Trastuzumab-induced Cardiotoxicity Research Articles

Trastuzumab chemotherapy subclinical cardiotoxicity in patients with breast cancer: A two-dimensional speckle tracking echocardiography study

Trastuzumab chemotherapy has been associated with left ventricular (LV) dysfunction. We aimed to assess early changes in LV and right ventricular (RV) mechanics associated with trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)-speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity. Thirty-one patients with breast cancer who received Trastuzumab treatment were included. Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), 4 months (T1), and 12 months (T2). All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. Cardiotoxicity developed in 6 of the 31 patients (19%). The mean (±SD) LVEF at T0 was 66% (± 6); at T1 60% (± 7); and at T2, 54% (± 6). Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, −14.7; sensitivity, 91%; specificity, 82%; P = 0.003). The average 2D LV GLS was −20.58% (± 2.2) with a statistically significant decrease at T1 and T2 (LVGLS −19.35 (± 2.1) and−18.55 (± 2.3), P < 0.001 respectively). The average 2D LV radial strain was 34.71% (± 7.8) and the circumferential strain was −18.92% (± 3.9). Compared with baseline (T0), LVGLS, LV circumferential strain, and right ventricular longitudinal strain at T1 and T2 were reduced significantly in patients with cardiotoxicity ( P < 0.05). Trastuzumab treatment leads to early deterioration of LV GLS and circumferential strain. Right ventricular GLS and radial strain were also affected. Early changes in GLS are good predictors of subsequent development of trastuzumab-induced cardiotoxicity.

A Genome-Wide Association Study Identifies Five Novel Genetic Markers for Trastuzumab-Induced Cardiotoxicity in Japanese Population.

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.

The Preventive Role of Angiotensin Converting Enzyme Inhibitors/Angiotensin-II Receptor Blockers and β-Adrenergic Blockers in Anthracycline- and Trastuzumab-Induced Cardiotoxicity.

Anthracycline (doxorubicin) and trastuzumab treatments for cancer patients have been known to cause cardiotoxicity. The current recommendations for prevention of cardiac events from cancer chemotherapies are largely based on opinion. The American Society of Clinical Oncology recommends active screening and prevention of modifiable cardiovascular risk factors. The risk factors are defined as tobacco use, high blood pressure, high cholesterol, alcohol use, obesity, and physical inactivity. Beta-adrenergic blockers and angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) have been the mainstay of treatment for heart failure patients with reduced left ventricular ejection fraction for many years. This review analyzed the use of beta-adrenergic blockers and ACE inhibitors/ARBs as protection against cardiomyopathy caused by anthracyclines and trastuzumab. Although many more studies are warranted, it was concluded that the addition of a beta-blocker early in the treatment of cancer patients who are undergoing anthracycline or trastuzumab treatment can have beneficial effects in preserving left ventricular ejection fraction and preventing chemotherapy-induced cardiotoxicity. The effects are more apparent in the short term. More studies of the long-term effects are warranted, as are the additive effects of using a beta-blocker and ACE inhibitor/ARB together to prevent chemotherapy-induced cardiotoxicity.

Early Detection of Radiation- and Trastuzumab-Induced Acute Cardiotoxicity by Echocardiography in Mice

Early Detection of Radiation- and Trastuzumab-Induced Acute Cardiotoxicity by Echocardiography in Mice

Trastuzumab-Induced Cardiomyopathy.

Trastuzumab targets the human epidermal growth factor receptor 2 (HER2). Its overexpression occurs in 25% of breast cancers and is associated with aggressive tumor characteristics and poor prognosis in absence of targeted therapy. Trastuzumab dramatically improves HER2-positive breast cancer outcomes; however, its clinical use is associated with left ventricular dysfunction and heart failure. Patients receiving trastuzumab or other HER2-targeted therapies undergo routine cardiac function assessment. Holding and/or stopping trastuzumab treatment in the setting of left ventricular dysfunction is recommended. This article summarizes the role of trastuzumab in cancer treatment, the mechanisms of trastuzumab-induced cardiotoxicity, recent clinical investigations, and current controversies.

