Decline In Left Ventricular Ejection Fraction Research Articles

420O - Role of cardioprotective therapies for prevention of cardiotoxicity in breast cancer: A systematic review and meta-analysis

BackgroundCardiotoxicity is a well-recognized adverse outcome following adjuvant breast cancer treatment including anthracyclines, trastuzumab, and chest radiation. Its prevention remains an important challenge in clinical practice. We aimed to determine the effectiveness of prophylactic cardioprotective agents in preventing treatment-related cardiotoxicity in women with breast cancer. MethodsA systematic review of published literature was conducted by searching PubMed, EMBASE and EBSCO host databases. Studies where prophylactic intervention was given to breast cancer patients without a prior history of heart disease were included. The outcomes of interest were preservation of left ventricular ejection fraction (LVEF), or development of cardiac events. Mean differences (MD) in LVEF, and relative risks (RR) of cardiac events, were evaluated using random-effects models. ResultsThirteen randomized controlled trials (RCTs), which used prophylactic beta-blockers, dexrazoxane, angiotensin receptor blockers, angiotensin converting enzyme (ACE) inhibitors or other pharmacologic agents were included. Overall, the use of prophylactic cardioprotective agents resulted in a statistically significant smaller LVEF decline compared to use of placebo (MD = 2.42%, 95% confidence interval (CI): 0.59%-4.24%). While there were 52 cardiac events in the intervention arm (n = 405) compared to 79 in the control arm (n = 396), use of prophylactic cardioprotective agents did not significantly protect against incident cardiac events (RR = 0.63, 95%CI: 0.33-1.22). ConclusionsIn breast cancer patients without a history of heart disease, use of cardioprotective agents appear to confer only a very marginal protection against LVEF decline, falling below the ideal 10% cardioprotection. However, given the sample number of RCTs in this area, more studies are needed to substantiate the effectiveness of prophylactic cardioprotective agents in prevention of cardiotoxicity in women with breast cancer. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Changes of Left Ventricular Systolic Function in Patients Undergoing Coronary Artery Bypass Grafting.

AIM:This prospective study was designed to evaluate the changes in left ventricular (LV) systolic function after coronary artery bypass grafting (CABG) in patients with both normal and abnormal pre-operative systolic function.METHODS:During the period from October 2017 to October 2018, forty-seven consecutive patients undergoing CABG were enrolled in this prospective study. Transthoracic echocardiography was performed within 1 week before CABG as well as 4 to 6 months after surgery. All measurements were made by a single experienced investigator.RESULTS:While the mean LV ejection fraction (LVEF) showed neither improvement nor significant reduction in the whole group of patients following CABG (from 54.21 ± 15.36 to 53.66 ± 11.56%, p = 0.677), significant improvement in LVEF was detected in the subgroup of patients with pre-operative LV dysfunction (from 40.05 ± 8.65 to 45.85 ± 9.04%, p = 0.008). On the other hand, there was a significant decline in LEFT in the subgroup of patients with normal pre-operative LEFT (from 64.70 ± 9.72 to 59.44 ± 9.75%, p = 0.008). As for the other parameters of systolic function, significant decrease in LV end-diastolic volume index (LVEDVI) (p = 0.001), LV end-systolic volume index (LVESVI) (p = 0.0001), wall motion score index (WMSI) (p = 0.013) and LVmass index in male patients (p = 0.011) was shown only in patients with decreased LVEF after CABG. Patients with improved postoperative LVEF (53.2% of all patients) had significantly lower baseline LVEF (p = 0.0001), higher LVESVI (0.009) and higher WMSI (p = 0.006) vs patients with worsened postoperative LVEF (38.3% of all patients). Postoperative improvement of LVEF was correlated with stabile angina, lack of preoperative myocardial infarction and smoking, higher baseline WMSI, higher LV internal diameters and indexed volumes in diastole and systole and lower baseline LVEF. In stepwise linear regression analysis the value of baseline LVEF appeared as independent predictor of improved LVEF after CABG (B = 0,836%; 95% CI 0.655-1.017; p = 0.0001).CONCLUSION:Our study showed that LVEF, internal baseline diameters and indexed volumes of LV in diastole and systole are important determinants of postoperative change in LVEF. In patients with preoperative depressed myocardial function, there is an improvement in systolic function, whereas in patients with preserved preoperative myocardial function, the decline in postoperative LVEF was detected.

