Decline In Left Ventricular Ejection Fraction Research Articles

Global ECG Measures and Cardiac Structure and Function: The ARIC Study (Atherosclerosis Risk in Communities).

Electric excitation initiates myocardial mechanical contraction and coordinates myocardial pumping. We hypothesized that ECG global electric heterogeneity (GEH) and its longitudinal changes are associated with cardiac structure and function. Participants from the ARIC study (Atherosclerosis Risk in Communities) (N=5114; 58% female; 22% blacks) with resting 12-lead ECGs (visits 1-5) and echocardiographic assessment of left ventricular (LV) ejection fraction, LV global longitudinal strain, LV mass index, LV end-diastolic volume index, and LV end-systolic volume index at visit 5 were included. Longitudinal analysis included ARIC participants (N=14 609) with measured GEH at visits 1 to 4. GEH was quantified by spatial ventricular gradient, QRS-T angle, and sum absolute QRS-T integral. Cross-sectional and longitudinal regressions were adjusted for manifest and subclinical cardiovascular disease. Having 4 abnormal GEH parameters was associated with a 6.4% (95% confidence interval, 5.5-7.3) LV ejection fraction decline, a 24.2 g/m2 (95% confidence interval, 21.5-26.9) increase in LV mass index, a 10.3 mL/m2 (95% confidence interval, 8.9-11.7) increase in LV end-diastolic volume index, and a 7.8 mL/m2 (95% confidence interval, 6.9-8.6) increase in LV end-systolic volume index. Altogether, clinical and ECG parameters accounted for approximately one third of LV volume and 20% of systolic function variability. The associations were significantly stronger in cardiovascular disease. Sum absolute QRS-T integral increased by 20 mV*ms for each 3-year period in participants who demonstrated LV dilatation at visit 5. Sudden cardiac death victims demonstrated rapid GEH worsening, whereas those with LV dysfunction demonstrated slow GEH worsening. Healthy aging was associated with a distinct pattern of spatial ventricular gradient azimuth decrement. GEH is a marker of subclinical abnormalities in cardiac structure and function.

BLINDED LATE GADOLINIUM ENHANCEMENT QUANTIFICATION OF AGE MATCHED ADOLESCENT AND YOUNG ADULT BECKER AND DUCHENNE MUSCULAR DYSTROPHY CARDIOMYOPATHY

Becker Muscular Dystrophy(BMD) cardiomyopathy varies widely in regards to onset, severity, and progression. Evidence-based treatment of myocardial fibrosis attenuates fibrosis progression associated with left ventricular ejection fraction(LVEF) decline. However, a lack of early natural history

Abstract P5-20-04: Safety of adjuvant treatment with pertuzumab plus trastuzumab after neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive localized breast cancer: Updated results from the BERENICE study