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 2951: A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity

Abstract Purpose: Trastuzumab has been administered to HER2-positive breast or gastric cancer patients as an effective treatment, however, the cardiotoxicity is identified as one of the life-threatening side effects. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a genome-wide association study (GWAS). Experimental Design: We carried out a GWAS using 11 cases (with trastuzumab-induced cardiotoxicity) and 257 controls (showing no sign of trastuzumab-induced cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed smallest P value in GWAS (P = 1.61 x 10-7 -1.97 x 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. Results: The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (chromosome 13q14.3, 4q25, 15q26.3, 17q25.3 and another 15q26.3, Pcombined = 6.00 x 10-6, 8.60 x 10-5, 1.01 x 10-4, 1.07 x 10-4, 1.60 x 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity, using five SNPs which revealed smallest P value at each locus. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was 42.5% (P =8.69 x 10-15) . This scoring system using five candidate loci could be used to predict the risk of the adverse event before administration of trastuzumab. Conclusion: We identified five novel loci, which could be associated with trastuzumab-induced cardiotoxicity. These findings provide new insights into personalized trastuzumab therapy for patients with HER2-positive cancer. Citation Format: Chihiro Udagawa, Mari Hara, Arata Shimo, Yasuyuki Kojima, Reiko Yoshie, Hisamitsu Zaha, Norie Abe, Tokiwa Motonari, Mikiko Unesoko, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Hiroshi Okamura, Taisei Mushiroda, Koichiro Tsugawa, Hitoshi Zembutsu. A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2951.

Single-cell RNA sequencing reveals novel gene expression signatures of trastuzumab treatment in HER2+ breast cancer: A pilot study.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for ∼20% of invasive breast cancers and is associated with poor prognostics. The recent outcome of HER2+ breast cancer treatment has been vastly improved owing to the application of antibody-targeted therapies. Trastuzumab (Herceptin) is a monoclonal antibody designed to target HER2+ breast cancer cells. In addition to improved survival in the adjuvant treatment of HER2+ breast cancer, trastuzumab treatment has also been associated with cardiotoxicity side effect. However, the molecular mechanisms of trastuzumab action and trastuzumab-mediated cardiotoxicity are still not fully understood. Previous research utilized bulk transcriptomics analysis to study the underlining mechanisms, which relied on averaging molecular signals from bulk tumor samples and might have overlooked key expression features within breast cancer tumor. In contrast to previous research, we compared the single cancer cell level transcriptome profile between trastuzumab-treated and nontreated patients to reveal a more in-depth transcriptome profile. A total of 461 significantly differential expressed genes were identified, including previously defined and novel gene expression signatures. In addition, we found that trastuzumab-enhanced MGP gene expression could be used as prognostics marker for longer patient survival in breast invasive carcinoma patients, and validated our finding using TCGA (The Cancer Genome Atlas) breast cancer dataset. Moreover, our study revealed a 48-gene expression signature that is associated with cell death of cardiomyocytes, which could be used as early biomarkers for trastuzumab-mediated cardiotoxicity. This work is the first study to look at single cell level transcriptome profile of trastuzumab-treated patients, providing a new understanding of the molecular mechanism(s) of trastuzumab action and trastuzumab-induced cardiotoxicity side effects.

Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer

BackgroundTrastuzumab is highly effective for human epidermal growth factor receptor type 2 (HER2)–positive breast cancer but is associated with a decline in left ventricular ejection fraction. ObjectivesThe purpose of this study was to determine whether angiotensin-converting enzyme inhibitors or beta-blockers reduce the rate of trastuzumab-induced cardiotoxicity (left ventricular ejection fraction decrease >10%, or >5% if below 50%) and limit treatment interruptions. MethodsIn this double-blind, multicenter, placebo-controlled trial, cardiotoxicity and treatment interruptions in patients with HER2-positive breast cancer treated with trastuzumab for 12 months were evaluated over a 2-year period. Patients were stratified by anthracycline use and then randomized to receive lisinopril, carvedilol, or placebo. ResultsThe study included 468 women, age 51 ± 10.7 years. For the entire cohort, cardiotoxicity was comparable in the 3 arms and occurred in 32% of patients on placebo, 29% on carvedilol, and 30% on lisinopril. For patients receiving anthracyclines, the event rates were higher in the placebo group (47%) than in the lisinopril (37%) and the carvedilol (31%) groups. Cardiotoxicity-free survival was longer on both carvedilol (hazard ratio: 0.49; 95% confidence interval: 0.27 to 0.89; p = 0.009) and lisinopril (hazard ratio: 0.53; 95% confidence interval: 0.30 to 0.94; p = 0.015) than on placebo. In the whole cohort, as well as in the anthracycline arm, patients on active therapy with either angiotensin-converting enzyme inhibitor or beta-blockers experienced fewer interruptions in trastuzumab than those on placebo. ConclusionsIn patients with HER2-positive breast cancer treated with trastuzumab, both lisinopril and carvedilol prevented cardiotoxicity in patients receiving anthracyclines. For such patients, lisinopril or carvedilol should be considered to minimize interruptions of trastuzumab. (Lisinopril or Coreg CR in Reducing Side Effects in Women With Breast Cancer Receiving Trastuzumab; NCT01009918)

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.

