discuss the most important cardiovascular side-effects, prognosis, and potential treatment. We will contrast these effects to those of conventional cardiotoxic chemotherapeutics.

Recent Findings: Modern anticancer therapeutics can cause cardiovascular ischemia, arrhythmias, cardiac dysfunction, heart failure, and arterial hypertension. Anti-HER2 drugs, or more specifically trastuzumab, can induce cardiac dysfunction and heart failure. Newer data show that these effects occur predominantly during treatment and patients who experience the side-effects often have a good cardiovascular prognosis. Antiangiogenic agents can induce arterial hypertension, arterial and venous thromboembolism, and less frequently QTc prolongation. Recent findings indicate that a high rate of patients treated with antivascular endothelial growth factor drugs develop arterial hypertension and may experience related complications. Preventive strategies or optimal treatment have been tested but controlled studies are missing.

Summary: Cardiovascular side-effects of modern anticancer drugs can be a serious problem and need careful attention, prevention, or treatment.
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http://dx.doi.org/10.1097/CCO.0b013e32833ab6f1DOI Listing
July 2010