Abstract Background Anti-HER2 therapies are associated with a risk of cardiac toxicity, particularly as part of anthracycline-based regimens. BERENICE (NCT02132949), a nonrandomized, Phase 2 cardiac safety study showed neoadjuvant treatment with pertuzumab (P) + trastuzumab (H) and 2 common anthracycline–taxane-based regimens had a safety profile consistent with prior studies of P+H, and was associated with high pathologic complete response rates. Here we report safety data from the P+H adjuvant treatment period (AP). Methods Patients (pts) with centrally confirmed, localized HER2-positive breast cancer and normal cardiac function received 4 q2w dose-dense doxorubicin and cyclophosphamide cycles (60/600mg/m2) then 12 qw paclitaxel injections (80mg/m2; Cohort A), or 4 q3w fluorouracil/epirubicin/cyclophosphamide cycles (500/100/600 mg/m2) then 4 q3w docetaxel cycles (75mg/m2, up to 100mg/m2;Cohort B). In both cohorts, 4 q3w cycles of P (loading:840mg; maintenance:420mg) + H (loading:8mg/kg; maintenance:6mg/kg) were started with taxane therapy and continued in the adjuvant setting (for up to 13 cycles to complete 1 year of treatment). Surgery was scheduled after 8 cycles of preoperative therapy. Primary endpoints were incidence of New York Heart Association (NYHA) Class III/IV heart failure and incidence of left ventricular ejection fraction (LVEF) declines (≥10%-points from baseline to <50%; asymptomatic and symptomatic events) assessed by ECHO/MUGA. Confirmed LVEF declines were defined as significant LVEF declines at 2 consecutive visits. Results In total, 397 pts received ≥1 dose of study medication and were included in the overall treatment period (OTP) safety analysis. Of these, 371 (Cohort A:181; Cohort B:190) pts entered the AP and were included in the AP safety analysis. Mean (SD) number of AP treatment cycles of P and H were 12.3 (2.0) in Cohort A and 12.3 (2.2) in Cohort B. In the AP, incidence of heart failure was minimal (0.5%) and confirmed LVEF decline incidence was low (Table 1). Table 1: Cardiac AE Cohort ACohort B OTP n=199AP n=181OTP n=198OTP n=190NYHA Class III/IV heart failure Events, n4011Pts with event, n (%)3(1.5)01(0.5)1(0.5)LVEF decline Events, n36223429Pts with LVEF decline, n (%)21(10.6)14(7.7)22(11.1)20(10.5)Pts with confirmed LVEF decline, n (%)7(3.5)5(2.8)7(3.5)6(3.2) General adverse events (AEs) are shown in Table 2; 26 (14.4%) pts in Cohort A and 45 (23.7%) in Cohort B had diarrhea AEs (mostly grade 1). Table 2: General AE Cohort ACohort BPts, n (%)OTP n=199AP n=181OTP n=198AP n=190Any AE198(99.5)171(94.5)198(100.0)171(90.0)Grade ≥3 AE109(54.8)23(12.7)126(63.6)40(21.1)Serious AE54(27.1)15(8.3)61(30.8)17(8.9)AE leading to P or H discontinuation19(9.5)9(5.0)14(7.1)11(5.8) Conclusion P+H in the adjuvant setting, following P+H with anthracycline-based regimens in the neoadjuvant setting, are associated with low incidence of cardiac AEs. Cardiac safety results for P+H in the AP and OTP of BERENICE were consistent with results from prior studies evaluating adjuvant treatment with single-agent H, suggesting the addition of P to H in the adjuvant setting does not increase cardiac toxicity. Citation Format: Dang C, Ewer MS, Delaloge S, Ferrero J-M, Verrill M, Colomer R, Vieira C, de la Cruz Merino L, Lucas J, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Swain SM. Safety of adjuvant treatment with pertuzumab plus trastuzumab after neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive localized breast cancer: Updated results from the BERENICE study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-04.

Abstract P5-20-17: Safety of continuing chemotherapy in overt left ventricular dysfunction using antibodies to human epidermal growth factor receptor-2: A retrospective study

Abstract Introduction: Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor (HER)-2 and significantly improves survival in HER-2 positive early stage breast cancer. However, trastuzumab is also known to cause cardiotoxicity. Guidelines recommend withholding or discontinuing trastuzumab if left ventricular ejection fraction (LVEF) falls ≥15% from baseline, or to <50%, but there is little evidence to support this strategy. Additionally, premature discontinuation of trastuzumab may lead to poorer cancer outcomes. Trastuzumab cardiotoxicity is frequently reversible, and the use of angiotensin converting enzyme-inhibitors (ACE-I) and beta blockers is highly effective at treating impaired LVEF in other patient populations. We therefore hypothesize that it is safe to continue trastuzumab in patients with asymptomatic or mildly symptomatic fall in LVEF, when concomitantly treated with ACE-I and beta blockers. Methods: In this retrospective chart review, we identified 18 consecutive patients with stage 1-3 HER-2 positive breast cancer patients who had a decline in LVEF meeting the criteria above to withhold trastuzumab, and who were referred to our cardio-oncology service from the beginning of 2015 to March 2017. These patients were offered and consented to receive ongoing trastuzumab accompanied by ACE-I and/or beta blocker. Data on patient demographics, cancer therapies, clinical features, LVEF, and cardiac medications were extracted from medical charts. Results: Among the 18 patients identified, all were women, 12 (67%) were estrogen receptor positive, and 7 progesterone receptor positive (39%). 11 (61%) of patients had a left-sided breast cancer, 6 (33%) had right-sided breast cancer, and 1 (5%) had an unspecified side breast cancer. 17 (94%) of patients had previously undergone radiation therapy, and 4 (22%) had experienced a recurrence. 16 patients had received a prior anthracycline regimen (10 sequentially, 6 concurrently). The patients were treated with one or a combination of the following medications: carvedilol (n=13), ramipril (n=12), bisoprolol (n=1), candesartan (n=2), rosuvastatin (n=2), atorvastatin (n=2). The patients were followed up for an average of 7 months after starting cardiac therapy. Table 1 summarizes the mean±SD LVEF values over the follow up time period. All patient except one (94%) completed trastuzumab treatment successfully. This patient with concomitant moderate-severe mitral regurgitation was hospitalized for pulmonary edema. Trastuzumab was discontinued and LVEF has subsequently returned to normal values. Table 1: LVEF progression from baseline to end of follow-upMean±SD LVEF at baseline57.59±5.49%Mean±SD LVEF on referral to cardio-oncology clinic50.75±4.76%Mean±SD LVEF at end of follow-up56.35±3.50% Conclusion: Treating cardiac dysfunction related to trastuzumab in a cardio-oncology clinic, using beta blockers and ACE-I may enable completion of trastuzumab therapy. Randomized trials are necessary before it can be widely recommended, however findings from our experience suggest this may be a promising new treatment strategy. Citation Format: Bharaj UK, Leong D, Dhesy-Thind S, Ellis P, Mukherjee S, Bordeleau L, Phillips C, Brown M, Kumar Tyagi N. Safety of continuing chemotherapy in overt left ventricular dysfunction using antibodies to human epidermal growth factor receptor-2: A retrospective study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-17.

