Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE.

BACKGROUND: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions. METHODS: We performed post-hoc analyses to evaluate the association in 3124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n = 346) and SBP ≥ 180 mmHg (hypertensive crisis) (n = 69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis. RESULTS: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10-9; OR = 5.2). CONCLUSION: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity.

Supervised exercise training in patients with cancer during anthracycline-based chemotherapy to mitigate cardiotoxicity: a randomized-controlled-trial.

Background: Exercise training (ET) has been shown to mitigate cardiotoxicity of anthracycline-based chemotherapies (AC) in animal models. Data from randomized controlled trials in patients with cancer are sparse. Methods: Patients with breast cancer or lymphoma receiving AC were recruited from four cancer centres and randomly assigned to 3 months supervised ET. Primary outcome was change in left ventricular global longitudinal strain (GLS) from baseline (before AC) to post AC (AC-end) compared between the EXduringAC group, who participated in an exercise intervention during AC including the provision of an activity tracker, and the control group EXpostAC, who received an activity tracker only. Secondary outcome parameters were changes in high sensitivity Troponin T (hsTnT), NT-pro-brain natriuretic peptide (NT-proBNP), peak oxygen consumption (peak VO2) and objectively measured physical activity (PA) during this same time-period. All assessments were repeated at a 12-week follow-up from AC-end, when also the EXpostAC group had completed the ET, that started after AC. In exploratory analyses, robust linear models were performed to assess the association of PA with changes in echocardiographic parameters and biomarkers of LV function. Results: Fifty-seven patients (median age 47 years; 95% women) were randomized to EXduringAC (n = 28) and EXpostAC (n = 29) group. At AC-end, GLS deteriorated in both study groups (albeit insignificantly) with 7.4% and 1.0% in EXduringAC (n = 18) and EXpostAC (n = 18), respectively, and hsTnT and NT-proBNP significantly increased in both groups, without difference between groups for any parameter. Change in peak VO2 (-1.0 and -1.1 ml/kg/min) at AC-end was also similar between groups as was duration of moderate-to-vigorous PA (MVPA) with a median of 33 [26, 47] min/day and 32 [21, 59] min/day in the EXduringAC and EXpostAC group, respectively. In the robust linear model including the pooled patient population, MVPA was significantly associated with a more negative GLS and lesser increase in hsTnT at AC-end. Conclusion: In this small scale RCT, supervised ET during AC was not superior to wearing a PA tracker to mitigate cardiotoxicity. The dose-response relationship between PA and cardioprotective effects during AC found in our and previous data supports the notion that PA should be recommended to patients undergoing AC. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03850171.

Incidental detection of malignancy during preprocedural workup for transcatheter aortic valve implantation: A longitudinal cohort study.

The aim of this retrospective analysis was to investigate the prevalence and prognostic importance of incidental malignancy detected during pre-TAVI computed tomography. Among 579 patients, CT-work-up for TAVI exposed previously undetected malignancy in 4.5% of patients. TAVI patients with a new malignancy had a 2.9-fold increased risk of death at 1 year, and a 16 month shorter mean survival time compared to patients with no malignancy.

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

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/m2) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m2 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/m2 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.

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.

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.

The cancer patient and cardiology.

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.

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.

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.

Cardio-oncology in clinical studies and real life.

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.

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

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.

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.

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.

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

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 <10-5, 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.

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.

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.

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

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.

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

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.