Asymptomatic Left Ventricular Ejection Fraction Research Articles

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase II single-arm study.

Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin (PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (BC). In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD (30-35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 90-100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, rate of breast-conserving surgery (BCS), and safety (with a focus on cardiotoxicity). Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42 (53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval (95% CI), 48.5%-71.2%] patients achieved tpCR, and 49 (62.8%) achieved bpCR. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine (11.5%) patients experienced asymptomatic left ventricular ejection fraction (LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP (NT-proBNP), troponin I, or high-sensitivity troponin. This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile, especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Effects of trastuzumab and trastuzumab emtansine on corrected QT interval and left ventricular ejection fraction in patients with metastatic (HER2+) breast cancer

BackgroundTrastuzumab and trastuzumab emtansine are specific antibody and antibody–drug conjugates used in the treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. The aim of this study was to test their effect on the QTc interval duration and left ventricular ejection fraction (LVEF) in our patients, two parameters used in evaluation of cardiotoxicity. From May 2015 to October 2017, 26 patients with preserved LVEF were included in the study. All of them were previously treated with standard paclitaxel and cisplatin-based chemotherapy regimens. Electrocardiogram (ECG) was recorded just before each trastuzumab dose application and six months after the last dose. Echocardiography with LVEF measurement was performed several days before the application of the initial dose, and six months after the last cycle. Later, 24 patients with metastatic disease received additional treatment with trastuzumab emtansine after six months and the same ECG and echocardiography protocol was performed again. Due to reduction in LVEF, two patients were discontinued from additional treatment.ResultsA statistically significant QTc prolongation was found after each drug dose application, with an increase in mean QTc duration with every successive application, reaching the peak QTc values just before the fifth cycle of treatment. The QTc interval returned to its initial value six months after the last cycle (p < 0.001). These results were similar for both drugs. Mean LVEF before both treatment protocols was significantly higher compared to LVEF value after the treatment. LVEF before trastuzumab emtansine treatment was non-significantly higher than LVEF after trastuzumab treatment.ConclusionTrastuzumab and trastuzumab emtansine cardiotoxicity manifested as a significant and progressive QTc prolongation after successive drug applications, reaching the peak value just before the fifth cycle of both drugs. Both medications also caused statistically significant but asymptomatic LVEF reduction. Complete reversibility of cardiotoxic effects of both drugs was confirmed by QTc interval and LVEF normalisation after the treatment discontinuation.

Cardiac outcomes of subjects on adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT) study (TBCRC033): a randomized controlled trial

The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3–4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.Clinical Trial Registration: ClinicalTrials.gov, NCT01853748

Mechanoenergetic coupling in heart failure with preserved, mid-range and reduced left ventricular ejection fraction

Abstract Background Heart failure (HF) classification based on left ventricular ejection fraction (LVEF) can vary because of changes in filling pressures, afterload, and contractile function. 11C-acetate positron emission tomography (PET) provides a load-independent measure of myocardial external efficiency (MEE) by simultaneous assessment of myocardial oxygen consumption (MVO2), cardiac work, left ventricular mass (LVM), end-systolic wall stress (ESWS), and myocardial blood flow (MBF). Purpose We aimed to characterize mechanoenergetic derangements in patients with HF and to study its interrelation with age, sex and obesity. Methods MEE was measured in 121 participants with 11C-acetate PET, and LVEF was acquired with echocardiography. We investigated healthy controls (n=20) and patients with HF and reduced LVEF &amp;lt;40% (HFrEF; n=25), mid-range LVEF 40–49% (HFmrEF; n=23), as well as patients with asymptomatic aortic valve stenosis (AS) and LVEF ≥50% (AS-asymp; n=38), and symptomatic AS and LVEF ≥50% (defined as HF with preserved LVEF (HFpEF); n=15). Results MEE declined in tandem with reduced LVEF from HFpEF and HFmrEF to HFrEF (p=0.041, p&amp;lt;0.001, and p&amp;lt;0.001 versus control, respectively; Figure 1). Impaired MEE was aggravated with increasing LVM (p=0.001) due to a disproportionate increase in overall left ventricular MVO2. In a multivariate analysis, female sex (p&amp;lt;0.001), a lower body mass index (p&amp;lt;0.001), and advanced age (p=0.01) were associated with a lower MEE (Figure 2). HFpEF, HFmrEF, and HFrEF patients had distinct energetic profiles involving MEE, MVO2, MBF, ESWS, and LVM (Figure 2). Conclusions Mechanoenergetic uncoupling was evident in every clinical state within the HF syndrome and associated with left ventricular hypertrophy and progressive systolic dysfunction. Sex, age, and obesity impacted myocardial energetics. To date, the present study is the largest investigation of mechanoenergetic coupling across several categories of patients with heart failure. 11C-acetate PET extends our pathophysiological comprehension of the HF syndrome beyond LVEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Heart FoundationThe Lundbeck Foundation Relationship between LVEF and MEEMyocardial energetics in heart failure