Abstract P6-12-17: Identifying risk factors and effect modifiers of trastuzumab-induced cardiotoxicity among multi-ethnic women with early-stage HER2-positive breast cancer

Abstract Introduction: Trastuzumab-based adjuvant therapy is the current standard of care for early-stage HER2-positive breast cancer. However, trastuzumab has also been associated with an increased risk of cardiotoxicity, especially when given following an anthracycline. Trastuzumab-induced cardiotoxicity (TIC) can present as asymptomatic left ventricular ejection fraction (LVEF) decline or symptomatic heart failure. Our objective was to identify predictors of TIC among multi-ethnic patients with early-stage HER2-positive breast cancer. Unlike prior observational studies, our study included a high representation of racial/ethnic minorities, who are at increased risk of cardiovascular disease (CVD) compared to non-Hispanic whites. Methods: We conducted a retrospective cohort study in patients with stage I-III HER2-positive breast cancer, diagnosed from 2007 to 2015 at Columbia University Medical Center (CUMC) in New York, NY, who had received adjuvant trastuzumab therapy. Participants had at least two serial echocardiograms or MUGA scans to assess TIC, which was defined as at least a 10% decrease in LVEF from baseline or LVEF <50%. LVEF recovery was defined as at least a 10% increase in LVEF or LVEF >50%. We conducted descriptive statistics and univariate and multivariable logistic regression to estimate the associations between socio-demographic factors, breast tumor and treatment characteristics, and CVD risk factors (including smoking status, body mass index [BMI], hypertension, diabetes, hyperlipidemia, coronary artery disease) and TIC. Interactions between race/ethnicity and CVD risk factors were assessed using a logistic regression model. Results: In our study population (N=279), the mean age was 52.7 years (standard deviation, 12.1) with 36.6% non-Hispanic white, 18.3% non-Hispanic black, 34.8% Hispanic, and 10.4% Asian patients. There were no differences by race/ethnicity in tumor and treatment characteristics (over half had prior anthracyclines), but racial/ethnic minorities had higher BMI and were more likely to have hypertension compared to non-Hispanic whites. About a third of patients developed TIC and 14.7% had an LVEF decline to <50%, of which 15 (16.1%) experienced LVEF recovery. In multivariable analysis, prior anthracycline use and hypertension were significantly associated with increased odds of developing TIC (odds ratio [OR]: 2.25, 95% confidence interval [CI]: 1.25, 4.06; OR: 2.13, 95% CI: 1.15, 3.93, respectively). There was a significant interaction (p=0.027) between race/ethnicity and hypertension on odds of developing TIC with hypertensive non-Hispanic white patients experiencing 6.05 (95% CI: 2.19, 16.75) times the odds of developing TIC compared to non-hypertensive non-Hispanic whites. Discussion: We observed a higher incidence of TIC and lower incidence of LVEF recovery compared to previous clinical trials. Given patient selection for clinical trials, our results may be more representative of clinical practice settings. We found a particularly high risk among non-Hispanic white patients with hypertension. Patients with hypertension may require closer blood pressure monitoring and treatment with anti-hypertensives in order to reduce risk of developing cardiotoxicity. Citation Format: Yuan A, Topkara V, Hershman DL, Kalinsky K, Accordino MK, Trivedi MS, Yu A, Genkinger JM, Crew KD. Identifying risk factors and effect modifiers of trastuzumab-induced cardiotoxicity among multi-ethnic women with early-stage HER2-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-17.