P6237Clinical utility of echocardiographic left-ventricular ejection fraction monitoring for cardiotoxicity risk assessment in patients with HER2+ early breast cancer undergoing trastuzumab-based therapy

Abstract Background Monitoring left-ventricular ejection fraction (LVEF) is a routinely-practiced strategy to survey patients with breast cancer (BC) towards cardiotoxic treatment effects. However, whether the LVEF as a single measurement or as a trajectory over time is truly sufficient to identify patients at high risk for cardiotoxicity is currently debated. Purpose To quantify the prognostic impact of LVEF and its change over time for predicting cardiotoxicity in women with HER2+ early BC. Methods We analyzed 1,136 echocardiography reports from 185 HER2+ early BC patients treated with trastuzumab ± chemoimmunoendocrine therapy in the neoadjuvant/adjuvant setting (Table 1). Cardiotoxicity was defined as a 10% decline in LVEF below 50%. Results Median baseline LVEF was 64% (25th-75th percentile: 60–69). Nineteen patients (10%) experienced cardiotoxicity (asymptomatic n=12, symptomatic n=7, during treatment n=19, treatment modification/termination n=14), Median time to cardiotoxicity was 6.7 months, and median LVEF decline in patients with cardiotoxicity was 18%. One-year cardiotoxicity risk was 7.6% in the 35 patients with a baseline LVEF≥60% and 24.5% in the 150 patients with a baseline LVEF<60% (Hazard Ratio (HR)=3.45, 95% CI: 1.35–8.75, Figure 1). During treatment, LVEF declined significantly faster in patients who developed cardiotoxicity than in patients without cardiotoxicity (1.3%/month vs. 0.1%/month, p<0.0001). A higher rate of LVEF decrease predicted for higher cardiotoxicity risk (HR per 0.1%/month higher LVEF decrease/month=2.50, 95% CI: 1.31–4.76, p=0.005), and cardiotoxicity risk increased by a factor of 1.7 per 5% absolute LVEF decline from baseline to first follow-up (HR=1.70, 95% CI: 1.30–2.38, p<0.0001). Thirty-six patients (19%) developed an LVEF decline of at least 5% from baseline to first follow-up (“early LVEF decline”). One-year cardiotoxicity risk was 6.8% in those without early LVEF decline and a baseline LVEF≥60% (n=117), 15.7% in those without an early LVEF decline and a baseline LVEF<60% (n=65), and 66.7% in those with an early LVEF decline and a baseline LVEF<60% (n=3), respectively (log-rank p<0.0001). Table 1. Baseline characteristics Age (years, median [IQR]) 55 [49–65] Estrogen receptor positive (n, %) 124 (67%) Neoadjuvant setting (n, %) 103 (56%) Figure 1. Risk of Cardiotoxicity. Conclusion Both a single LVEF measurement and the rate of LVEF decrease strongly predict cardiotoxicity in early BC patients undergoing HER2-targeted therapy. Routine LVEF monitoring identifies individuals at high risk of cardiotoxicity that may benefit from more sensitive screening techniques such as strain imaging.

Acute Cardiotoxicity With Concurrent Trastuzumab and Hypofractionated Radiation Therapy in Breast Cancer Patients.