Effect of HER2/neu 655 polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.

1025 Background: HER2 overexpression in breast cancer is associated with a poor outcome, high risk of metastasis and a reduced overall survival. The introduction of Trastuzumab in the treatment scheme improved the prognosis of these patients. Nevertheless, around 20% of patients develop cardiotoxicity. The purpose of this study is to analyze the association of the HER2 Ile655Val A &gt; G polymorphism with trastuzumab-induced cardiotoxicity and with survival. Methods: The study included 93 patients recruited from San Cecilio University Hospital in Granada (Spain) who were treated intravenously with Trastuzumab. The cardiotoxicity was diagnosed during the treatment follow-up considering a decrease of the left ventricular ejection fraction (LVEF) from baseline or clinical manifestation of congestive heart failure. HER2 655 A &gt; G was genotyping using TaqMan SNP technology. Results: Genotype frequencies of HER2/neu 655 met Hardy-Weinberg equilibrium ( p= 0.363). We did not find differences in baseline LVEF in patients who developed cardiotoxicity vs those who did not. However, in cardiotoxicity group, the symptomatic patients had a baseline LVEF significantly lower than non-symptomatic patients (57.7 vs 66.1, p &lt; 0.028). Logistic regression analysis adjusted by hormonal status and anthracycline treatment showed significant differences between AG and AA (OR = 3.00, CI95% 1.07-8.41, P= 0.037) or AG and AA+GG (OR = 3.21, CI95% 1.15-8.96, P= 0.026). However, we did not find association between Her2/neu Ile655Val polymorphism and disease-free survival or global survival. Conclusions: HER2 655 A &gt; G polymorphism is significantly associated with higher risk of trastuzumab-induced cardiotoxicity but is not associated to a differential survival rate.

Chemotherapy and trastuzumab-induced cardiotoxicity in geriatric breast cancer patients.

e23043 Background: Cardiotoxicity is a known side effect of anthracyclines &amp; trastuzumab. Dilated cardiomyopathy is the most common form of cardiotoxicity associated with this treatment. Cardiovascular disease &amp; cancer are common conditions in the geriatric populations. These comorbidities complicate the treatment of geriatric breast cancer patients. The purpose of this study was to determine the cardiotoxic effects of chemotherapy &amp; trastuzumab in a geriatric population of breast cancer patients. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Patients were divided in groups depending on the therapy (AC/TAC, CMF, TC and Trastuzumab) they received. Fisher’s exact test was used to calculate overall survival (OS). Results: Of the 269 patients, 72 (26.8%) were offered chemotherapy &amp; 197 (73.2%) were not. Of the patients offered chemotherapy, 58 (21.6%) accepted treatment &amp; 14 (5.2%) declined. 17 (6.7%) had an early termination, AC n = 11,( 4.1%), TAC n = 13, (4.8%), CMF n = 0, (0%), Trastuzumab n = 12, (4.5%), TC n = 11, (4.1%). Cardiovascular risk factors taken into consideration were, CAD n = 30, (13.8%), HLD n = 23, (10.6%), HTN n = 98, (45.2%), HTN/HLD n = 66, (30.4%), DM (N = 45, (16.7%), Smoking n = 121, (46.4%) &amp; BMI &gt; 30, n = 116,( 48.1%). Patients completing chemotherapy had higher OS than patients who had early termination (P = 0.017). Of the 24 patients who received Anthracycline containing regimen, 1 experienced cardiotoxicity. There was no statistically significant difference in OS between AC, TAC &amp; Trastuzumab (P = 0.570, P = 0.547, P = 0.614). A decrease in OS was seen for patient who received TC (P = 0.002). Of the 12 who received trastuzumab, 1 experienced cardiotoxicity. There was a significant association between patients with a high BMI ( &gt; 30) &amp; increased cardiovascular comorbidities (P = 0.0009) but had no impact early on termination of chemotherapy or OS, NS (P = 0.7). Conclusions: The cardiotoxic effect of anthracyclines and trastuzumab are well known, however in our study, only 2 elderly breast cancer patients who received chemotherapy experienced cardiotoxicity. As would be expected, those who completed chemotherapy had improved OS. There were no difference in OS between AC, TAC and Trastuzumab, however TC treatment was associated with a decrease in OS.BMI had an impact on cardiovascular comorbidities but not on early termination of chemotherapy or OS.