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure–response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies.

Immune response proteins as predictive biomarkers of doxorubicin-induced cardiotoxicity in breast cancer patients.

Cancer treatment with doxorubicin (DOX) can induce cumulative dose-dependent cardiotoxicity. Currently, there are no specific biomarkers that can identify patients at risk during the initial doses of chemotherapy. The aim of this study was to examine plasma cytokines/chemokines and potential cardiovascular biomarkers for the prediction of DOX-induced cardiotoxicity. Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-based chemotherapy of 27 breast cancer patients, including five patients who presented with >10% decline of left ventricular ejection fraction (LVEF), five patients with LVEF decline of 5-10%, and 17 patients who maintained normal LVEF at the end of chemotherapy (240mg/m2 cumulative dose of DOX from four cycles of treatment). Multiplex immunoassays were used to screen plasma samples for 40 distinct chemokines, nine matrix metalloproteinases, 33 potential markers of cardiovascular diseases, and the fourth-generation cardiac troponin T assay. The results showed that the patients with abnormal decline of LVEF (>10%) had lower levels of CXCL6 and sICAM-1 and higher levels of CCL23 and CCL27 at T0; higher levels of CCL23 and lower levels of CXCL5, CCL26, CXCL6, GM-CSF, CXCL1, IFN-γ, IL-2, IL-8, CXCL11, CXCL9, CCL17, and CCL25 at T1; and higher levels of MIF and CCL23 at T2 than the patients who maintained normal LVEF. Patients with LVEF decline of 5-10% had lower plasma levels of CXCL1, CCL3, GDF-15, and haptoglobin at T0; lower levels of IL-16, FABP3, and myoglobin at T1; and lower levels of myoglobin and CCL23 at T2 as compared to the patients who maintained normal LVEF. This pilot study identified potential biomarkers that may help predict which patients are vulnerable to DOX-induced cardiotoxicity although further validation is needed in a larger cohort of patients. Impact statement Drug-induced cardiotoxicity is one of the major concerns in drug development and clinical practice. It is critical to detect potential cardiotoxicity early before onset of symptomatic cardiac dysfunction or heart failure. Currently there are no qualified clinical biomarkers for the prediction of cardiotoxicity caused by cancer treatment such as doxorubicin (DOX). By using multiplex immunoassays, we identified proteins with significantly changed plasma levels in a group of breast cancer patients who were treated with DOX-based chemotherapy and produced cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment or at early doses of treatment, thus they could be potential predictive biomarkers of cardiotoxicity although further validation is required to warrant their clinical values.

Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial.

The major clinical side effect of the ERBB2-targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer. A genome-wide association study was performed on all patients with available DNA (N=1446). We used linear regression to identify single nucleotide polymorphisms (SNPs) associated with decline in LVEF, adjusting for age, baseline LVEF, antihypertensive medications, and the first two principle components. In total, 618 863 SNPs passed quality control and DNA from 1191 patients passed genotyping quality control and were identified as Whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (P=7.73×10 to 8.93×10), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6, and LINC01060, in patients who received chemotherapy plus trastuzumab (arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (arm A, N=391) and did not increase in significance in the combined analysis of all patients. We did not observe association, P<0.05, with SNPs previously associated with trastuzumab-induced cardiotoxicity at ERBB2, I655V, and P1170A. We replicated association, P<0.05, with SNPs previously associated with anthracycline-induced cardiotoxicity at CBR3 and ABCB1. Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.

TRASTUZUMAB ASSOCIATED LEFT VENTRICULAR DYSFUNCTION: CAN THE NEED FOR TREATMENT INTERRUPTION BE PREDICTED AND DOES INTERRUPTION AFFECT CARDIOVASCULAR OR ONCOLOGIC OUTCOMES?