Racial and Socioeconomic Disparities in Cardiotoxicity Among Women With HER2-Positive Breast Cancer

Breast cancer and cardiovascular-specific mortality are higher among blacks compared with whites, but disparities in cancer therapy-related adverse cardiovascular outcomes have not been well studied. We assessed for the contribution of race and socioeconomic status on cardiotoxicity among women with HER2-positive breast cancer. This retrospective cohort analysis studied women diagnosed with stage I-III HER2-positive breast cancer from 2004-2013. All underwent left ventricular ejection fraction assessment at baseline and at least one follow-up after beginning trastuzumab. Multivariable logistic regression was used to assess the association between race and socioeconomic status (SES) on cardiotoxicity, defined by clinical heart failure (New York Heart Association class III or IV) or asymptomatic left ventricular ejection fraction decline (absolute decrease ≥ 10% to < 53%, or ≥ 16%). Blacks had the highest prevalence of hypertension, diabetes, and increased BMI. Neighborhood-level SES measures including household income and educational attainment were lower for blacks compared with whites and others. The unadjusted cardiotoxicity risk was significantly higher in black compared with white women (OR, 2.10; 95% CI, 1.42 to 3.10). In a multivariable analysis, this disparity persisted after controlling for relevant cardiovascular risk factors (adjusted OR, 1.88; 95% CI, 1.25 to 2.84). Additional models adjusting for SES factors of income, educational attainment, and insurance status did not significantly alter the association between race and cardiotoxicity. In conclusion, black women are at increased risk of cardiotoxicity during HER2-targeted breast cancer therapy. Future etiologic analyses, particularly studies exploring biologic or genetic mechanisms, are needed to further elucidate and reduce racial disparities in cardiotoxicity.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5years. Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. Median follow-up as of June 2020 is 42months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function.

12069 Background: HER2-targeted therapies are associated with cardiotoxicity, mostly asymptomatic and reversible. The impact of withholding these therapies on breast cancer outcomes is unknown. SAFE-HEaRt trial was the first study to evaluate the safety of HER2-targeted agents in patients with reduced left ventricular ejection fraction (LVEF) receiving concomitant cardioprotective medications and close cardiac monitoring. We report the 3-year follow-up (f/u) results. Methods: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with asymptomatic LVEF 40-49%, were started on beta blockers (ß-blockers) and/or ACE inhibitors/ARBs, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. Results: Patients were accrued from 10/2013 to 12/2017 and median f/u as of 2/7/20 is 37 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. 24 patients were reconsented for long-term f/u. There were 23 evaluable patients (1 lost for f/u). Off study, 2 patients continued treatment with trastuzumab, 3 with trastuzumab and pertuzumab, and 3 with TDM-1 for metastatic disease. 1 of the 2 patients who had developed a CE with symptomatic heart failure (HF) died of progressive oncological disease, and the second had LVEF recovery on cardiac medications after completion of adjuvant HER2-targeted therapy. Almost 5 years later, she had an asymptomatic decline in her LVEF to 35% after deciding to stop her ß-blocker and ARB. Of the remaining 21 patients, 15 had recovery of their LVEF to ≥50%, 9 of whom remain on cardiac medications. 5 patients had stable LVEF 40-49% and remain asymptomatic on cardiac medications. Only 1 patient had symptoms suggestive of HF, with last documented LVEF stable at 45-50%, but she has not sought medical care for the last 15 months since relocating to another country. There were no new CE and no cardiac deaths. Mean LVEF was 45% at baseline, 46% at end of treatment, and 51.5% at long term f/u. Conclusions: Long-term f/u of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is essential for improved patient outcomes. Clinical trial information: NCT04143594 .

