Discontinuation Of Trastuzumab Research Articles

Cardiac Toxicity of Trastuzumab in Patients Treated for Breast Cancer HER2 3+ An Algerian Study

Breast cancer is the most common cancer in women worldwide, its incidence is increasing but mortality has decreased in a huge way due to the growth of various cancer treatments. Patients with a contraindication for trastuzumab, an incomplete cardiographic echo record, and patients with already heart disease were excluded from the history. The means of cardiac monitoring was cardiac ultrasound or isotopic ventriculography, the toxicity criteria were those of the New York Heart Association (NYHA), a detailed operating sheet was made for each of our patients. The main objective of our study was to assess the incidence of cardiotoxicity in patients treated for breast cancer HER 2 3+ by trastuzumab.06% of our patients had had trastuzumab cardiotoxicity (i.e. 3 cases); two patients had an asymptomatic decrease in reversible LVEF and one patient had clinically significant heart failure requiring appropriate treatment for ICS and permanent discontinuation of trastuzumab. The protocols of targeted therapy with trastuzumab are an essential progress in oncology and cardiac toxicity is the major limiting factor for its use. Our work focuses on a retrospective study, conducted at the Department of Oncology and the Hospital Ahmida Ben adjila discussing cardiotoxicity of tarstuzumab in 50 patients with breast cancer HER2 3+ collected from january 2014 to december 2019.we have included in this study all patient with breast cancer overexpressing HER2 3+ treated by trastuzumab with an initial heart function and preserved LVEF ≥5 5%. We excluded patients contre to trastuzumab, incomplete echocardiographic folder, patients who received neoadjuvant trastuzumab and patients with metastatic breast cancer. Cardiotoxicity with trastuzumab is not common enough in our series but it does exist, which requires several careful preventive measures including monitoring by echocardiography.

Abstract 6298: The value of routine trastuzumab-related cardiac toxicity monitoring in gastrointestinal cancers

Abstract Background: It is a common practice to monitor trastuzumab-related cardiac toxicity (TRCT) using left ventricular ejection fraction (LVEF) in patients who receive trastuzumab-containing therapy for human epidermal growth factor receptor 2 (HER2)-positive cancers. However, this monitoring approach does not appear cost effective in patients with HER2-positive gastrointestinal (GI) cancers given poor overall survival (OS). Here, we aim to examine the incidence of clinically significant TRCT in this target population. Methods: This is a retrospective cohort study of patients with advanced HER2-positive GI cancers who received trastuzumab-containing therapies (trastuzumab +/- pertuzumab, chemotherapy +/- immunotherapy + trastuzumab, trastuzumab deruxtecan) between 2011 and 2023. HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, and/or next generation sequencing. LVEF was estimated by serial transthoracic echocardiograms (TTE). Continuous variables were summarized as median and interquartile range (IQR). Paired Wilcoxon signed rank test was used to compare serial LVEF. OS was estimated using Kaplan-Meier method. Results: A total of 243 patients were included in this study with a median age of 64 (IQR: 55-70) years. 139 (57%) patients had esophageal or GEJ adenocarcinoma; 45 (19%) patients had gastric cancer; 37 (15%) patients had colorectal cancer; and the rest had other GI cancers. Median follow-up time was 18.6 (IQR: 9.2-36) months. Median OS from cancer diagnosis and the first dose of trastuzumab-containing therapy were 24.1 (95%CI: 20.2-30.2) and 11.7 (95%CI: 10.4-15.6) months, respectively. Patients received a median of 13 cycles of trastuzumab-containing therapy for a median duration of 4.1 (IQR: 1.4-10.1) months. The median number of TTE each patient had throughout therapy was 2 (IQR: 1-4). Median baseline LVEF was 61% (IQR: 56-65%) which was significantly higher (p<0.001) than the median lowest LVEF of 58% (IQR: 53-62%) during therapy, but not different (p=0.14) from the most recent median LVEF of 60% (IQR: 56-64%) after discontinuation of trastuzumab. Among 176 patients with serial LVEF data, 16 (9%) had > 10% LVEF drop; 7 (44%) of these 16 patients had LVEF recovery. None of the cardiovascular risk factors prior to trastuzumab treatment including hypertension, diabetes, hyperlipidemia, peripheral arterial disease, coronary artery disease, and stroke were significantly associated with the development of TRCT. Conclusion: The incidence of clinically significant LVEF drop appears low in patients with advanced GI cancers as post-treatment LVEF recovery to baseline was observed at the population level. The value of using TTE to monitor TRCT in these patients with short OS should be further assessed in the perspective of cost effectiveness. Citation Format: Samual R. Kosydar, Matteo Castrichini, Mojun Zhu, Hao Xie. The value of routine trastuzumab-related cardiac toxicity monitoring in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6298.