Trastuzumab (T) has been shown to significantly reduce the risk of breast cancer recurrence. Current standards of practice recommend administering adjuvant T in 17 doses over one year. However, the use of T may be associated with an often reversible, left ventricular dysfunction (LVD). When LVD occurs, clinicians must decide whether to interrupt or continue treatment. This retrospective study was conducted to assess the cardiovascular and oncologic outcomes associated with each of these clinical decisions in the context of mild LVD. We included patients who received adjuvant T therapy in British Columbia for local breast cancer between September 2005 and December 2013 and experienced a treatment-emergent drop in left ventricular ejection fraction (LVEF) to 40-49%. The study cohort was divided into two groups based on whether or not T was held at any point during the course of therapy. Charts were reviewed for demographic information, cardiovascular events, and cancer outcomes. 2401 patients received adjuvant T during the study period. Of these, 261 (10.9%) patients had a LVEF decline to 40-49%. T was interrupted in 229 (87.7%), while 32 (12.3%) underwent continuous therapy. Pre-existing structural heart disease and cardiac risk factors, including smoking, hypertension, and diabetes, were not significantly more prevalent in the interruption group. Adverse cardiovascular outcomes (subsequent LVEF drop to < 40% or clinical heart failure) were more frequent in those who had treatment interruption compared to those who received continuous T. The number of patients experiencing a cancer relapse in the T interruption and continuous groups were 38 (16.6%) and 2 (6.25%), respectively (P=0.19). Among those receiving 17 doses of T with a temporary interruption in therapy, there was a 17.5% breast cancer recurrence rate. Pre-existing cardiovascular disease and cardiac risk factors did not appear to increase the likelihood of a T hold. Following the development of mild LVD, the risks of adverse cardiovascular outcomes were not increased by continuation of T. However, holding T was associated with a 10% absolute risk increase in breast cancer recurrence. Moreover, even when 17 doses of T were given, there was an 11% absolute risk increase in breast cancer relapse when trastuzumab was transiently held. While there results are not statistically significant, they suggest the need for a larger study to inform evidence-based guidelines on the interruption of T in the context of LVD.

Electrocardiographic Strain Pattern Is Associated With Left Ventricular Concentric Remodeling, Scar, and Mortality Over 10Years: The Multi-Ethnic Study of Atherosclerosis.

BackgroundBoth ECG strain pattern and QRS measured left ventricular (LV) hypertrophy criteria are associated with LV hypertrophy and have been used for risk stratification. However, the independent predictive value of ECG strain in apparently healthy individuals in predicting mortality and adverse cardiovascular events is unclear.Methods and ResultsMESA (Multi‐Ethnic Study of Atherosclerosis) is a multicenter, prospective cohort of 6441 participants (mean age, 62 years; 54% women). In 2847 of these participants, cardiac magnetic resonance imaging was repeated ≈10 years later (Year‐10). At Year‐10, 1759 participants underwent cardiac magnetic resonance imaging with gadolinium to detect myocardial scar. During a median follow‐up of 11.7 years, ECG strain (n=168, 2.6%) was significantly associated with all‐cause death (adjusted hazard ratio, 1.33; 95% confidence interval, 1.01–1.77; P=0.045), heart failure (2.62; 1.73–3.97; P<0.001), myocardial infarction (1.86; 1.09–3.18; P=0.024), and incident cardiovascular disease (1.45; 1.06–2.00; P=0.022). ECG strain was also associated with an increase in LV mass (β=9.29 g; P<0.001) and LV mass‐to‐volume ratio (β=0.07 g/mL; P=0.007) and a decline in LV ejection fraction (β=−3.30%; P<0.001). Moreover, ECG strain either at baseline and Year‐10 was associated with LV scar (odds ratio, 4.93 and 5.22; P=0.002 and <0.001, respectively), whereas these associations were not observed in ECG LV hypertrophy.ConclusionsECG strain is independently associated with all‐cause mortality, adverse cardiovascular events, development of LV concentric remodeling and systolic dysfunction, and myocardial scar over 10 years in multiethnic participants without past cardiovascular disease. ECG strain may be an early marker of LV structural remodeling that contributes to development of adverse cardiovascular events.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov/. Unique identifier: NCT00005487.

P.53 - Effects of long-term treatment with eteplirsen on cardiac function

Duchenne muscular dystrophy (DMD) is an X-linked, recessive genetic disease characterized by dystrophin deficiency or absence. Eteplirsen, a phosphorodiamidate morpholino oligomer, targets DMD pre-mRNA to trigger skipping of exon 51 in order to restore the reading frame, thereby enabling production of internally truncated dystrophin protein. Herein we report effects of long-term treatment with eteplirsen on cardiac function in patients with DMD in comparison to reports from disease natural history and a clinical study of perindopril. Eteplirsen patients were treated in two consecutive studies. Study 201 was a randomized, double-blind, 28-week trial. Patients aged 7–13 years with DMD amenable to exon 51 skipping were randomized to receive 1 of 2 once-weekly intravenous (IV) eteplirsen infusions (30 mg/kg, n = 4; 50 mg/kg, n = 4) or placebo (n = 4). At week 25, all patients received open-label eteplirsen through week 28. Study 202 was an open-label extension of study 201; all patients received once-weekly eteplirsen at the same dose (30 mg/kg or 50 mg/kg) for up to 240 weeks. Both trials included longitudinal evaluation of cardiac function using echocardiographic left ventricular ejection fraction (LVEF). We found that the mean annual rate of decline in ejection fraction for eteplirsen-treated patients over the 240-week trial was 0.18%. A study of perindopril (N = 57; mean age at baseline, 10.6 years) reported a 1.28% annual decline in perindopril-treated patients (n = 28) and a 1.88% annual decline in placebo-to-perindopril patients (n = 29; placebo treatment, 3 years; perindopril treatment, 2 years) over the 5-year study period, as measured by radionuclide ventriculography. A disease natural history study of 98 DMD patients aged 7–29 years reported a 0.58% annual decline in LVEF, as measured by magnetic resonance. In conclusion, safety monitoring showed gross LVEF stability in eteplirsen-treated patients over the 240-week study period.

