scholarly journals A Polyphenol-Rich Muscadine Grape Extract Inhibits HER + Breast Cancer and Protects Against Trastuzumab-Induced Cardiotoxicity

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 334-334
Author(s):  
Jessica Mackert ◽  
Patricia Gallagher ◽  
Elisabeth Tallant
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Tumor Growth ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Oxidative Stress Marker ◽  
Her2 Receptor ◽  
Ventricular Ejection Fraction ◽  
Her2 Breast Cancer ◽  
Muscadine Grape

Abstract Objectives Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is characterized by overexpression of the HER2 receptor. Although targeted HER2 drugs such as trastuzumab (TRZ) are effective for some patients, many patients experience resistance and cardiotoxicity, highlighting the need for additional therapies. The objective of this study was to determine the effects of a polyphenol-rich muscadine grape skin/seed extract (MGE) on TRZ-sensitive and –resistant HER2 + BC and TRZ cardiotoxicity. Methods Human HER2 + BC cells were treated with MGE and/or TRZ and proliferation was analyzed using the IncuCyte® ZOOM. Synergy was assessed using the Chou-Talalay method. Tumor growth and cardiotoxicity were measured in HER2 + xenografts treated with MGE and/or TRZ. TRZ-resistant JIMT-1 cells (2 × 106) were injected in the fourth mammary fat pad of female nude mice and, when tumors reached 50 mm3, mice were divided into four groups: control, MGE, TRZ, MGE + TRZ (n = 10/group, five week treatment). Cardiac parameters were measured using echocardiography and markers of proliferation/oxidative stress were measured by immunohistochemistry. Results The combination of MGE and TRZ inhibited proliferation to a greater extent than either agent alone and was synergistic in TRZ-sensitive SKBR3 cells at five dose combinations. MGE reduced TRZ-resistant JIMT-1 tumor volume by 35% (p ≤ 0.05); however MGE + TRZ inhibited tumor growth to a greater extent (62%) than either agent alone [combination vs. MGE (p ≤ 0.05); combination vs. TRZ (p ≤ 0.01)]. In tumors, MGE + TRZ reduced Ki-67 and activated AKT to a greater extent than MGE or TRZ alone [combination vs. MGE (p ≤ 0.05); combination vs. TRZ (p ≤ 0.0001)]. TRZ significantly reduced left ventricular ejection fraction and fractional shortening, which was prevented by MGE (p ≤ 0.01). Additionally, MGE significantly attenuated the 3-fold TRZ-induced increase in the oxidative stress marker 4-hydroxynonenal in the left ventricle (p ≤ 0.0001). Conclusions MGE inhibited the proliferation of HER2 + BC and was synergistic when combined with TRZ while protecting against TRZ cardiotoxicity. Thus, MGE may serve as an effective therapeutic either administered singly or in combination with TRZ for the treatment of HER2 + BC. Funding Sources Chronic Disease Research Fund.

Abstract 17055: Novel Dual mTOR Inhibitor/AMPK Activator Mitigates Doxorubicin Cardiotoxicity and Potentiates Its Chemotherapeutic Efficacy Against Triple Negative Breast Cancer

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anindita Das ◽  
Sahak Hovsepian ◽  
Sayantanee Das ◽  
Arun Samidurai ◽  
Adolfo G Mauro ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Mtor Inhibitor ◽  
Triple Negative ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Chemotherapeutic Efficacy

Background: Doxorubicin (DOX) is a first-line anticancer drug for the treatment of triple negative breast cancer (TNBC). However, its dose-dependent delayed and progressive cardiotoxicity limits its therapeutic application. NovoMedix (NM922) is a novel dual mTOR inhibitor/AMPK activator that was shown to attenuate adverse cardiac remodeling and fibrosis in a pressure-overload mouse model of heart failure. We investigated whether combination therapy with DOX and NM922 exhibits synergistic chemotherapeutic effect while mitigating DOX cardiotoxicity. Methods & Results: Tumors were generated in athymic female BALB/cAnNCr-nu/nu mice by implanting MDA-MB-231 cells into the rear right flank. Mice with tumors (volume≈200mm 3 ) were randomized into 6 groups and treated as follows: 1) Control (n=10); 2) DOX (3 mg/kg; i.p. twice weekly, total 15 mg/kg; n=10); 3) NM922 (25 mg/kg/d; p.o. n=5); 4) DOX+NM922 (25 mg/kg/d; p.o. n=15); 5) NM922 (100 mg/kg/d; p.o. n=5); 6) DOX+NM922 (100 mg/kg/d; p.o. n=15). Tumor size, body weight and cardiac function were assessed throughout the study. DOX alone, and to a significant extent when in combination with NM922 (25 mg/kg) reduced tumor growth compared to control. NM922 (100 mg/kg) with/without DOX significantly reduced tumor growth as compared to DOX alone (Fig A). DOX caused reduction in body weight and survival of tumor-bearing mice. NM922 did not prevent DOX-induced cachexia, but significantly improved survival in DOX-treated mice (Fig B). DOX treatment caused a significant decline in left ventricular ejection fraction compared to control over 3 weeks, which was ameliorated with NM922 (100 mg/kg) co-treatment (Fig C&D). Conclusion: Our results suggest that NM922 may potentiate the chemotherapeutic efficacy of DOX in TNBC, while mitigating its cardiotoxicity. Moreover, these findings advocate the potential efficacy of utilizing lower DOX dosages when combined with NM922, which would have significant clinical implications.