Purpose: Radiotherapy for patients with non-metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer is commonly administered concurrently with adjuvant trastuzumab. However, there is limited data on the use of concurrent trastuzumab and hypofractionated radiotherapy (Hypo-RT), which is now standard of care for the majority of women receiving whole breast irradiation. In this study, we compared acute cardiotoxicity rates in HER2-positive breast cancer patients treated with concurrent trastuzumab and Hypo-RT or conventionally fractionated radiotherapy (Conv-RT).Methods: We performed a review of our institutional database to identify HER2-positive breast cancer patients treated with trastuzumab and Hypo-RT or Conv-RT from 2005 to 2018 who underwent serial cardiac Left Ventricular Ejection Fraction (LVEF) evaluation. Decrease in LVEF was assessed by either echocardiography (ECHO) or multiple gated acquisition (MUGA) scan performed at baseline and every 3 months during trastuzumab therapy. Significant LVEF decline was defined as an absolute decrease in LVEF of ≥10% below the lower limit of normal or ≥16% from baseline value.Results: We identified 41 patients treated with Hypo-RT and 100 patients treated with Conv-RT. Median follow-up was 32 months (range, 13–90 months). Baseline median LVEF was 62% (range, 50–81%) in Hypo-RT group and 64% (range, 51–76%) in Conv-RT group (p = 0.893). Final median LVEF was 60% (range, 50–75%) in both groups. Three patients (7%) in Hypo-RT and five (5%) in Conv-RT group developed significant asymptomatic LVEF decline (p = 0.203). There was no significant difference in mean heart dose in patients who developed significant asymptomatic LVEF decline vs. those who did not in Hypo-RT (p = 0.427) and Conv-RT (p = 0.354) groups. No symptomatic congestive heart failure was reported in either group.Conclusions: The rate of asymptomatic LVEF decline in patients receiving concurrent trastuzumab and Hypo-RT was low (7%) and was similar to the rate observed in patients receiving Conv-RT. Longer follow-up is warranted to assess late cardiotoxicity.

Comprehensive Assessment of Changes in Left Ventricular Diastolic Function With Contemporary Breast Cancer Therapy

ObjectivesThis study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction. BackgroundDoxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined. MethodsIn a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy−related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%. ResultsOver a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e′ velocities, and increases in E/e′ (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (−2.1%; 95% confidence intervals [CI]: −3.1 to −1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e′ ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022). ConclusionsA modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341)

Efficacy of Neurohormonal Therapies in Preventing Cardiotoxicity in Patients With Cancer Undergoing Chemotherapy

ObjectivesThis study sought to assess the effects of neurohormonal therapies in preventing cardiotoxicity in patients receiving chemotherapy. BackgroundVarious cardioprotective approaches have been evaluated to prevent chemotherapy-related cardiotoxicity; however, their overall utility remains uncertain. MethodsThis meta-analysis included randomized clinical trials of adult patients that underwent chemotherapy and neurohormonal therapies (β-blockers, mineralocorticoid receptor antagonists, or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) versus placebo with follow-up ≥4 weeks. The primary outcome was change in left ventricular ejection fraction (LVEF) from baseline to the end of the trial. Other outcomes of interest were measures of LV size, strain, and diastolic function. Pooled estimates for each outcome were reported as standardized mean difference and weighted mean difference between the neurohormonal therapy and placebo groups using random effects models. ResultsWe included 17 trials, collectively enrolling 1,984 participants. In pooled analysis, neurohormonal therapy (vs. placebo) was associated with significantly higher LVEF on follow-up (standardized mean difference: +1.04 [95% confidence interval (CI): 0.57 to 1.50]) but with significant heterogeneity in the pooled estimate (I2 = 96%). Compared with placebo-treated patients, those randomized to neurohormonal therapies experienced a 3.96% (95% CI: 2.90 to 5.02) less decline in LVEF estimated by weighted mean difference, but with significant heterogeneity (I2 = 98%). There was a trend toward lower adverse clinical events with neurohormonal therapy (vs. placebo) that did not meet statistical significance (risk ratio: 0.80 [95% CI: 0.53 to 1.20]; I2 = 71%). ConclusionsNeurohormonal therapies are associated with higher LVEF in follow-up among cancer patients receiving chemotherapy, although absolute changes in LVEF are small and may be within inter-test variability. Furthermore, significant heterogeneity is observed in the treatment effects across studies highlighting the need for larger trials of cardioprotective strategies.

Myocardial global longitudinal strain: An early indicator of cardiac interstitial fibrosis modified by spironolactone, in a unique hypertensive rat model.