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 P2-13-05: Prevalence of trastuzumab-induced cardiotoxicity in a real-world setting

Abstract Background: Trastuzumab treatment plus adjuvant or neoadjuvant chemotherapy is the standard of care for women with HER2 positive breast cancer. Despite relative low rates of cardiotoxicity observed in randomized clinical trials, trastuzumab interruption driven by LVEF reduction is a major concern in current clinical practice. Patients and methods: We retrospectively identified women with stage I-III HER2 positive breast cancer who received 12 months of trastuzumab treatment after adjuvant or neoadjuvant chemotherapy at Instituto Nacional de Cancerología (INCan, Mexico City), between 2006 and 2018. Patients were eligible if a pre-therapy MUGA scan and ≥2 subsequent follow-up scans were available. Cardiotoxicity was defined as a ≥10% LVEF reduction to a value &amp;lt; 50%, associated with trastuzumab interruption. Results: 910 patients were included, with a median age at diagnosis of 50 (24-85) years and a median follow up of 7 (2-11 ) years. Among the whole cohort, 10.3% of patients had diabetes, 15.4% had hypertension, 78% were obese/overweight, and 40% had positive estrogen and/or progesterone receptor status. Anthracycline-based therapy was used in 819 (90%) patients, with a median (doxorubicin equivalent) cumulative dose of 200 mg/m2 (IQR 180-240). The median baseline LVEF was 61.8% (50-88.9). In total, 94 (10.3%) patients developed cardiotoxicity, but symptomatic heart failure was observed in only 31 (3.4%) individuals. In univariable analyses, the development of cardiotoxicity was not associated significantly with cardiovascular risk factors. Conclusions: In this large single-center cohort, cardiotoxicity rates remain high, thus, interventions to minimize the risk of cardiotoxicity and trastuzumab treatment interruption should be considered. Citation Format: Calvillo-Argüelles O, Flores-Diaz D, Gonzalez-Serrano J-P, López-Rojas A, Mendoza-Galindo L, Matus-Santos J-A, Reynoso-Noverón N, Cabrera-Galeana P, Bargalló-Rocha E, Arce-Salinas C. Prevalence of trastuzumab-induced cardiotoxicity in a real-world setting [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 P2-13-05.

Serial Measurements of Left Ventricular Systolic and Diastolic Function by Cardiac Magnetic Resonance Imaging in Patients with Early Stage Breast Cancer on Trastuzumab

Our aim was to evaluate the temporal changes in left ventricular (LV) diastolic filling in relation to other LV parameters using cardiac MRI (CMR) in patients with HER2 positive breast cancer receiving trastuzumab therapy. Fourty-one women with early stage HER2+ breast cancer underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab therapy. A single, blinded observer measured LV parameters on de-identified CMRs in random order. Linear mixed models were used to investigate temporal changes. Compared to baseline, there were significant decreases in systolic function as measured by both left ventricular ejection fraction (LVEF) (p <0.001 at 6 and 12 months) and peak ejection rate corrected for end-diastolic volume (PER/LVEDV) (p = 0.008 at 6 months, p = 0.01 at 12 months). However, these differences were no longer significant at 18 months. In contrast, significant reductions in diastolic function as measured by LV peak filling rate corrected for end-diastolic volume (PFR/LVEDV) were observed at 6 months (p = 0.012), 12 months (p = 0.031), and up to 18 months (p = 0.034). There were no significant temporal changes in the time to peak filling rate corrected for cardiac cycle (TPF/RR). The reduction in PFR/LVEDV at 18 months was no longer significant when corrected for heart rate. In conclusion, there were significant subclinical deleterious effects on both LV systolic and diastolic function among patients receiving trastuzumab. While there was recovery in LV systolic function after therapy cessation at 18 months, reduction in PFR/LVEDV appeared to persist. Thus, diastolic dysfunction may serve as a marker of trastuzumab-induced cardiotoxicity that needs to be confirmed in a larger study.

Risk Factors Associated with Trastuzumab-induced Cardiotoxicity in Patients with Human Epidermal Growth Factor Receptor 2-positive Breast Cancer.