145 - Incidence of Left Bundle Branch Block—Associated Cardiomyopathy

Background: The presence of left bundle branch block (LBBB) is often an indicator of primary structural or ischemic heart disease. Accordingly, patients who develop LBBB are at increased risk of heart failure and sudden cardiac death. In patients with reduced left ventricular ejection fraction (LVEF) and LBBB, cardiac resynchronization therapy (CRT) improves survival and reduces heart failure hospitalizations. Indeed, CRT can affect dramatic improvement if not normalization of LVEF in selected patients with LBBB. These observations have led to the notion that LBBB may play a causative role in the development of dilated cardiomyopathy and heart failure but the true incidence of LBBB-associated cardiomyopathy is not well established. We therefore examined the incidence of a progressive decline in LVEF among patients with an initial normal LVEF in the absence of clinically relevant coronary artery disease (CAD). Methods: We retrospectively examined records of patients with LBBB from our institution's electrocardiogram database and identified those with an initial preserved LVEF (≥45%) without evidence of coronary artery disease (CAD) or other identifiable cause of structural heart disease. Follow up imaging and clinical information was analyzed to establish how many of these patients exhibited a significant decline in their LVEF (defined as ≤40%). Numerical data are presented as mean ± sd. Results: Among a total of 350 patients with LBBB, 94 fit our entry criteria having a mean baseline LVEF of 57 ± 6 %. The mean age of the population was 71 ± 12years. Of these 94 subjects, 13 (14%) developed a significant decline in LV systolic function to an LVEF of 31 ± 7% over a mean follow up period of 40 ± 24 months. Conclusions: These data therefore support that LBBB is associated with the development of progressive LV systolic dysfunction in the absence of CAD or other identifiable etiologies. Moreover, our data suggest that the incidence of LBBB-associated or “dyssynchrony” cardiomyopathy may be higher than previously reported in some series. Further work will be needed to examine predictive clinical variables that may aid in selecting at-risk patients who warrant longitudinal follow up along with serial assessments of LV structure and function.

Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer.

Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting. A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (>10% to<55% or>16% from baseline). A total of 165 patients were identified with a median age of 59years (range 32-85years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF>50% (median 67%; range 50-80%) at baseline.Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to>50% and resolution of heart failure symptoms.Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy. The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines.

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%-17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601-9. ©2017 AACR.

A phase III trial of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2+ breast cancer: The TRAIN-2 study (BOOG 2012-03).

507 Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p &lt; 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF &lt; 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( &lt; 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.

Detailed Echocardiographic Phenotyping in Breast Cancer Patients: Associations With Ejection Fraction Decline, Recovery, and Heart Failure Symptoms Over 3 Years of Follow-Up.