Is global longitudinal strain (GLS) a more accurate non-invasive measure of histological myocardial fibrosis than left ventricular ejection fraction (LVEF) in a hypertensive rodent model. Hypertension results in left ventricular hypertrophy and cardiac dysfunction. Speckle-tracking echocardiography has emerged as a robust technique to evaluate cardiac function in humans compared with standard echocardiography. However, its use in animal studies is less clearly defined. Cyp1a1Ren2 transgenic rats were randomly assigned to three groups; normotensive, untreated hypertensive or hypertensive with daily administration of spironolactone (human equivalent dose of 50 mg/day). Cardiac function and interstitial fibrosis development were monitored for three months. The lower limit of normal LVEF was calculated to be 75%. After three months hypertensive animals (196±21 mmHg systolic blood pressure (SBP)) showed increased cardiac fibrosis (8.8±3.2% compared with 2.4±0.7% % in normals), reduced LVEF (from 81±2% to 67±7%) and impaired myocardial GLS (from -17±2% to -11±2) (all p<0.001). Myocardial GLS demonstrated a stronger correlation with cardiac interstitial fibrosis (r2 = 0.58, p<0.0001) than LVEF (r2 = 0.37, p<0.006). Spironolactone significantly blunted SBP elevation (184±15, p<0.01), slowed the progression of cardiac fibrosis (4.9±1.4%, p<0.001), reduced the decline in LVEF (72±4%, p<0.05) and the degree of impaired myocardial GLS (-13±1%, p<0.01) compared to hypertensive animals. This study has demonstrated that, myocardial GLS is a more accurate non-invasive measure of histological myocardial fibrosis compared to standard echocardiography, in an animal model of both treated and untreated hypertension. Spironolactone blunted the progression of cardiac fibrosis and deterioration of myocardial GLS.

Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity

ObjectivesThe aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BackgroundCardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. MethodsA total of 222 patients with early-stage human epidermal growth factor receptor 2–positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. ResultsTRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a “low-risk TRC score” to identify patients with low TRC incidence. ConclusionsLow baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039)

An evaluation of the safety of continuing trastuzumab despite overt left ventricular dysfunction.

The major limitation in the use of trastuzumab therapy is cardiotoxicity. We evaluated the safety of a strategy of continuing trastuzumab in patients with breast cancer despite mild, asymptomatic left ventricular impairment. Charts of consecutive patients referred to a cardio-oncology clinic from January 2015 to March 2017 for decline in left ventricular ejection fraction (lvef), defined as a fall of 10 percentage points or more, or a value of less than 50% during trastuzumab therapy, were reviewed. The primary outcome of interest was change in lvef, measured before and during trastuzumab exposure and up to 3 times after initiation of cardiac medications during a median of 9 months. All 18 patients referred for decline in lvef chose to remain on trastuzumab and were included. All patients were treated with angiotensin converting-enzyme inhibitors or beta-blockers, or both. After initiation of cardiac medications, lvef increased over time by 4.6 percentage points (95% confidence interval: 1.9 percentage points to 7.4 percentage points), approaching baseline values. Of the 18 patients, 17 (94%) were asymptomatic at all future visits. No deaths occurred in the group. Many patients with mildly reduced lvef and minimal heart failure symptoms might be able to continue trastuzumab without further decline in lvef, adverse cardiac events, or death when treated under the supervision of a cardiologist with close follow-up.

NT-proBNP correlates with LVEF decline in HER2-positive breast cancer patients treated with trastuzumab

BackgroundEarly identification of cardiac dysfunction by non-invasive imaging in HER2-positive breast cancer patients treated with trastuzumab is challenging. In particular multigated acquisition (MUGA) scan, which is most widely used, is unable to detect subclinical cardiac changes. The use of N-terminal pro-brain natriuretic peptide (NT-proBNP), a serum biomarker of myocardial stress, might improve timely diagnosis.MethodsThis prospective, single-center, cohort study included patients with HER2-positive breast cancer who started trastuzumab therapy. Echocardiography was scheduled at regular intervals every 3 months during one year follow-up for cardiac function monitoring. For research purposes, NT-proBNP was determined at the same time points. Trastuzumab-induced cardiotoxicity (TIC) was the primary study endpoint, defined as a left ventricular ejection fraction (LVEF) < 45%, and/or an absolute decline in LVEF > 10% since inclusion, and/or the incidence of a clinical cardiac event.ResultsA total of 135 patients were enrolled between April 2008 and June 2016, with a median age of 54 years (IQR: 47–61). By three-dimensional echocardiography (3DE), the median LVEF at baseline was 62% (IQR: 58–65). At a median of 6 months (IQR: 5–11), 45 patients (33%) reached the study endpoint of TIC. Patients with TIC had a mean change of − 9.5% in LVEF (95% CI -7.2 to − 11.7; p = 0.001) during 1 year of trastuzumab treatment. Both NT-proBNP at baseline (HR 1.04, 95% CI 1.02–1.07; p = 0.003) and LVEF decline during anthracycline treatment prior to the start of trastuzumab (HR 1.16, 95% CI 1.07–1.25; p < 0.001) were independently associated with development of TIC. The level of NT-proBNP during follow-up was associated too with development of TIC (HR 1.06 per 10 pmol/l difference, 95% CI 1.02–1.10; p = 0.008). No steadily or sudden increase in NT-proBNP prior to TIC was observed.ConclusionsNT-proBNP cannot be used as a surrogate monitoring tool for trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients during the first year of treatment. Patients showing an LVEF decline during anthracycline pre-treatment appeared vulnerable for trastuzumab-induced cardiotoxicity.