Late-onset cardiotoxicity in patients with HER2-positive metastatic breast cancer receiving trastuzumab-based therapy.

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. Thirty-seven patients were included. Mean age was 56 years (range: 33-78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14-140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11-29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2-6.6, SD 1.1). Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon.

Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab.

Cardiotoxicity, manifest by reduced left ventricular ejection fraction (LVEF), is the most common reason for the premature discontinuation of trastuzumab. While permissive cardiotoxicity (where mild cardiotoxicity is accepted to enable ongoing trastuzumab) has been shown feasible, the longer-term outcomes are unknown. We aimed to study the intermediate-term clinical outcomes of patients who underwent permissive cardiotoxicity. We performed a retrospective cohort study of patients referred to the cardio-oncology service at McMaster University from 2016 to 2021 for LV dysfunction following trastuzumab administration. Fifty-one patients underwent permissive cardiotoxicity. The median (25th-75th percentile) follow-up time from cardiotoxicity onset was 3 years (1.3-4 years). Forty-seven (92%) patients completed trastuzumab; 3 (6%) developed severe LV dysfunction or clinical heart failure (HF) while on trastuzumab and prematurely discontinued therapy. One discontinued trastuzumab by patient choice. At final follow-up after therapy completion, 7 (14%) patients still had mild cardiotoxicity, including 2 who had clinical heart failure and stopped trastuzumab early. Among those with recovered LV function, 50% had normalized LVEF or GLS by 6 and 3 months, respectively, after initial cardiotoxicity. There was no difference in characteristics between those who did or did not recover their LV function. Among patients exposed to permissive trastuzumab cardiotoxicity for HER2-positive breast cancer, 6% were unable to complete planned trastuzumab due to severe LV dysfunction or clinical HF. Although most patients recover their LV function after trastuzumab discontinuation or completion, 14% still have persistent cardiotoxicity by 3-year follow-up.

Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer.

To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Usefulness of Global Longitudinal Strain-Guided Management in Preventing Human Epidermal Growth Factor Receptor 2 (HER2) Inhibitor-Induced Myocardial Damage.

Background: Trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is a specific first-line treatment for patients with HER2-positive cancers. Cardiac dysfunction is among the most problematic adverse events associated with trastuzumab. Although regular echocardiographic screening is recommended for early detection of cardiac damage, few reports have investigated the validity of echocardiographic screening in chemotherapy. Therefore, the aim of this study was to determine whether a GLS-guided management approach could reduce cardiotoxicity and discontinuation of trastuzumab chemotherapy. Methods and Results: To evaluate the usefulness of global longitudinal strain (GLS)-guided cardioprotective interventions, we retrospectively analyzed 67 patients treated with trastuzumab who underwent structured echocardiographic assessments before and after 1, 3, and 6 courses of trastuzumab administration. If a >15% relative decrease in GLS was identified, cardioprotective agents were administered. Thirty (44.8%) patients had breast cancer; the remaining patients had salivary gland cancer. The median observation period for the intervention group was 304 days from the initial evaluation. Nineteen (28.4%) patients exhibited a >15% relative decrease in GLS, and consequently received cardioprotective agents. The incidence of trastuzumab discontinuation for cardiogenic reasons was significantly lower among patients receiving GLS-guided interventions than among those not receiving the intervention (2.4% vs. 24.0%; P=0.009). The incidence of a subsequent decline in left ventricular ejection fraction was lower among patients receiving the intervention than among those not receiving the intervention (4.8% vs. 24.0%; P=0.04). Conclusions: GLS-guided cardioprotective intervention significantly decreased the incidence of trastuzumab discontinuation.