Cardiovascular disease in patients with breast cancer is of growing concern. The longitudinal effects of commonly used therapies, including doxorubicin and trastuzumab, on cardiac remodeling and function remain unknown in this population. We aimed to define the changes in echocardiographic parameters of structure, function, and ventricular-arterial coupling, and their associations with left ventricular ejection fraction (LVEF) and heart failure symptoms. In a longitudinal prospective cohort study of 277 breast cancer participants receiving doxorubicin (Dox), trastuzumab (Tras), or both (Dox+Tras), we obtained 1249 echocardiograms over a median follow-up of 2.0 (interquartile range, 1.0-3.0) years. Left ventricular structure, diastolic and contractile function, and ventricular-arterial coupling measures were quantified in a core laboratory blinded to participant characteristics. We evaluated changes in echocardiographic parameters over time, and used repeated-measures regression models to define their association with LVEF decline and recovery. Linear regression models defined the association between early changes in these parameters and subsequent changes in LVEF and heart failure symptoms. Overall, 177 (64%) received Dox, 51 (18%) received Tras, and 49 (18%) received Dox+Tras. With Dox, there was a sustained, modest decrease in LVEF over the follow-up duration (1-year change in LVEF -3.6%; 95% confidence interval [CI], -4.4% to -2.8%; 3-year change -3.8%; 95% CI, -5.1% to -2.5%). With Tras, a similar LVEF decline was observed at 1 year (-4.5%; 95% CI, -6.0% to -2.9%) and 3 years (-2.8%; 95%CI, -5.3 to -0.4%). Participants receiving Dox+Tras demonstrated the greatest declines at 1 year (-6.6%; 95% CI, -8.2 to -5.0%), with partial recovery at 3 years (-2.8%; 95% CI, -4.8 to -0.8%). LVEF declines and recovery were associated primarily with changes in systolic volumes, longitudinal and circumferential strain, and ventricular-arterial coupling indices, effective arterial elastance (Ea) and the coupling ratio Ea/Eessb, without evidence for effect modification across therapies. Early changes in volumes, strain, and Ea/Eessb at 4 to 6 months were associated with 1- and 2-year LVEF changes. Similarly, early changes in strain and Ea were associated with worsening heart failure symptoms at 1 year. Doxorubicin and trastuzumab resulted in modest, persistent declines in LVEF at 3 years. Changes in volumes, strain, and ventricular-arterial coupling were consistently associated with concurrent and subsequent LVEF declines and recovery across therapies.

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer.

Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy. The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy. The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen. Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

Frequency of Left Ventricular End-Diastolic Volume–Mediated Declines in Ejection Fraction in Patients Receiving Potentially Cardiotoxic Cancer Treatment

We sought to determine the frequency by which decreases in left ventricular (LV) end-diastolic volume (LVEDV) with and without increases in end-systolic volume (LVESV) influenced early cancer treatment-associated declines in LV ejection fraction (LVEF) or LV mass. One hundred twelve consecutively recruited subjects (aged 52 ± 14years) with cancer underwent blinded cardiovascular magnetic resonance measurements of LV volumes, mass, and LVEF before and 3months after initiating potentially cardiotoxic chemotherapy (72%of participants received anthracyclines). Twenty-six participants developed important declines in LVEF of >10% or to values <50% at 3months, in whom 19% versus 60%, respectively, experienced their decline in LVEF due to isolated declines in LVEDV versus an increase in LVESV; participants who dropped their LVEF due to decreases in LVEDV lost more LV mass than those who dropped their LVEF due to an increase in LVESV (p=0.03). Nearly one fifth of subjects experience marked LVEF declines due to an isolated decline in LVEDV after initiating potentially cardiotoxic chemotherapy. Because reductions in intravascular volume (which could be treated by volume repletion) may account for LVEDV-related declines in LVEF, these data indicate that LV volumes should be reviewed along with LVEF when acquiring imaging studies for cardiotoxicity during the treatment for cancer.