Impact of pericardial effusion for patients receiving immune checkpoint inhibitors.

e14121 Background: Various immune-related adverse events (IRAE) have been reported with the use of immune checkpoint inhibitors (ICI). Although a rare event, the increasing incidence of ICI related myocarditis and its reported high mortality raises concern. Cardiovascular IRAE such as pericardial effusions (PE) have been documented in case reports and case series but their clinical significance is unclear. Methods: Retrospective chart review was performed on 1075 patients receiving ICI between 2015 and 2017 with baseline echocardiograms without pericardial effusions and follow up echocardiograms at MD Anderson Cancer Center. We collected baseline characteristics, laboratory findings, echocardiograms, and dates of ICI initiation, PE development, last follow up and death. Overall survival (time from first ICI therapy to death or last follow up) was calculated. Univariate Fine-Gray regression analyses were conducted to identify variables associated with PE to account for death as a competing risk event. A p-value of less than 0.05 indicated statistical significance. Results: After initiation of ICI, 78 patients (7.3%) developed PE of which 45 patients died (58%) compared to 347 deaths (35%) out of the 997 patients without PE. The median follow-up time was 445 days. Univariate Fine-Gray analyses predicting PE demonstrated lower body surface area, lowest nadir in left ventricular ejection fraction (LVEF), higher troponin levels, lower platelet counts, absence of ectopy and hyperlipidemia, and lack of avelumab in therapy as well as a history of heart failure with preserved or reduced ejection fraction, hematologic cancer, and peripheral artery stents were significantly associated with higher incidence of PE. Conclusions: While the development of PE is an IRAE or progression of cancer itself cannot be determined, this study indicates patients receiving ICI who developed PE had higher mortality. Those with greater troponin levels and substantial decline in LVEF were shown to have a greater propensity of developing PE, suggesting the possibility of an underlying myopericarditis. If PE develops during ICI therapy, providers should consider an expedited workup and treatment of ICI related myocarditis.

A phase III, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P) + trastuzumab (H) + docetaxel (D) versus Pla + H+ D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN).

1026 Background: In CLEOPATRA (NCT00567190), adding P to H + D significantly improved progression-free and overall survival (PFS/OS) v Pla + H + D in patients (pts) with previously untreated HER2-positive LR/MBC. PUFFIN (NCT02896855) is a China bridging study; the objective being to assess consistency of efficacy with CLEOPATRA. Methods: Pts with previously untreated HER2-positive LR/MBC were randomized 1:1 to P + H + D or Pla + H + D, stratified by visceral v non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR in pts with measurable baseline disease), OS, and safety. The target sample size (240) was determined based on the consistency threshold for PFS, defined as hazard ratio (HR) &lt; 0.81, which maintains ≥ 50% of the risk reduction determined in CLEOPATRA (HR 0.62). Results: Two hundred forty-three pts were randomized. Baseline/disease characteristics and prior therapies were generally balanced between arms. For PFS, the HR was 0.69 (95% CI 0.49, 0.99) in the ITT population. No cases of heart failure or symptomatic left ventricular ejection fraction decline were reported. Efficacy/safety are shown in the table. Conclusions: PUFFIN met its primary endpoint. Overall, efficacy data were consistent with CLEOPATRA (ITT population and Asian subgroup). Safety was also consistent and in line with the known P safety profile, with no new or unexpected signals reported. PUFFIN adds to the totality of data with P in previously untreated HER2-positive LR/MBC, and supports the favorable benefit–risk profile of P in Chinese pts. Clinical trial information: NCT02896855. [Table: see text]