Herceptin-Mediated Cardiotoxicity: Assessment by Cardiovascular Magnetic Resonance.

Herceptin (trastuzumab) is a recombinant, humanized, monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of HER2-positive breast and gastric cancers. However, it carries a risk of cardiotoxicity, manifesting as left ventricular (LV) systolic dysfunction, conventionally assessed for by transthoracic echocardiography. Clinical surveillance of cardiac function and discontinuation of trastuzumab at an early stage of LV systolic dysfunction allow for the timely initiation of heart failure drug therapies that can result in the rapid recovery of cardiac function in most patients. Often considered the reference standard for the noninvasive assessment of cardiac volume and function, cardiac magnetic resonance (CMR) imaging has superior reproducibility and accuracy compared to other noninvasive imaging modalities. However, due to limited availability, it is not routinely used in the serial assessment of cardiac function in patients receiving trastuzumab. In this article, we review the diagnostic and prognostic role of CMR in trastuzumab-mediated cardiotoxicity.

Interventions for Preventing Cardiotoxicity in Breast Cancer Patients Receiving Trastuzumab: A Systemic Review and Bayesian Network Meta-Analysis.

Background: Trastuzumab is associated with the risk of cardiotoxicity. Here, we aim to explore interventions for preventing trastuzumab-related cardiotoxic effects in breast cancer patients.Methods: A systematic review was performed including trials of breast cancer patients with intervention to prevent cardiotoxicity of trastuzumab. Trials were searched through databases including PubMed, Embase, and Cochrane Library.Results: Eight RCTs were included. Five trials reported the outcomes of short-duration interventions, including 6-month and 9-week durations, and only 9-week treatment has a significant difference from the 12-month group (OR 0.38; 95% CI 0.18–0.83) using cardiotoxicity as the outcome. However, 6-month treatment turned out to yield less occurrence of trastuzumab discontinuation (OR 0.32; 95% CI 0.24–0.42). Three trials reported interventions of cardioprotective drugs, and there is no significant difference shown in any cardioprotective group compared with placebo (cardiotoxicity outcome: angiotensin-converting enzyme inhibitor: OR 0.48; 95% CI 0.057–2.3; angiotensin receptor blocker: OR 1.3; 95% CI 0.12–14; β-blocker: OR 0.48; 95% CI 0.057–2.3; trastuzumab interruption outcome: angiotensin-converting enzyme inhibitor: OR 0.45; 95% CI 0.12–1.3; angiotensin receptor blocker: OR 0.87; 95% CI 0.15–4.8; β-blocker: OR 0.41; 95% CI 0.11–1.2).Conclusion: Only the 9-week group has a significant difference from the 12-month group using cardiotoxicity as the outcome. And 6-month treatment turned out to yield less occurrence of trastuzumab discontinuation. The use of cardioprotective drugs failed to prevent trastuzumab-related cardiotoxic effects in breast cancer patients.

Incidence of cardiotoxicity and validation of the Heart Failure Association-International Cardio-Oncology Society risk stratification tool in patients treated with trastuzumab for HER2-positive early breast cancer.

Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates [left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation] and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice. Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher's exact test, Chi-squared and logistic regression were used. 931 patients were included in the analysis. Median age was 54years (range 24-83) and Charlson comorbidity index 0 (0-6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1-18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III-IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high; p = 0.002). Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.

Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab

BackgroundFew data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors. Patients and methodsWe retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity. ResultsWithin 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups. ConclusionOur study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.

