Can flaxseed "milk" prevent anthracycline mediated cardiotoxicity in women with breast cancer (CANFLAX-BC)?

Introduction Cardio-oncology focuses on the prevention, diagnosis, and management of cancer patients who are at risk of developing cardiovascular complications as a result of their anti-cancer treatment. Amongst the various pharmacological therapies which may prevent anthracycline mediated cardiotoxicity in women with breast cancer, including renin-angiotensin system (RAS) antagonists, beta blockers, and statins, there has been an increased interest on the role of nutraceuticals in this setting. Although we recently demonstrated the cardioprotective role of dietary flaxseed (FLX) in the prevention of adverse cardiovascular remodeling in a chronic in vivo female murine model of anthracycline mediated cardiotoxicity, little is known on the effects of this dietary agent in the clinical setting. Purpose The aim of the "Can flax "milk" prevent chemotherapy mediated cardiotoxicity in women with breast cancer (CANFLAX-BC)" study was to investigate whether consumption of FLX "milk" can prevent cardiac dysfunction in women with breast cancer treated with anthracyclines. Methods In this double-blinded, single centre, prospective randomized controlled clinical trial, women with breast cancer were randomized to oral consumption of either placebo oat fiber "milk" or FLX "milk" [each containing 30 grams of oat or flaxseed, respectively] for a total of 4 months while receiving anthracycline-based chemotherapy. Serial echocardiography was performed at baseline, 4-month, and 6-month follow-up. Results Between September 2021 and December 2023, a total of 21 women with early-stage breast cancer (EBC) (mean age 48±10 years, BMI 28±5 kg/m2) were enrolled in the CANFLAX-BC study. During the 4-month intake period, a total of 8 women received oat fibre "milk" and 13 women received FLX "milk", with a comparable adherence rate of approximately 70% for both groups. At baseline, 4-month, and 6-month follow-up, the LVEF was 68±4%, 69±3%, 66±4% for the oat fibre "milk" group, and 67±5%, 68±4%, 66±5% for the FLX "milk" group (no significant difference; Table 1, Figure 1A). Although the mean global longitudinal strain (GLS) was comparable between both groups at baseline, the GLS was significantly lower at -13.8±0.3% (4 months) and -15.1±0.3% (6 months) for the oat fibre "milk" group, as compared to a preserved GLS of -18.4±0.3% (4 months) and -18.5±0.2% (6 months) for the FLX "milk group (*p<0.05; Table 1, Figure 1B). Conclusion In women receiving anthracycline based chemotherapy for breast cancer, FLX "milk" consumption prevents early cardiotoxicity, as reflected by the preservation of GLS parameters. Table 1 Figure 1

Objective The objective of this study was to evaluate the role of molecular and genetic biomarkers in the development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy. Methods A total of 176 women, median age of 45,0 [42,0; 50,0] years with breast cancer without cardiovascular diseases who received anthracycline antibiotics as part of polychemotherapeutic treatment were enrolled in the study. Two-dimensional transthoracic echocardiography and 6-minute walk test were performed at baseline and at the 12 months after polychemotherapy. Serum levels of NT-proBNP, sFas-L were measured using an enzyme immunoassay after polychemotherapeutic treatment. Evaluation of gene polymorphisms of p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522) and nitric oxide synthase (NOS3, Glu298Asp, rs1799983) were carried out by polymerase chain reaction at baseline. Results After the 12 months of polychemotherapy all patients had breast cancer remission and were divided into 2 groups: group 1 (n=52) comprised patients with anthracycline-induced cardiotoxicity, group 2 (n=124) comprised those without it. After polychemotherapeutic treatment the median value of NT-proBNP in group 1 was higher (p<0,00001) by 52,4% than in group 2 (113 [101,8; 126,15] pg/mL and 53,8 [43,4; 63,0] pg/mL, respectively). The median value of sFas-L in group 1 was higher (p<0,00001) by 44,3% than in group 2 (125,3 [111,85; 133,95] pg/mL and 69,8 [59,8; 77,6] pg/mL, respectively). Based on ROC-analysis, sFas-L concentration of 95.8 pg/mL (sensitivity of 92.2%, specificity of 92.1%, and AUC=0,951; p=0,0001) and NT-proBNP concentration of 71.5 pg/mL (sensitivity of 99.9%, specificity of 91.9%, and AUC=0,951; p=0,0001) were identified as a cut-off values predicting the development of anthracycline-induced cardiotoxicity. The development of anthracycline-induced cardiotoxicity in women with breast cancer at the 12 months after polychemotherapy significantly was related to the presence of T/T genotype of NOS3 gene (OR = 3,059; p=0,018) and with Arg/Arg genotype of p53 protein gene (OR = 2,972; p=0,001). While, the presence of Pro/Pro the Pro53 gene genotype of p53 protein gene was related to the absence of anthracycline-induced cardiotoxicity. Conclusion Our data suggest that evaluation of polymorphisms gene of p53 (rs1042522) and NOS3 (rs1799983) can be recommended before polychemotherapy in women with breast cancer for the risk assessment of anthracycline-induced cardiotoxicity. The serum levels of NT-proBNP and sFas-L after polychemotherapy may be considered as non-invasive biomarkers for prediction of the development of anthracycline-induced cardiotoxicity in women with breast cancer during the 12 months after polychemotherapy. Funding Acknowledgement Type of funding source: None