Abstract P4-21-41: Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer

Abstract Background: Neoadjuvant pertuzumab (P)+trastuzumab (H)+standard chemotherapy (CT) significantly increases pathologic complete response (pCR) rates v H+CT. However, anti-HER2 therapy following anthracyclines can cause heart failure, and data are limited or lacking on combining P+H after epirubicin or doxorubicin. We report cardiac and overall safety as well as total pCR (tpCR) rates with widely used but understudied anthracycline-containing regimens. Methods: BERENICE (NCT02132949), a non-randomized, open-label, phase II study, enrolled patients (pts) with centrally confirmed HER2-positive, locally advanced, inflammatory, or early-stage, unilateral, and invasive breast cancer, Eastern Cooperative Oncology Group performance status ≤1, and baseline left ventricular ejection fraction (LVEF) ≥55%. In the neoadjuvant period, Cohort A pts received four q2w dose-dense doxorubicin+cyclophosphamide cycles (60 mg/m2/600 mg/m2 with granulocyte-colony stimulating factor support as needed) followed by 12 qw paclitaxel doses (80 mg/m2) + four q3w P+H cycles (P 840 mg, then 420 mg; H 8mg/kg, then 6 mg/kg). Cohort B received four q3w fluorouracil/epirubicin/cyclophosphamide cycles (500 mg/m2/100 mg/m2/600 mg/m2) followed by four q3w docetaxel cycles (75 mg/m2 escalated to 100 mg/m2) + four q3w P+H cycles. Surgery was performed after cycle 8 for both cohorts. The primary objective was to evaluate cardiac safety during the neoadjuvant period, assessed by incidence of 1) New York Heart Association (NYHA) Class III/IV heart failure and 2) significant LVEF declines (≥10% from baseline with a value of &amp;lt;50%). Secondary objectives included assessments of adverse event (AE) rates and tpCR (ypT0/Tis ypN0; NX was considered non-tpCR). Results are descriptive; no statistical hypothesis testing was planned. Results: Four hundred one pts were enrolled between Jul 2014–Aug 2015. Clinical cutoff was Mar 3, 2016. Demographics and baseline characteristics were generally balanced between cohorts; 64.3% v 61.7% of pts had centrally confirmed hormone receptor (HR)-positive disease and 95.0% v 93.0% had T1–T3 primary tumors. Three pts in Cohort A and none in Cohort B experienced NYHA Class III/IV heart failure during neoadjuvant treatment (table). Thirteen pts in Cohort A v four in Cohort B had significant LVEF declines (table). One Cohort B pt's LVEF decline was prior to anti-HER2 treatment. AE and serious AE (SAE) rates were well balanced between cohorts. The most common AEs were nausea, diarrhea, and alopecia. The most common SAE was febrile neutropenia. tpCR rates were similar between cohorts (table). Neoadjuvant periodCohort ACohort BSafety: Pts, n (%)N=199N=198NYHA Class III/IV heart failure3 (1.5%)0Significant LVEF decline13 (6.5%)4 (2.0%)tpCR (ypT0/Tis ypN0): Pts, n/N (%) Intention-to-treat123/199 (61.8%)122/201 (60.7%)HR-positive66/128 (51.6%)71/124 (57.3%)HR-negative53/65 (81.5%)51/75 (68.0%) Conclusion: Cardiac and general safety of the two anthracycline-containing regimens in BERENICE were as expected and were consistent with the known P+H+CT profiles. Both regimens were active, and tpCR rates were high. Citation Format: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Dang C. Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-41.

Abstract P4-21-38: Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer

Abstract Background: Trastuzumab and pertuzumab are approved for the treatment of HER2-postiive breast cancer in the neoadjuvant setting. However, limited cardiac safety data is available when used in combination with doxorubicin-based chemotherapy. At a single center we retrospectively report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. Methods: Patients treated with neoadjuvant dose dense AC followed by THP from September 1, 2014 to March 1, 2015 were retrospectively identified. Patients then had breast surgery and completion of anti-HER2 therapy for 1 year. The primary outcome was cardiac event rate, defined by New York Heart Association (NYHA) class III/IV or cardiac death. The secondary outcome was significant asymptomatic decline in left ventricular ejection fraction (LVEF) of 10%-15% from baseline to below the lower limit of normal, or &amp;gt; 16% from baseline. Patients underwent LVEF monitoring at baseline prior to AC, prior to initiation of THP, and serially during 1 year of anti-HER2 therapy (neoadjuvant to adjuvant phases). Results: Fifty-seven patients were included in the study. The median age was 46 years (range 26-68 years). The median number of cycles of trastuzumab and pertuzumab in the neoadjvuvant setting was 6 (range 3-8) and 6 (range 2-8), respectively. In the adjuvant setting, 56 (98%) patients received trastuzumab with pertuzumab with a median cycle number of 12 (range 1-13). Two of 57 (3.5%) patients developed NYHA class III/IV heart failure after 5 and 9 months of trastuzumab, leading to permanent discontinuation of anti-HER2 treatment. Additionally, 7 (12.3%) patients developed a significant LVEF decline (without severe HF symptoms). The median LVEF was 65% (range 55-75%) at baseline and 64% (range 53-72%) after AC. There was a reduction in median LVEF to 60% (range 35-70%), 60% (range 23- 73%), 61% (range 25-73%), and 58% (range 28-66%) at 3, 6, 9, and 12 months (+/- 6 weeks) of trastuzumab-based therapy. Conclusion: In patients with HER2-positive breast cancer treated with neoadjuvant dose-dense AC and THP followed by completion of anti-HER2 therapy in adjuvant setting, the overall rate of NYHA Class III/IV heart failure was comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity when pertuzumab is added to trastuzumab following a doxorubicin-based regimen. Citation Format: Yu AF, Wang R, Singh J, Liu JE, Eaton A, Jones L, Oeffinger K, Steingart RM, Hudis CA, Dang CT. Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-38.