Does trastuzumab-related cardiotoxicity influence long-term outcome in patients with HER-2 positive breast cancer? A prospective study

IntroductionTrastuzumab is a monoclonal antibody directed against the HER-2 receptor that has led, in an adjuvant setting, to higher disease-free (DFS) and overall survival (OS) in HER-2 positive breast cancer (BC) compared with chemotherapy alone. Cardiotoxicity often results in early discontinuation of trastuzumab, which may elevate the risk of cancer recurrence or mortality. Our study aimed to assess how early interruption or early permanent termination of adjuvant trastuzumab treatment influences DFS and OS of patients with HER-2 positive BC.Material and methodsThis is a prospective observation of 253 women (55 ±10 years of age) with HER-2 positive unilateral, non-metastatic BC treated with trastuzumab in an adjuvant setting. To monitor the safety of the treatment echocardiography was performed at baseline and every 3 months up to 12 months after the end of therapy. If cardiotoxicity developed, trastuzumab was stopped early. Overall survival and DFS were assessed.ResultsTrastuzumab-associated cardiac complications resulting in treatment discontinuation developed in 52 (20.55%) patients. Median DFS time was 21.1 months in the group with interruption compared with 25.7 months in the group with full trastuzumab treatment, being significantly shorter (HR = 2.32, 95% CI: 1.15–4.71, p = 0.0106). Two year OS in the interruption and no-interruption groups were 80.8% and 88.5%, respectively, which were not statistically significantly different (p = 0.268). In a multivariate regression analysis the cumulative dose of anthracycline (OR = 1.01, 95% CI: 1.00–1.01, p = 0.002) and LVEF at baseline (OR = 0.83, 95% CI: 0.70–0.99, p = 0.0344) were independent predictors of a cardiotoxic effect.ConclusionsTrastuzumab-related cardiotoxicity resulting in early treatment discontinuation negatively influences DFS, but does not seem to influence OS.

Trastuzumab increases pulmonary vein arrhythmogenesis through modulating pulmonary vein electrical and conduction properties via phosphatidylinositol 3-kinase signaling.

Objective(s):Drug-induced atrial fibrillation (AF) is considered an adverse effect of chemotherapeutic drugs. AF is a crucial risk factor for stroke, heart failure, myocardial infarction, and mortality. Pulmonary veins (PVs) are considered triggers inducing AF, and the sinoatrial node (SAN) may modulate PV activity and participate in AF genesis. AF was associated with early discontinuation of trastuzumab in patients with breast cancer. However, whether trastuzumab directly modulates the electrophysiological characteristics of PV and SAN remains unclear. Materials and Methods:ECG and conventional microelectrode system were used to record rabbit heart rhythm in vivo and electrical activities in vitro from isolated SAN, PV, and SAN-PV preparations. Results:Trastuzumab reduced the beating rate in isolated PV and SAN preparations at 1, 10, and 30 μM (particularly in isolated SAN preparations) and induced burst firings in isolated PV preparations at 10 μΜ. In addition, trastuzumab (10 μM) induced SAN-PV conduction block and burst firings, which were blocked by wortmannin (a PI3K inhibitor, 100 nM). Similarly, ECG recordings showed that acute intravenous administration of trastuzumab (10 mg/kg) reduced rabbit heart rates. Conclusion:Trastuzumab increased PV arrhythmogenesis through interfering with PI3K signaling, which may contribute to the genesis of AF.

Impact of Stopping Trastuzumab in Early Breast Cancer: APopulation-Based Study in Ontario, Canada.

Adjuvant trastuzumab for early-stage (I-III) HER2-positive breast cancer (BC) has led to statistically significant improvement in cancer outcomes but carries a risk of cardiotoxicity. Trastuzumab is discontinued early in many patients for asymptomatic changes in left ventricular ejection fraction. We evaluated the impact of early discontinuation of trastuzumab on cancer outcomes. We conducted a retrospective population-based cohort study of early BC patients treated with adjuvant trastuzumab in Ontario, Canada, 2007-2016. Four groups were analyzed: group A was full treatment, 17-18 cycles trastuzumab; group B was cardiac event (CE) within treatment period; group C was ≤16 cycles, no CEs, stopped within 30 days from last cardiac imaging; and group D was ≤16 cycles, no CEs, stopped more than 30 days from cardiac imaging. Primary outcome was disease-free survival (DFS); secondary outcomes were: overall survival, cancer-specific mortality, and cardiovascular mortality. Sensitivity analyses were performed 14 months after cycle 1 trastuzumab to control for early relapse. A total of 5547 patients met the inclusion criteria: group A = 3921, group B = 309, group C = 362, and group D = 955. The 5-year DFS was 94.1% in group A, 80.1% in group B, 81.4% in group C, and 82.4% in group D. Using a Cox model, the hazard ratio for 5-year DFS was 3.15 (95% confidence interval [CI] = 2.13 to 4.65) for group B, 1.94 (95% CI = 1.30 to 2.89) for group C, and 1.92 (95% CI = 1.46 to 2.53) for group D. Overall, 26 patients (0.5%) died of cardiac causes. BC patients in Ontario who did not complete adjuvant trastuzumab had a statistically significantly higher risk of BC relapse and death and low incidence of cardiac death. These findings support 1 year of adjuvant trastuzumab in early-stage BC.