Context:Although trastuzumab is a highly effective and selective targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the drug-induced cardiotoxicity may confine its usefulness in patients.Aim:To explore risk factors associated with the development of cardiotoxicity in patients with HER2-positive breast cancer.Settings and Design:A retrospective review of medical records and chart review for all patients with breast cancer treated with trastuzumab was conducted at King Abdulaziz Medical City and King Abdullah Specialized Children Hospital in Riyadh, Kingdom of Saudi Arabia, between October 2015 and February 2018. Patients with declined left ventricular ejection fraction, either with or without cardiac symptoms, were recognized as those with cardiotoxicity due to trastuzumab administration.Results:A total of 146 patients were included in the study with an average age of 52.7 (standard deviation = 12.2) years. Thirty-two (21.9%) patients developed cardiotoxicity. However, only 24 (16.4%) were symptomatic with an apparent heart failure but it did not necessitate interruption of trastuzumab therapy. The majority of patients had prior underlying cardiovascular diseases. This study identified unilateral tumor site (62.5%), breast surgery (37.5%), and concomitant taxane chemotherapy (62.5%) as the main risk factors associated with significant increase in cardiotoxicity in patients with breast cancer (with P values of 0.0269, 0.0482, and 0.0225, respectively).Conclusion:The majority of patients (more than 90%) developed cardiotoxicity after completion of chemotherapy. However, recruiting a larger sample size should be warranted to confirm or negate these findings.

Valvular heart disease as a possible predictor of trastuzumab-induced cardiotoxicity in patients with breast cancer.

Although the use of trastuzumab has been reported to improve overall survival in patients with HER2-positive breast cancer, there is increasing concern about the adverse effects of trastuzumab-induced cardiotoxicity (TIC). The aim of the present study was to investigate the predictor of TIC and to consider appropriate management for such patients. The present study breast cancer 119 patients with breast cancer who had been treated with trastuzumab. Patients were referred to our department for cardiac function screening. The patients' baseline characteristics, echocardiographic data, presence of trastuzumab-induced cardiotoxicity (TIC) and all-cause mortality were investigated. TIC was defined as a manifestation of overt heart failure or ≥10% reduction of left ventricular ejection fraction (LVEF) from baseline to an LVEF <55% in asymptomatic patients. During the follow-up period (mean, 1,410 days), symptomatic heart failure occurred in 2 out of 119 patients (1.6%), 11 patients (9.2%) had asymptomatic impairment of cardiac function that was ameliorated by discontinuing trastuzumab and 20 patients (16.8%) succumbed to cancer-associated fatality. In the logistic regression analysis, only the presence of valvular heart disease at the baseline was indicated to be a predictor of TIC. There was no other predictor for TIC, including baseline characteristics, other therapies and echocardiographic parameters. In addition, impairment of cardiac function was ameliorated by discontinuing trastuzumab. TIC occurred in ~10% of the patients treated with trastuzumab. Only the presence of valvular heart disease seems to be associated with occurrence of TIC, with no other specific predictor of TIC demonstrated in the present study. The present data suggests the importance of regular monitoring of cardiac function, and that presence of valvular heart disease may be a possible predictor of TIC.

Diastolic dysfunction can precede systolic dysfunction on MUGA in cancer patients receiving trastuzumab-based therapy

BackgroundTrastuzumab (T) and anthracycline (A)-based chemotherapy is considered the standard of care in human epidermal growth factor receptor-2+ overexpressing breast cancer, but requires monitoring for known cardiotoxicity using left ventricular (LV) ejection fraction (EF) every 3–4 months during treatment. It is not conclusively established whether diastolic dysfunction (DD) precedes LVEF decrease in patients developing trastuzumab-induced cardiotoxicity (TIC).ObjectiveThe aim was to elucidate whether DD precedes LVEF decrease in trastuzumab-treated patients being monitored with radionuclide multigated acquisition for TIC.Patients and methodsPatients treated with T±A-based chemotherapy who had undergone multigated acquisition were selected by date range (January 2006–September 2015). Up to four scans were analyzed per patient: (a) pre-A therapy, (b) pre-T therapy, (c) 4 months into T therapy, and (d) at end of T therapy. Baseline referred to the first scan of each patient (i.e. pre-A or pre-T). LV systolic and DD were defined as follows: EF less than 50% or a 10-point decrease from baseline and LV peak filling rate (PFR) less than 2.5 end-diastolic volume/s and time to peak LV filling rates (TPFR) greater than 180 ms, respectively.ResultsA total of 202 patients were screened for this study, of whom 153 had received A therapy (5.1±4.1 months duration) before T, 192 had 4 months of follow-up data, and 146 had 4 months of follow-up data and beyond (10.5±5.0 months). LVEF decreased with A and T therapy (P<0.005), but remained stable between 4 months and the final exam (P=0.26). In patients with normal diastolic function at baseline (45.5%), PFR decreased with A and T, and DD preceded SD by 73 days on average. In the remaining patients, with abnormal diastolic function at baseline (54.5%), PFR did not change over the course of treatment (P>0.1), nor did TPFR (P>0.3).ConclusionPatients with normal diastolic function at baseline receiving trastuzumab±anthracycline adjuvant therapy may develop DD before SD, therefore offering an opportunity for early referral to cardiologists to optimize cardiovascular risk factors and manage cardiotoxicity.