Using Biomarkers to Detect the Temporal Trend of Subclinical Cardiotoxicity in Patients with Breast Cancer Treated with Anthracyclines and Her2+ Antagonists

2020 ◽  
Author(s):  
Wendy Bottinor ◽  
Natalie Kelsey ◽  
Elizabeth C Riley ◽  
John Craycroft ◽  
Maiying Kong
Keyword(s):  
Breast Cancer ◽  
Troponin I ◽  
Cohort Analysis ◽  
Temporal Trends ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Area Of Interest ◽  
Her2 Breast Cancer

ABSTRACT Background: Standard of care treatment for human epidermal growth factor receptor 2 (HER2) positive (HER2+) breast cancer often involves HER2 antagonism and anthracyclines. Anthracyclines and HER2 antagonists are associated with cardiotoxicity and cardiac screening is suggested. The optimal strategy for cardiac monitoring is not definitively established and the potential role of biomarkers to detect subclinical cardiotoxicity is an active area of interest within the field of cardio-oncology. Methods: This single center retrospective cohort analysis, examined the role of troponin I (Tp I) to detect subclinical cardiotoxicity and predict subsequent cardiovascular dysfunction in patients undergoing treatment for HER2+ breast cancer treated with combination trastuzumab and pertuzumab therapy. Subjects were identified by review of cardio-oncology and medical oncology clinical registries. Demographic and clinical data were obtained through chart review. Tp I absolute values and temporal trends, and subsequent decline in left ventricular ejection fraction or development of symptomatic heart failure were evaluated and compared for different chemotherapeutic regimens. Results: The incidence of Tp I elevation was significantly higher in patients treated with both anthracycline and HER2 antagonism when compared to patients treated with anthracycline or HER2 antagonism alone. In patients treated with both anthracycline and HER2 antagonism (either trastuzumab alone or in combination with pertuzumab), Tp I levels became positive (greater than 0.03 ng/mL) after the completion anthracycline therapy and 3.8 + 1.93 infusions of anti-HER2 therapy. The average peak Tp I was 0.104 + 0.05. Resolution of Tp I elevation occurred by infusion 14 + 1.94. Conclusions: Patients treated with a combination of anthracycline and HER2 antagonism, demonstrated elevated Tp I values with peak Tp I occurring after completion of anthracyclines and approximately 7 infusions of HER2 antagonist therapy.

Safety of adjuvant trastuzumab (T) in elderly patients with breast cancer.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 282-282 ◽  
Author(s):  
L. Militello ◽  
P. Carli ◽  
S. Spazzapan ◽  
C. Lestuzzi ◽  
G. Miolo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Elderly Patients ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Her2 Breast Cancer ◽  
Minor Adverse Event