Cardiotoxicity of trastuzumab given for 12 months compared to shorter treatment periods: a systematic review and meta-analysis of six clinical trials

BackgroundTreatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question.Materials and methodsA meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting.ResultsClinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11 250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I2=65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I2=5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I2=11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I2=0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I2=78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias.ConclusionsCompared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity.

Safety of Continuing Trastuzumab Despite Mild Cardiotoxicity: A Phase I Trial

ObjectivesThis study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor–positive breast cancer who developed mild cardiotoxicity. BackgroundCardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity. MethodsPatients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF <40% together with any heart failure symptoms, or LVEF <35%. ResultsAll 20 participants received ACE inhibitors and/or beta-blockers. A total of 18 participants (90%) received all planned trastuzumab doses. Two (10%) participants developed cardiac dose-limiting toxicity (heart failure with LVEF <40%). Their LVEF and heart failure symptoms improved to nearly normal following permanent trastuzumab discontinuation. There were no deaths. LVEF rose progressively from a mean of 49% at enrollment to 55% at 12 months (p < 0.001). ConclusionsIt may be feasible to continue trastuzumab despite mild cardiotoxicity in the setting of a cardio-oncology clinic, where ACE inhibitors and beta-blockers are administered. Approximately 10% of patients may develop moderate to severe heart failure using this approach. (Safety of Continuing Chemotherapy in Overt Left Ventricular Dysfunction Using Antibodies to Human Epidermal Growth Factor Receptor-2 [SCHOLAR]; NCT02907021)

Concomitant use of renin-angiotensin-aldosterone system inhibitors prevent trastuzumab-induced cardiotoxicity in HER2+ breast cancer patients: an institutional retrospective study

BackgroundCardiotoxicity is an adverse effect of trastuzumab (TRA) in the treatment of human epidermal growth factor 2 positive (HER2+) breast cancer. Current literature on the cardioprotective effects of agents targeted against the renin-angiotensin-aldosterone system (RAAS) and beta-blockers (BB) in TRA-treated HER2+ breast cancer patients is conflicting. We hypothesized that concurrent use of RAAS inhibitors would prevent TRA-induced cardiotoxicity (TIC).Methods and materialsSurveillance ejection fraction (EF) at 3-month intervals up to 36 months obtained from echocardiogram or multigated acquisition (MUGA) scans were retrospectively compared to baseline EF in TRA-treated HER2+ breast cancer patients between 2011 to 2016 at a tertiary cancer center. TIC was defined as a decrease of EF by more than 15 EF percentage points from baseline on surveillance imaging. Cardiac medications and comorbidities were compared between patients with reduced EF secondary to TIC (rEF) and patients who did not experience TIC (pEF). A published clinical risk score (CRS) was applied to the patient population with calculated sensitivity analyses to determine if the CRS could predict TIC.ResultsOf 127 patients with TRA-treated HER2+ breast cancer, 11% developed cardiotoxicity resulting in discontinuation of TRA. Cardiotoxicity with reduced EF was seen as early as 3 months and at subsequent 3-month follow up intervals up to the 15-month follow-up. Co-existing arrhythmia, coronary artery disease (CAD), hypertension (HTN) and diabetes mellitus (DM) tended to infer an increased risk for cardiotoxicity. Patients with pEF were found to be concurrently on a RAAS inhibitor more than the rEF group (OR of 0.24, 95% CI 0.05–1.11, p 0.06). The CRS high-risk cut-off had a sensitivity of 0.17 (95% CI 0.03–0.49), specificity of 0.89 (95% CI 0.82–0.94), positive predictive value of 0.14 (95% CI 0.03–0.44) and negative predictive value of 0.91 (95% CI 0.84–0.95).ConclusionOur data suggest that the concurrent use of a RAAS inhibitors during TRA treatment may provide a protective effect against TIC and warrants further investigation. The low sensitivity and positive predictive value demonstrated that the CRS has minimal utility as a screening tool for prediction of patients at high risk for TIC. Therefore, closer surveillance of patients receiving TRA is warranted for early detection of TIC.