A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.

Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10years (119.2-137.2months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity. One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.

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.

Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2–positive breast cancer

BackgroundWe assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2–positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study. MethodsPatients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS. ResultsA total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26–0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS. ConclusionCardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor. Clinical trial registration numbersNCT02771795 (EudraCT 2015-005663-17).

Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity.

Significant and symptomatic cardiac comorbidity is a contraindication to adjuvant trastuzumab in breast cancer patients. However, some patients with asymptomatic, nonlimiting cardiac comorbidity and normal baseline left ventricular ejection fraction (LVEF) receive adjuvant trastuzumab in the clinical practice. We sought to describe the tolerability of trastuzumab in these patients. Retrospective analysis of patients with baseline asymptomatic, nonlimiting cardiac comorbidity receiving adjuvant trastuzumab at six Institutions between July 2007 and January 2016. Thirty-seven patients with HER2-positive, surgery treated breast cancer at high risk of relapse were studied. Median age was 64years (range 36-82), median baseline LVEF 61% (range 50%-85%). Thirteen patients (35%) received trastuzumab with adjuvant anthracycline and taxane-based regimens, 19 (51%) with taxane-based, three (8%) with off-label vinorelbine and two (5%) with off-label endocrine therapy. Most frequent cardiac comorbidities were ischemic heart disease (35%), valvular disease (30%), atrial fibrillation (19%), and conduction disorders (14%). Nine patients (24.3%) experienced a cardiac event: congestive heart failure (one patient, 3%), asymptomatic LVEF reduction (six patients, 16%), and rhythm disturbances (two patients, 5%). Trastuzumab had to be discontinued either permanently (five patients, 14%) or temporarily (two patients, 5%). At the time of last follow-up visit, all patients showed LVEF within normal limits, except one who had experienced a symptomatic cardiac event (LVEF value at last follow-up 46%). Caution is needed in patients with significant ongoing cardiovascular risk factors, but when adjuvant trastuzumab is deemed beneficial on breast cancer outcomes, nonlimiting cardiac comorbidity should not preclude treatment.

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.

Echocardiographic Findings in Patients with Mild to Moderate Chronic Kidney Disease without Symptomatic Heart Failure: A Population-Based Study

Background: Renal dysfunction is an established risk factor for cardiovascular disease, but early disease states in both organs are poorly studied. Objective: This cross-sectional population-based study aims to investigate if there is an early association between kidney function and echocardiographic markers of cardiac structure and diastolic function. Methods: The study population consisted of 1,504 individuals with no prior history of congestive heart failure or asymptomatic left ventricular ejection fraction ≤40% and an estimated glomerular filtration rate (eGFR) based on cystatin C >15 mL/min/1.73 m². The participants were categorized according to eGFR ≥90, 75–89, 60–74, 45–59, 30–44, and 15–29 mL/min/1.73 m². We evaluated associations between eGFR categories and echocardiographic findings specific to cardiac structure and diastolic function. Results: Associations between eGFR categories and echocardiographic findings were found for left atrium area/body surface area (p = 0.013) indicating structural changes, and peak early mitral valve velocity (A; p = 0.003), peak late atrial mitral valve velocity/peak systolic myocardial velocity at mitral annulus in the lateral wall (E/Élat; p = 0.002), É mean of lateral and septal wall/Á mean of lateral and septal wall (mean É/Á; p = 0.027) indicating diastolic dysfunction. Associations between E/Élat and mean É/Á and eGFR categories were already present in individuals with eGFR 45–60 mL/min/1.73 m². In sex-specific analysis these associations were only significant among men. Conclusion: A significant association between mild to moderate impairment of renal function and echocardiographic markers of cardiac structure and diastolic function was observed, supporting the hypothesis that interaction between the kidney and heart exists even in the early stages of renal impairment.