Personalized Decision Making in Early Stage Breast Cancer: Applying Clinical Prediction Models for Anthracycline Cardiotoxicity and Breast Cancer Mortality Demonstrates Substantial Heterogeneity of Benefit-Harm Trade-off

BackgroundAnthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms of anthracycline chemotherapy may balance or exceed the benefits. Patients and MethodsA clinical prediction model for anthracycline cardiotoxicity was created in 967 patients with human epidermal growth factor receptor-negative breast cancer treated with doxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to < 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk. ResultsOf the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (< 2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a > 10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year. ConclusionOlder age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.

Left Ventricular Dysfunction in Breast Cancer Patients Receiving Trastuzumab: An Observational Study in a Cohort of Iraqi Breast Cancer Patients

Background : Cardiotoxicity is a well recognized adverse event of trastuzumab. This study was designed to evaluate the frequency of decline in left ventricular ejection fraction (LVEF) to less than 50% in patients with breast cancer who have received trastuzumab in a daily practice setting. Methods : Retrospective observational study of 116 patients with HER2 positive breast cancer treated with trastuzumab in one center between May 2012 and January 2017. Results : Left ventricular ejection fraction decline to less than 50% was observed in 7 patients (6%). Patients above 70 years of age have the highest frequency of LVEF decline (33%). All events of LVEF decline was reported in the first six months of treatment. Prolonged administration of trastuzumab beyond one year was not associated with adverse cardiac events. Previous anthracycline exposure and chest irradiation was not found to be associated with LVEF decline. Conclusions : Events of LVEF decline to less than 50% associated with trastuzumab use seems to be slightly higher in general daily practice than in clinical trial setting, especially in patients above 70 years, calling for better patient selection. First year of trastuzumab therapy carries the highest risk of cardiac events which necessitates a close cardiac monitoring, thereafter, periodic LVEF&nbsp; measurements can be reduced to reduce the costs.

Left ventricular function after noninvasive cardiac ablation using proton beam therapy in a porcine model

Noninvasive cardiac ablation of ventricular tachycardia (VT) using radiotherapy has recently gained interest among electrophysiologists. The effects of left ventricular (LV) ablative radiation treatment on global LV function and volumes are unknown. The purpose of this study was to investigate the effects of noninvasive ablation on LV function over time. Twenty domestic swine underwent proton beam treatment of LV sites in a dose-finding design and were followed for up to 40 weeks by cardiac magnetic resonance imaging at 4-week intervals. Doses investigated were either 40 Gy at 1 site (n = 8) or 30 Gy at 2 sites (n = 4) in the low-dose group and 40 Gy at 3 sites (n = 8) in the high-dose group. LV mean dose (13.2 ± 1.8 Gy vs 4.6 ± 1.8 Gy) and the volume receiving at least 20 Gy (V20Gy) (24.7% ± 4.8% vs 6.4% ± 3.0%) differed significantly between groups. Dose-dependent effects on left ventricular ejection fraction (LVEF) and LV end-diastolic volume became manifest about 3 months after treatment. LVEF decline was correlated to mean dose (correlation coefficient ρ= -0.69; P = .008) and V20Gy (ρ = -0.66; P = .01), as was LV dilation (ρ = 0.72; P = .005; and ρ = 0.75, P = .003 respectively). Possible adverse effects on LV function, seen about 3 months after treatment, are dose dependent. Therefore, precise target definition and focused energy delivery are paramount in catheter-free ablation.

Cabozantinib-related cardiotoxicity: a prospective analysis in a real-world cohort of metastatic renal cell carcinoma patients.