Abstract P1-15-17: Liposomal-encapsulated doxorubicin (Myocet)as part of primary systemic therapy in HER2-positive operable breast cancer: Efficacy data, cardiotoxicity and long-term follow-up in 81 patients diagnosed from 2005-2016 at a single institution

Abstract Objectives To evaluate the efficacy, cardiotoxicity profile and long-term benefits of liposomal doxorubicin (Myocet) as part of neoadjuvant therapy in HER2-positive operable breast cancer patients. Methods The treatment consisted of a sequential regimen of paclitaxel and liposomal doxorubicin (Myocet) plus trastuzumab. Clinical and pathologic response were evaluated and correlated with clinical and biological factors. Cardiotoxicity profile and long-term benefits were analyzed. Results Median age was 48 years and 4%, 69%, and 27% were stage I, II, and III, respectively, while 12% had inflammatory breast cancer at diagnosis. Hormone receptor (HR) status was negative in 43% and 70% were grade III. Patients Characteristics Total number (%)Age, years Median (Range)48 (30-79)Tumor (cT)* Tx1 (1)T14 (5)T253 (66)T313 (16)T410 (12)Nodal Status N024 (30)N1-257 (70)Stage I3 (4)II56 (69)III22 (27)Hormone Receptor Status HR+35 (43)HR-46 (57)HER2 IHC 3+74 (91)IHC 2+7 (9)FISH/SISH21 (26)Grade I1(1)II22 (27)III57 (71)Unknown1 (1)Ki-67 &amp;lt;20%6 (7)20-35%32 (40)&amp;gt;35%43 (53)Surgical Indication at Diagnosis Mastectomy58 (72)Tumorectomy22 (27)Any surgery in breast*1 (1)* One patient had an occult carcinoma. pCR by SubgroupsPathologic ResponsepCRNo pCR(n=81)n (%)n (%)Tumor Size (MRI) &amp;lt;/=5 cm26 (49)27 (51)&amp;gt; 5 cm10 (67)5 (33)Nodes Positive26 (46)31 (54)Negative18 (75)6 (25)Histological Subtype Ductal43 (56)34 (44)Lobular0 (0)2 (100)Other1 (50)1 (50)Hormone Receptor Negative23 (66)12 (34)Positive21 (46)25 (54)Ki-67 &amp;lt;204 (67)2 (33)20-3512 (38)20 (62)&amp;gt;3528 (65)15 (35)Grade I0 (0)1 (100)II12 (55)10 (45)III31 (54)26 (46) The clinical complete response rate by ultrasound and MRI were 47% and 65%, respectively, and allowed a high rate of conservative surgery (72%). The pathologic complete response (pCR) rate in breast and axilla was 54%, higher in HR-negative (66%) than in HR-positive (46%),in ki-67&amp;gt;35% (65%) than ki-67 between 20-35% (38%) and similar in grade III (54%) and grade II (55%). Patients who achieved pCR had longer DFS and a trend to improve OS. Four percent of patients showed a decrease in the left ventricular ejection fraction below 50% during treatment. All except one of them recovered after discontinuation of trastuzumab. Conclusion: A sequential regimen of taxanes and liposomal doxorubicin (Myocet) plus trastuzumab was active with high pCR rates and long-term benefit with a very good cardiotoxicity profile. Citation Format: Antolin S, Calvo L, Prato J, Molina A, Reboredo C, Mosquera J. Liposomal-encapsulated doxorubicin (Myocet)as part of primary systemic therapy in HER2-positive operable breast cancer: Efficacy data, cardiotoxicity and long-term follow-up in 81 patients diagnosed from 2005-2016 at a single institution [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 P1-15-17.