Protective role of beta-blockers in chemotherapy-induced cardiotoxicity\u2014a systematic review and meta-analysis of carvedilol

Some randomized controlled trials (RCTs) have tested the efficacy of beta-blockers as prophylactic agents on cancer therapy-induced cardiotoxicity; however, the quality of this evidence remains undetermined. This systematic review and meta-analysis study aims to evaluate the prophylactic effects of beta-blockers, especially carvedilol, on chemotherapy-induced cardiotoxicity. RCTs were identified by searching the MEDLINE (PubMed), Embase (OvidSP), Cochrane CENTRAL (OvidSP), etc., until December 2017. Inclusion criteria were randomized clinical trial and adult cancer patients started beta-blockers before chemotherapy. We evaluated the mean differences (MD) by fixed- or random-effects model and the odds ratio by Peto’s method. Primary outcome was the left ventricular ejection fraction (LVEF) of patients after chemotherapy, and secondary outcomes were all-cause mortality, clinically overt cardiotoxicity, and other echocardiographic measurements. In total, we included six RCTs that used carvedilol as a prophylactic agent in patients receiving chemotherapy. The LVEF was not significantly distinct between those using carvedilol and placebo after chemotherapy (MD, 1.74; 95% confidence interval (CI), − 0.18 to 3.66; P = 0.08). The incidence of clinically overt cardiotoxicity was lower in the carvedilol group compared with the control group (Peto OR, 0.42; 95% CI, 0.20–0.89; P = 0.02). Furthermore, after chemotherapy, the LV end-diastolic diameter did not increase in the carvedilol group compared with the placebo group (MD, − 1.41; 95% CI, − 2.32 to − 0.50; P = 0.002). The prophylactic use of carvedilol exerted no impact on the early asymptomatic LVEF decrease but seemed to attenuate the frequency of clinically overt cardiotoxicity and prevent ventricular remodeling.

Abstract PD3-09: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study

Abstract Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at higher risk of chemotherapy-induced toxicity raising high interest in a less toxic backbone such as metronomic chemotherapy and in chemo-free dual HER2 blockade (TP). Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed.T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6 months seeking a difference of ≥ 10% between the two arms. Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 71% and/or to short physical performance battery (&amp;lt;10) 81%, Charlson comorbidity score &amp;gt; 0 in 40%. With 20.7 months of median follow-up, 6-month and median PFS were 46.2% (95% CI 30.2-60.7) and 5.6 months (95% CI 3.6-16.8) versus 73.4% (95% CI 56.6-84.6) and 12.7 months (95% CI 6.7-24.8) for TP and TPM, respectively. Four patients in TPM and 2 in TP developed brain metastases only as progression event. OS and breast cancer specific survival were comparable between the two arms; 9/29 deaths were not breast cancer-related. Response rate was 44% in TP arm and 53% in TPM arm. In 29 patients who received T-DM1 second line, 6-month PFS, median PFS and response rate were 49.5% (95% CI 29.2-66.9), 5 months (95% CI 2.5-12.5) and 13.5%. In patients who discontinued TP(M), 37, 9 and 14 stopped because of progression, toxicity or other reasons, respectively. During TPM treatment, 1 patient died of heart failure and 1 developed grade 3 heart failure; 1 patient in each arm developed a ≥ 10% asymptomatic left ventricular ejection fraction decrease below 50%. Diarrhea any grade and grade ≥ 3 were observed in 56% and 8% versus 71% and 12% patients in TP and TPM arms, respectively. No grade 3 or febrile neutropenia was reported. There was no relevant difference in functional evolution between both groups. In the whole population, several geriatric items were of prognostic value by multivariate analysis: e.g. for OS, G8 &amp;gt;14 vs ≤ 14 HR=0.12 (95% CI 0.03-0.55, p 0.006). In 29 patients receiving T-DM1, grade 3 toxicity was rare: fatigue (2 patients), thrombocytopenia and epistaxis (1 patient). Conclusions: Metronomic chemotherapy-based dual blockade (TPM) seems to be superior to dual blockade alone (TP) in an elderly/frail HER2+ MBC population, with an attractive safety profile. TPM, followed by T-DM1 after progression, may delay or supersede taxane chemotherapy in this population. Citation Format: Wildiers H, Tryfonidis K, dal Lago L, Vuylsteke P, Curigliano G, Waters S, Brouwers B, Aalders K, Meulemans B, Litiere S, Touati N, Cardoso F, Brain E. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II 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 PD3-09.

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 &amp;lt;50%. LVEF recovery was defined as at least a 10% increase in LVEF or LVEF &amp;gt;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 &amp;lt;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.

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.