Data regarding the cardiac toxicity of cabozantinib lacks. The aim of our study was to assess the risk of cabozantinib-related cardiotoxicity in mRCC patients. We performed a multicentre prospective study on mRCC patients treated with cabozantinib between October 2016 and November 2017. Transthoracic echocardiogram and plasma biomarkers assay were assessed at baseline, 3 and 6months after cabozantinib initiation. The study population included 22 mRCC patients. At baseline, 9.1% had a reduced left ventricular ejection fraction (LVEF), but none had a left ventricular systolic dysfunction. Patients with baseline reduced LVEF did not show further significant LVEF modification after 3months. After 6months, only 1 had an LVEF decline >10% compared to baseline, resulting in LV systolic dysfunction. At baseline, 64.7% and 27.3% of patients had elevated precursor brain natriuretic peptide (proBNP) and high-sensitivity troponin I (hsTnI), respectively. Among patients with basal normal proBNP and hsTnI, none had elevated values at 3 and 6months. No correlation was found between basal elevated proBNP and basal reduced LVEF (P=.29), and between elevated proBNP and reduced LVEF after 6months (P=.37). Similarly, we found no correlations between elevated hsTnI and reduced LVEF or elevated proBNP at baseline (P=.47; P=.38), at 3 (P=.059; P=.45) and after 6months (P=.72; P=1.0). This prospective study revealed a modest risk of developing left ventricular systolic dysfunction related to cabozantinib. A lack of correlation between elevated cardiac biomarkers and reduced LVEF at different time-points was detected. Assessments of the cardiac function should be reserved at the occurrence of clinical symptoms.

QIM19-132: Trastuzumab Induced Cardiotoxicity: Are We Monitoring and Managing Appropriately?

Background: Per the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer (available at NCCN.org), left ventricular ejection fraction (LVEF) should be evaluated prior to and during treatment with trastuzumab. Optimal frequency of assessment is unknown. The FDA label recommends monitoring prior to and every 3 months during therapy. Trastuzumab should be held for 4–8 weeks when LVEF decreases ≥16% from pretreatment values or LVEF is below normal limits and decreases ≥10% from pretreatment values. Trastuzumab should be permanently discontinued for persistent (&gt;8 weeks) LVEF decline or if trastuzumab is stopped &gt;3 times for cardiomyopathy (trastuzumab package insert). Methods: A retrospective chart review was performed analyzing 98 charts of patients with stage I–III HER2-positive breast cancer who were seen at the Edwards Comprehensive Cancer Center (ECCC) in Huntington, WV from January 1, 2012–December 30, 2017. Patients who received trastuzumab at ECCC (59) were further reviewed to see if cardiac function was assessed prior to treatment, at 3 month intervals, and if trastuzumab was held or discontinued permanently if indicated. Results: Analysis of 98 patient charts with stage I–III HER2-positive breast cancer was performed. 59 patients (60.2%) received trastuzumab under supervision of medical oncology at ECCC and continued in the study. LVEF was evaluated in all patients (100%) prior to treatment. LVEF was evaluated every 3 months in 36 (61%) patients while 23 (38.9%) occurred at longer time intervals. Preserved EF was seen in 41 (69.4%) patients. 18 (30.5%) patients had a decrease in LVEF by the defined criteria. Trastuzumab was not held appropriately in 4 of those patients (22.2%). 10 of 18 patients that had a drop in LVEF had persistent LVEF decline or had stopped treatment &gt;3 times for cardiomyopathy. Trastuzumab was permanently discontinued appropriately in 4 of the 10 patients (40%). Conclusions: Better compliance is needed to monitor LVEF at 3-month intervals while on trastuzumab. Improvement to recognize when to hold trastuzumab to prevent cardiotoxicity is needed. Better documentation, easier accessibility to previous EF results, and a multidisciplinary team (breast navigator, cardiologist, oncologist, and pharmacist) will likely improve adherence to current recommendations for cardiac assessment and to determine if Trastuzumab should be held or stopped.

Abstract P6-17-17: Pertuzumab, trastuzumab, and docetaxel for HER2-positive early or locally advanced breast cancer in the neoadjuvant setting: Efficacy and safety analysis of a randomized phase III study in Asian patients (PEONY)