Prolonged electromechanical delay as an early predictor of trastuzumab-induced cardiotoxicity in patients undergoing treatment for breast cancer.

We aimed to investigate if left ventricular electromechanical delay (LVEMD) prolongation predicts trastuzumab-induced cardiotoxicity (TIC) in breast cancer patients. LVEMD prolongation on serial echocardiograms could be an indicator of subclinical TIC. We included 237 breast cancer patients receiving trastuzumab chemotherapy, who underwent echocardiography at baseline and at 6 and 12 months after trastuzumab initiation. LVEMD was defined as the time from electrical activation to myocardial contraction. TIC was defined as left ventricular ejection fraction (LVEF) worsening to <55%, either as symptomatic decrease of ≥5% or asymptomatic decrease of ≥10%. During a mean follow-up of 547 days, TIC occurred in 27 patients (11.4%). Changes in the time intervals from QRS onset on electrocardiography to the beginning and peak of transaortic flow on pulsed-wave Doppler echocardiography (ie, ΔLVEMDi and ΔLVEMDp, respectively) were independent predictors of TIC. On receiver operating characteristic curve analysis, the optimal cutoff value for TIC prediction was 23 milliseconds for ΔLVEMDi (sensitivity, 0.85; specificity, 0.78; area under the curve [AUC], 0.882) and 21 milliseconds for ΔLVEMDp (sensitivity, 0.96; specificity, 0.68; AUC, 0.860). The C-index for TIC prediction increased significantly after adding ΔLVEMDi and ΔLVEMDp to conventional models that included clinical variables, baseline LVEF, and changes in global longitudinal peak systolic strain. Similarly, adding ΔLVEMDi or ΔLVEMDp to conventional models provided significant improvement in discrimination capability for TIC prediction (integrated discrimination improvement and continuous net reclassification improvement index). ΔLVEMDi and ΔLVEMDp may serve as predictors of subclinical cardiac dysfunction in breast cancer patients receiving trastuzumab.

Prediction of trastuzumab-induced cardiotoxicity in breast cancer patients receiving anthracycline-based chemotherapy.

Adjuvant trastuzumab improved overall survival and reduced the risk for disease recurrence in women with breast cancers, because of its potential cardiotoxicity, careful monitoring of left ventricular (LV) function during treatment is required. This study investigates, whether myocardial strain imaging and level of N-terminal pro-brain natriuretic peptide (NT-pro BNP) could predict subsequent reduction in LVEF in breast cancer patients received adjuvant trastuzumab. 61 women with pathologically proven breast cancer HER-2 positive received AC (Doxorubicin-Cyclophosphamide) for 4 cycles, followed by paclitaxel with Trastuzumab were enrolled. Clinical, conventional echocardiographic parameters, myocardial strain imaging [global longitudinal peak systolic strain (GLS), radial and circumferential systolic strain] and level of NT pro-BNP were measured at baseline, after 3, 6, 9 and 12months of trastuzumab therapy. Of 61 patients, 18 patients (29.5%) developed trastuzumab-induced cardiomyopathy (CM) at 6 and 9months of therapy (LVEF declines ≥ 10%), GLS and radial strain significantly decreased in CM group at 3months of trastuzumab treatment, the value of GLS at 3months was the strongest predictors of cardiotoxicity its area under the curve (AUC 0.98) with an optimal cut-off for GLS (- 18%) having 92.5% sensitivity and 83% specificity. NT-pro BNP levels were not predictive of later trastuzumab-induced cardiac dysfunction. Myocardial strain imaging has been able to predict pre-clinical changes in LV systolic function and GLS is an independent early predictor of subsequent reduction in EF in breast cancer patients treated with trastuzumab.