Abstract P4-21-05: Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study

Abstract INTRODUCTION Targeting HER2 by dual blockade with trastuzumab (T) and pertuzumab (P) in a taxane-based regimen is an active neoadjuvant treatment (NAT) of HER2+ early breast cancer (EBC). Addition of an anthracycline could further enhance this response, but potential cardiac toxicity is a concern. The Opti-HER HEART trial (NCT01669239) aims to optimize neoadjuvant treatment while minimizing cardiac risk, by combining T+P with a taxane and non-pegylated liposomal doxorubicin (NPLD). MATERIAL AND METHODS Phase II open-label, single-arm study of six 21-day cycles of NPLD (50mg/m2 D1), paclitaxel (80mg/m2 D1,8,15), T (4mg/kg C1D1, followed by 2mg/kg weekly), and P (840mg C1D1, followed by 420mg C2-6D1) as NAT for patients (pts) with stage II-IIIB HER2+ BC. Primary objective was to evaluate cardiac safety of the combination, measured by the incidence of type A (symptomatic congestive heart failure ) or type B [asymptomatic reduction of Left Ventricular Ejection Fraction (LVEF) value: ≥10% absolute decrease and LVEF&amp;lt;50%, LVEF&amp;lt;40% or any absolute decrease ≥20%] events, during NAT. Eighty-three pts were required to reject with 80% confidence the null hypothesis that the combination increases the incidence of cardiac events above the historical control of 18% (3% type A; 15% type B). RESULTS Between June 2013 and January 2015, 83 pts with HER2+ EBC (stage II 78%, stage III 22%) and adequate cardiac function (LVEF≥55%) were enrolled. Mean age was 50 years, N+ 47%, hormone receptor (HR) positive 71% and median baseline LVEF 66%. Eighty-five percent of pts completed 6 cycles of NAT, whereas 15% discontinued NAT due to toxicity. Adverse events (AEs) leading to dose adjustments/temporary interruptions and discontinuation of at least 1 drug occurred in 70% and 21% of pts, respectively. Primary objective was met with an incidence of cardiac events during NAT of 4% (95%CI 1-10, 3pts, all type B). Cardiac events until study completion (1 year) were 8% (all type B). All (but 2 cases with no follow-up data) were reversible and only 1 pt presented an asymptomatic LVEF&amp;lt;40%. Neutropenia (45%) was the most frequent hematological toxicity (G3/4 34%; febrile neutropenia 6%), less frequent in the 71% of pts that received primary G-CSF prophylaxis (G3/4 25% vs. 67%). Common non-hematological toxicities were diarrhea (74%; G3 7%), asthenia (78%; G3 11%) and neurotoxicity (52%; G3/4 10%). Pathological complete response (pCR) in breast+axilla (ypT0/is ypN0) was 60% (87% in HR-) and 69% in breast (91% in HR-). TOTALHR-HR+% ypT0/is (95% CI)69 (58-79)91 (72-99)61 (47-74)% ypT0/is ypN0 (95% CI)60 (46-71)87 (66-97)50 (36-64) CONCLUSIONS The neoadjuvant combination of T+P, paclitaxel and NPLD does not increase the risk for cardiac events in HER2+ BC pts. Since cardiac toxicities may present later, long-term cardiac monitoring is essential. Efficacy in terms of pCR was remarkable, being higher to historical values of combinations with dual anti-HER2 blockade and one of the highest reported among HR-HER2+ BC. This regimen administered with primary G-CSF prophylaxis and cardiac function monitoring may be an effective and secure option for early and locally advanced HER2+ pts with good cardiac function. Citation Format: Gavilá J, Perez-Garcia J, Calvo I, Ciruelos E, Muñoz M, Virizuela JA, Ruiz I, Andrés R, Morales S, Perelló A, Sánchez P, Garcia-Saenz JA, Quero Guillen JC, González-Santiago S, Garau Llinas I, González-Martín A, Cantos Sánchez de Ibargüen B, Zaragoza K, de la Peña L, Llombart-Cussac A, Oliveira M. Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study [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 P4-21-05.