Abstract GS5-01: A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab

Abstract Background: Exposure to trastuzumab for one year is an integral part of therapy for patients with early stage HER2-positive breast cancer. Yet, cardiac side effects, particularly in patients who also receive anthracyclines require frequent monitoring and result in dose interruptions and discontinuation of trastuzumab. Prophylactic use of angiotensin converting enzyme (ACE) nhibitors or beta blockers (BB) may prevent cardiotoxicity associated with chemotherapy and trastuzumab. Methods A large community-based prospective double-blind, placebo-controlled trial, evaluated the rates of pre-specified cardiotoxicity in patients with early stage breast cancer treated with one year of trastuzumab. Cardiac events were followed for two years. Patients were randomized to simultaneously receive either the ACE inhibitor, lisinopril, or the BB, carvedilol, or placebo and were further stratified by anthracycline use to determine whether ACE inhibitors or BB can prevent trastuzumab-induced decrease in left ventricular ejection fraction (LVEF) and trastuzumab interruptions. Results: The study included 468 eligible patients (median age:51, BMI:27 kg/m2, baseline systolic BP: 126mmHg and LVEF :63 ± 6.29%) from 127 community-based practices, 189 patients received an anthracycline. For the entire study population and the non-anthracycline group, no difference in number of trastuzumab interruptions were seen. For patients receiving an anthracycline, cardiac event rates were higher in the placebo group (47%), and reduced in both the lisinopril (37%), and the carvedilol (31%) groups. Interruptions of trastuzumab were required in 23% patients on lisinopril and 20% on carvedilol compared to 40% on placebo (p=0.007). Changes in LVEF from baseline (least square means, SE) were significantly reduced with both carvedilol (-4.5 (0.8), p=0.008, and lisinopril (-4.0 (0.8), p=0.002) than placebo, (-7.7 (0.8). Cardiotoxicity-free survival was longer on both carvedilol (hazard ratio 0.49, 95% confidence intervals 0.27, 0.89, p=0.009) or lisinopril (HR 0.53, CI 0.30, 0.94, p=0.015). Conclusions In patients with HER2-positive breast cancer receiving trastuzumab and an anthracycline, both lisinopril and carvedilol during treatment reduced cardiotoxicity in patients, but not in those with non-anthracyline containing regimens. The use of lisinopril or carvedilol may allow the use of an anthracycline without compromising trastuzumab treatment in those who might benefit from an anthracycline. Citation Format: Munster P, Krischer J, Tamura R, Fink A, Bello-Matricaria L, Guilin M. A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab [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 GS5-01.

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.

Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients.

Cardiotoxicity is the most important side effect of trastuzumab treatment. Heart function monitoring is recommended during the treatment which has led to growing use of resources. The aim of this retrospective study was to determine the frequency and timing of trastuzumab cardiotoxicity and its risk factors in real-world setting. Single institute, retrospective collection of data on HER2+ breast cancer patients (n = 246) was carried out through a pharmacy search for patients who had received trastuzumab in 2006-2014. Clinical and pathological factors, treatment history, EF measurements, cardiac medications, cardiovascular disease history, cardiac symptoms, and survival data were collected from patient records. 32 patients (13%) had EF decline ≥ 10%, eleven (4.5%) had EF decline ≥ 20% within 1year after trastuzumab initiation, and trastuzumab was discontinued due to suspected cardiotoxicity in six patients (2.4%). 49 patients (19.9%) experienced symptoms related to cardiotoxicity during therapy, which accumulated among those with EF drop. Underlying cardiovascular diseases and multiple (≥ 2) cardiac medications were related to EF drop (≥ 20%) and trastuzumab discontinuation. Majority of EF drops (≥ 10%) and trastuzumab discontinuations were seen within 6months of trastuzumab initiation and recovery of EF drop to < 10% of the baseline was seen in most cases (62.5%). There was no statistically significant difference in the survival of patients according to EF drop. Trastuzumab cardiotoxicity seems to accumulate among patients with underlying cardiac conditions. EF monitoring could be targeted to risk groups without compromising of the cardiac health or survival of HER2-positive breast cancer patients.