282 Background: T is a mainstay in adjuvant therapy for HER2+ breast cancer (BC) patients (pts). Safety and efficacy of T in elderly patients are largely unknown. In HERA trial, NSABP B-31, NCCTG N9831 only 16% of pts were older than 60 years. Risk factors for T related cardiotoxicity are age (>50 y/o), hypertension, baseline LVEF (left ventricular ejection fraction <55%), previous antracycline therapy and BMI. Methods: Charts of pts >65 y/o with early HER2+ BC treated with T as adjuvant or neoadjuvant therapy at our institution were retrospectively reviewed. Primary endpoint was the evaluation of T cardiac toxicity and safety. Results: 22 elderly out of 172 pts (12%) were identified: 19 pts were treated only with surgery and adjuvant chemotherapy with concomitant or sequential T, 3 more pts also received neoadjuvant chemotherapy concomitant with T. According to Balducci’s criteria, fit, vulnerable and frail pts were 20, 2, 0 respectively. Median age was 69 y/o (range 65-76). Hormonal status was negative in 10/22 (45%). 21/22 were histologic grade 3. Median follow-up was 33 months. Baseline comorbidities were the following: hypertension (G2-3) in 17 pts, diabetes mellitus in 1, supra/infraventricular arrhythmia (G1-2) in 3 and 1 pts. Antracyclines were administered in 16 pts (liposomal-doxorubicin in 5 pts), a sequential taxane-regimen was used in 3 more pts. Neoadjuvant weekly Paclitaxel and concomitant T was used in 3 pts. Median basal LVEF was 65% (range 59-74%). 2 pts developed an asymptomatic 10% LVEF drop from baseline (left ventricular systolic dysfunction G1) during T treatment. Known cardiac risk factors were hypertension in 1 pt and previous antracycline based chemotherapy in both. They recovered within 9 months. One minor adverse event was atrial fibrillation (G2) during T treatment. Conclusions: T was well tolerated in elderly pts. More data are needed in order to understand the correlations between T related toxicity and cardiovascular risk factors. Long term safety of T treatment should verify the reversibility of cardiac T related toxicity on elderly pts.

scholarly journals THE ROLE OF CARDIAC BIOMARKERS AS PREDICTORS OF TRASTUZUMAB CARDIOTOXICITY IN PATIENTS WITH BREAST CANCER

2015 ◽  
Vol 37 (1) ◽  
pp. 53-57 ◽  
Author(s):  
Y Urun ◽  
G Utkan ◽  
B Yalcin ◽  
H Akbulut ◽  
H Onur ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Diabetes Mellitus ◽  
Heart Failure ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Her2 Breast Cancer ◽  
Increased Risk ◽  
Significant Difference

Aim: Identification of patient with increased risk of cardiotoxicity would allow not only prevention and early diagnosis of chemotherapy related cardiotoxicity but also administration of optimal dose and duration of chemotherapy. Materials and methods: Fiftytwo women with HER2+ breast cancer treated with trastuzumab were included in this study. Patients were prospectively followed with routine cardiac evaluation. Before and after administration of trastuzumab blood samples for NT-proBNP were also taken. Results: The median age was 48.5 year (range: 26–74). Hypertension and obesity were two most common co-morbidities. The median duration application of trastuzumab was 52 weeks. During median 14.5 (3–33) months follow-up cardiac adverse events occurred in 5 (9.6%) patients and 2 out of 5 was grade III–IV heart failure. Both patients had preserved left ventricular ejection fraction and no symptom of heart failure before trastuzumab but older than 65 years old and had diabetes mellitus and obesity. High level of NT-proBNP (> 300 ng/ml) was observed in both patients and heart failure recovery was not observed. There was statistically significant difference regarding body mass index (p = 0.004) and diabetes mellitus (p = 0.002) between patients with and without cardiotoxicity. Conclusion: Although, cardiac biomarkers still cannot replace routine cardiac monitoring, natriuretic peptides may provide additional tool for detection of patients with high risk of cardiotoxicity and early detection of cardiotoxicity.

scholarly journals Long-Term Safety and Real-World Effectiveness of Trastuzumab in Breast Cancer

2019 ◽  
Vol 8 (2) ◽  
pp. 254 ◽  
Author(s):  
Marco Mazzotta ◽  
Eriseld Krasniqi ◽  
Giacomo Barchiesi ◽  
Laura Pizzuti ◽  
Federica Tomao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Real World ◽  
Growth Factor Receptor ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Cochrane Central Register ◽  
Ventricular Ejection Fraction ◽  
Her2 Breast Cancer ◽  
Trastuzumab Cardiotoxicity

Trastuzumab is a milestone in the treatment of human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC), in both the early and metastatic settings. Over the last two decades, clinical trials have established the good safety profile of trastuzumab. Cardiotoxicity remains the most frequent adverse event, more commonly exemplified by an asymptomatic decline in the left ventricular ejection fraction rather than congestive heart failure. Results from several long-term (>5 years) safety analyses have been recently published, with the inherent evidence substantially confirming the findings from previous trials. The clinical experience gained over the years in the use of trastuzumab has also fueled a number of observational studies focused on the effectiveness of this drug in the real-world settings. We herein reviewed the evidence available from tree major databases, namely, PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL), to explore and critically discuss key issues related to the long-term safety and effectiveness of trastuzumab in clinical practice.

scholarly journals CBR3 V244M is associated with LVEF reduction in breast cancer patients treated with doxorubicin