Abstract P4-14-09: Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience

Abstract Background: Trastuzumab (H) improves disease-free survival and overall survival in HER2+ early breast cancer (EBC) but is associated with risk of treatment-induced cardiotoxicity especially when administered after an anthracycline. We performed a single center retrospective study to assess the cardiac safety of adjuvant trastuzumab therapy without anthracyclines in a real-world clinical setting. Methods: Patients (pts) with HER2+ early breast cancer (EBC) who received H without anthracycline-based chemotherapy between January 2010 and June 2014 were studied. Patients enrolled in a clinical trial were excluded. Tumor characteristics, chemotherapy regimen, cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. A cardiac event (C.E.) was defined as New York Heart Association class III or IV heart failure with LVEF decline of &amp;gt; 10% to &amp;lt; 55% or possible/probable cardiac death, as previously defined by the NSABP B-31 trial. Results: In total, 174 pts with HER2+ EBC treated with H-based therapy without anthracyclines were identified. Median age was 59 years (range, 32 to 85 years), 72 (41%) had hypertension, 55 (32%) had hyperlipidemia, 29 (16%) had diabetes, and 5 (3%) had coronary artery disease. At baseline, all pts had a LVEF &amp;gt; 50% (median, 66%; range, 50% to 81%). Two (1.1%) pts developed a C.E. Both pts had risks factors for C.E. (1 - age &amp;gt; 60 years, hypertension, and prior history of anthracycline exposure; 1- age &amp;gt; 60 years, hypertension, hyperlipidemia, and baseline LVEF of 50-55%). After discontinuation of H, both patients had recovery of LVEF to &amp;gt; 50% and resolution of heart failure symptoms. Twelve (6.9%) pts developed asymptomatic LVEF decline of &amp;gt; 10% points to &amp;lt; 55% during H therapy. Of the 14 patients who developed cardiotoxicity, H was prematurely interrupted or discontinued in 8 patients. Conclusion: In our single center experience of patients being treated off study, the incidence of C.E.s and asymptomatic LVEF decline during H therapy without an anthracycline was 1.1% and 6.9%, respectively. These appeared higher than events reported in clinical trials possibly due to the inclusion of an older group of women with a higher prevalence of cardiovascular risk factors. Overall, the incidence of symptomatic heart failure is low for H without an anthracycline even in this older group. Citation Format: Mukku RB, Verma S, Liu J, Steingart R, Hudis C, Yu AF, Dang C. Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-09.

Trastuzumab induced cardiotoxicity in HER2-positive metastatic esogastric cancers.

152 Background: Trastuzumab is widely used in Her2 positive metastatic esophageal and gastric cancers along with chemotherapy. Cardiotoxicity of trastuzumab has been described precisely in Her2 positive breast cancers and occurs with asymptomatic lowering of LVEF (Left Ventricular Ejection Fraction) in up to 10% of cases. Esogastric cancer patients are usually older and have more comorbidities than patients followed for breast cancer. Methods: This monocentric retrospective study measured the incidence of symptomatic and asymptomatic cardiotoxicity in patients treated for metastatic esogastric cancers and its potential impact regarding overall survival from October 2009 to September 2015. Patients should receive trastuzumab with chemotherapy during the period of study for treatment of Her2 positive metastatic esogastric cancer as first-line chemotherapy. Results: 27 patients received trastuzumab along with chemotherapy during the period of study. Median age was 62.3 years, sex ratio 21 M/6 W. The median number of cycles of trastuzumab was 5 cycles. The asymptomatic cardiotoxicity rate, defined by a drop of more than 10% of LVEF between the enrollment echocardiogram and the third month treatment echocardiogram, was of 22%. Symptomatic cardiotoxicity was observed in two patients (7.4%), with one cardiac failure and one myocardial infarction, with no associated death. Cardiovascular comorbidities and cardiac irradiation which is recurrent in this indication did not appear as a predictive factor of cardiotoxicity (p = 1). Overall survival of patients was not statistically modified by the occurring of cardiotoxicity even if we noted a trend to better outcome of the patients presenting an asymptomatic LVEF lowering. Conclusions: This study is to our knowledge the first to focus specifically on the cardiotoxicity of trastuzumab in esogastric metastatic Her2 positive cancer in the real world. These patients seem to be at a higher asymptomatic cardiac risk than breast cancer patients. However cardiovascular comorbidities didn’t appear as predictive factors of trastuzumab induced cardiotoxicity and should not prevent patient from benefiting of this treatment.