Abstract Background Pertuzumab and trastuzumab (P and H; F. Hoffmann-La Roche Ltd, Basel, CH) bind to distinct HER2 subdomains and have complementary modes of anticancer activity in HER2-positive breast cancer (BC). A global Phase II study (NeoSphere) reported that neoadjuvant treatment with P+H+docetaxel (D) significantly increased breast pathologic complete response (bpCR) vs H+D in patients (pts) with early/locally advanced/inflammatory HER2-positive BC (Gianni et al. Lancet Oncol 2012). PEONY (NCT02586025), a randomized, multicenter, double-blind, placebo-controlled, Phase III trial conducted in an Asian population (mainland China, Taiwan, Korea, Thailand), primarily compared the efficacy, safety, and tolerability of P+H+D vs placebo (Pla)+H+D in the neoadjuvant setting. We present data from the primary analysis. Methods Pts with centrally confirmed HER2-positive early (T2–3, N0–1)/locally advanced (T2–3, N2 or N3; T4, any N) BC were randomized 2:1 to 4 cycles of P+H+D or Pla+H+D every 3 weeks, before surgery: P, 840 mg loading/420 mg maintenance doses (or Pla); H, 8 mg/kg loading/6 mg/kg maintenance; D, 75 mg/m2. Post-surgery, pts received 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of P+H or Pla+H for up to 1 year (total of 17 HER2-targeted therapy cycles). The primary endpoint was total pCR rate (tpCR; absence of any residual invasive cancer in the breast and lymph nodes [ypT0/is, ypN0]) assessed by independent review committee (IRC) when pts completed surgery with a tpCR assessment. Missing/invalid assessments were considered residual disease. Results A total of 329 pts were randomized: 219 to P, 110 to Pla. Baseline characteristics were well balanced. Most pts had early BC (69.6%) and were from mainland China (79.3%). In the intention-to-treat population, the tpCR rate by IRC was 39.3% in the P arm and 21.8% in the Pla arm; a clinically and statistically significant difference of 17.5% (95% CI 6.9–28.0; p=0.0014). The local pathologist-assessed tpCR rates were 39.3% and 20.9%, respectively. A consistent treatment benefit of P vs Pla was observed in subgroups. Incidences of grade ≥3 adverse events (Aes) were 48.6% in the P arm and 41.8% in the Pla arm. Of the most common grade 3 Aes (≥3% of pts), neutropenia was higher in the P arm (38.1% vs 32.7%). Of the most common any-grade Aes (≥5%), diarrhea was higher in the P arm (38.5% vs 16.4%). No heart failure (New York Heart Association Functional Classification III or IV) or significant left ventricular ejection fraction decline events (≥10 percentage points from baseline and to &amp;lt;50%) were observed during neoadjuvant therapy. Conclusions PEONY met its primary endpoint: P+H+D resulted in a clinically meaningful and statistically significant improvement in the tpCR rate by IRC vs Pla+H+D for the neoadjuvant treatment of HER2-positive early/locally advanced BC in Asian pts. Safety data were in line with the known P safety profile and generally comparable between treatment arms. Results were similar to NeoSphere, and confirm that P+H+D provides superior anticancer activity to H+D alone. Citation Format: Shao Z, Pang D, Yang H, Li W, Wang S, Cui S, Liao N, Wang Y, Wang C, Chang Y-C, Wang H, Kang SY, Jiang Z, Li J, Zhou J, Althaus B, Mao Y, Eng-Wong J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive early or locally advanced breast cancer in the neoadjuvant setting: Efficacy and safety analysis of a randomized phase III study in Asian patients (PEONY) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-17.

Subclinical Left Ventricular Dysfunction During Chemotherapy.

Subclinical left ventricular dysfunction is the most common cardiac complication after chemotherapy administration. Detection and early treatment are major issues for better cardiac outcomes in this cancer population. The most common definition of cardiotoxicity is a 10-percentage point decrease of left ventricular ejection fraction (LVEF) to a value <53%. The myocardial injury induced by chemotherapies is probably a continuum starting with cardiac biomarkers increase before the occurence of a structural myocardial deformation leading to a LVEF decline. An individualised risk profile (depending on age, cardiovascular risk factors, type of chemotherapy, baseline troponin, baseline global longitudinal strain and baseline LVEF) has to be determined before starting chemotherapy to consider cardioprotective treatment. To date, there is no proof of a systematic cardioprotective treatment (angiotensin-converting enzyme inhibitor and/or beta-blocker) in all cancer patients. However, early cardioprotective treatment in case of subclinical left ventricular dysfunction seems to be promising in the prevention of cardiac events.

Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction.

Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline. Patients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classifiedas the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classifiedas the interrupted group.Cardiac events were defined as HF (New York Heart Association class III-IV) or cardiovascular death. Sixty patients were included; the median age was 54years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25-42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29). Continuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.