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jennifer K. Lang ◽  
Badri Karthikeyan ◽  
Adolfo Quiñones-Lombraña ◽  
Rachael Hageman Blair ◽  
Amy P. Early ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Care Center ◽  
Left Ventricular ◽  
The Body ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Ventricular Ejection Fraction ◽  
Echocardiographic Parameters ◽  
The Impact

Abstract Background The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts. Objectives This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment. Methods We recruited 155 patients with breast cancer receiving treatment with doxorubicin (DOX) at Roswell Park Comprehensive Care Center (Buffalo, NY) to a prospective single arm observational pharmacogenetic study. Patients were genotyped for the CBR3 V244M variant. 92 patients received an echocardiogram at baseline (t0 month) and at 6 months (t6 months) of follow up after DOX treatment. Apical two-chamber and four-chamber echocardiographic images were used to calculate volumes and left ventricular ejection fraction (LVEF) using Simpson’s biplane rule by investigators blinded to all patient data. Volumetric indices were evaluated by normalizing the cardiac volumes to the body surface area (BSA). Results Breast cancer patients with CBR3 GG and AG genotypes both experienced a statistically significant reduction in LVEF at 6 months following initiation of DOX treatment for breast cancer compared with their pre-DOX baseline study. Patients homozygous for the CBR3 V244M G allele (CBR3 V244) exhibited a further statistically significant decrease in LVEF at 6 months following DOX therapy in comparison with patients with heterozygous AG genotype. We found no differences in age, pre-existing cardiac diseases associated with myocardial injury, cumulative DOX dose, or concurrent use of cardioprotective medication between CBR3 genotype groups. Conclusions CBR3 V244M genotype status is associated with changes in echocardiographic parameters suggestive of early anthracycline-related cardiomyopathy in subjects undergoing chemotherapy for breast cancer.

scholarly journals An Exploration of Heart Failure Risk in Breast Cancer Patients Receiving Anthracyclines with or without Trastuzumab in Thailand: A Retrospective Study

2021 ◽  
Vol 11 (3) ◽  
pp. 484-493
Author(s):  
Jukapun Yoodee ◽  
Aumkhae Sookprasert ◽  
Phitjira Sanguanboonyaphong ◽  
Suthan Chanthawong ◽  
Manit Seateaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Cancer Patients ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Ventricular Ejection Fraction ◽  
Factors Associated ◽  
Palliative Intent ◽  
Increased Risk

Anthracycline-based regimens with or without anti-human epidermal growth factor receptor (HER) 2 agents such as trastuzumab are effective in breast cancer treatment. Nevertheless, heart failure (HF) has become a significant side effect of these regimens. This study aimed to investigate the incidence and factors associated with HF in breast cancer patients treated with anthracyclines with or without trastuzumab. A retrospective cohort study was performed in patients with breast cancer who were treated with anthracyclines with or without trastuzumab between 1 January 2014 and 31 December 2018. The primary outcome was the incidence of HF. The secondary outcome was the risk factors associated with HF by using the univariable and multivariable cox-proportional hazard model. A total of 475 breast cancer patients were enrolled with a median follow-up time of 2.88 years (interquartile range (IQR), 1.59–3.93). The incidence of HF was 3.2%, corresponding to an incidence rate of 11.1 per 1000 person-years. The increased risk of HF was seen in patients receiving a combination of anthracycline and trastuzumab therapy, patients treated with radiotherapy or palliative-intent chemotherapy, and baseline left ventricular ejection fraction <65%, respectively. There were no statistically significant differences in other risk factors for HF, such as age, cardiovascular comorbidities, and cumulative doxorubicin dose. In conclusion, the incidence of HF was consistently high in patients receiving combination anthracyclines trastuzumab regimens. A reduced baseline left ventricular ejection fraction, radiotherapy, and palliative-intent chemotherapy were associated with an increased risk of HF. Intensive cardiac monitoring in breast cancer patients with an increased risk of HF should be advised to prevent undesired cardiac outcomes.

Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial

2007 ◽  
Vol 25 (25) ◽  
pp. 3859-3865 ◽  
Author(s):  
Thomas M. Suter ◽  
Marion Procter ◽  
Dirk J. van Veldhuisen ◽  
Michael Muscholl ◽  
Jonas Bergh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Adverse Effects ◽  
Cancer Patients ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Ventricular Ejection Fraction ◽  
Neo Adjuvant Chemotherapy

Purpose The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2–positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF ≥ 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. Results Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index. Conclusion Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.

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