Objective To evaluate role of molecular (endothelin-1, soluble Fas-L, NT-proBNP, TNF-α, interleukin-1β,) and genetic factors (NOS3 (rs1799983), EDNRA (C + 70G, rs5335), NADPH oxidase (C242T, rs4673), p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522), NOS3 (Glu298Asp, rs1799983), Caspase 8 (CASP8, rs3834129 and rs1045485), interleukin-1β gene (Il-1β, rs1143634), TNF-α gene (rs1800629), SOD2 (rs4880), GPX1 (rs1050450) in development of anthracycline-induced cardiotoxicity (AIC) in women without cardiovascular diseases. Methods A total of 176 women with breast cancer and without cardiovascular diseases who received anthracyclines were enrolled in the study. After the 12 months of chemotherapy (CT), all patients were divided into two groups: group 1 (n = 52) comprised patients with AIC, group 2 (n = 124) comprised those without it. Results Based on ROC-analysis, levels of endothelin-1 of ≥9.0 pg/mL (AUC of 0.699), sFas-L of ≥98.3 ng/mL (AUC of 0.990), and NT-proBNP of ≥71.5 pg/mL (AUC of 0.994;) were identified as a cut-off values predicting AIC during 12 months after CT. Whereas, NT-proBNP and sFas-L were more significant predictors than endothelin-1 (p < 0.001). The development of AIC was significantly related to Arg/Arg of p53 protein gene (OR = 2.972; p = 0.001), T/T of NOS3 gene (OR = 3.059, p = 0.018), T/T of NADPH oxidase gene (OR = 2.753, p = 0.008), and C/C of GPX1 (OR = 2.345; p = 0.007). Conclusion Evaluation of polymorphisms genes of p53 (rs1042522), NOS3 (rs1799983), GPX1 (rs1050450), and NADPH oxidase (rs4673) can be recommended before CT for the risk assessment of AIC development. The serum levels of NT-proBNP and soluble Fas-L after CT may be considered as non-invasive biomarkers for prediction of AIC development during the 12 months.

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

BackgroundThe mitral annular plane systolic excursion (MAPSE) is used to analyze the left ventricle longitudinal function. However, the accuracy of MAPSE in diagnosing oncological populations is unclear. In this study, we aimed to assess the accuracy of MAPSE in diagnosing subclinical cardiotoxicity in women with breast cancer undergoing anthracycline treatment.MethodsThis retrospective cohort study included echocardiographic assessments of patients with breast cancer who underwent anthracycline treatment as part of their therapeutic regimen. Assessments were performed before treatment, after administering the first dose of anthracycline, after completing anthracycline treatment, and 6 and 12 months after treatment. Left ventricular ejection fraction was calculated using the modified biplane Simpson method. The performances of MAPSE and global longitudinal strain (GLS) were analyzed using receiver operating characteristic (ROC) curves. Their accuracies were measured using the area under the ROC curves.ResultsSixty-one patients were included in this study. Of them, 8.2% presented cardiotoxicity 6 months after treatment completion. Patients with cardiotoxicity had lower LVEF (47% vs. 63%; p < 0.001), MAPSE (10.23 mm vs. 12.25 mm; p = 0.012), and LV GLS (16.13% vs. 19.05%; p = 0.005) values than those without. A 12% reduction in the GLS exhibited sensitivity, specificity, and overall accuracy of 80%, 70%, and 78%, respectively. A relative reduction of 15% in MAPSE exhibited a sensitivity, specificity, and accuracy of 80%, 77%, and 81.2%, respectively. An absolute MAPSE reduction of 2 mm exhibited a sensitivity, specificity, and accuracy of 80%, 73.21%, and 81.2%, respectively. No differences were observed between the ROC curves.ConclusionMAPSE showed similar accuracy to GLS in diagnosing subclinical cardiotoxicity in women with breast cancer undergoing anthracycline treatment.

Although anthracyclines are highly effective at treating certain cancers, their use is limited by the potential for cardiotoxicity. Studies report a wide range of the incidence of cardiotoxicity, related to differences in definitions, chemotherapy regimens, and patient populations. The occurrence of clinical heart failure seems to be in the range of 1% to 5%, and asymptomatic decrease in left ventricular function is in the range of 5% to 20%.1,2 Toxicity can occur early (within 1 year) or late (particularly among children, where late cardiac abnormalities are detectable in two thirds of surviving patients).3 The occurrence of cardiomyopathy is related to cumulative dose of anthracycline (especially doxorubicin doses >550 mg/m2), dosing schedule, age, gender, mediastinal irradiation, and combination with other agents, including trastuzumab.4 Other chemotherapy, including imatinib mesylate,5 can also cause cardiotoxicity, suggesting a broader potential for adverse cardiac effects from novel chemotherapy and, especially, from inhibitors of nonreceptor tyrosine kinases. Anthracycline-induced cardiomyopathy seems to have a similar impact on survival as other forms of heart failure.6 Thus, identification of individuals at risk, prevention, early diagnosis, and effective treatment are all important goals. Most of these needs have been addressed by uncontrolled or small studies, and guidelines have relatively sparse information on which to base recommendations for care, other than careful monitoring of left …

Introduction: Breast cancer is the most common malignancy affecting women, and the number of survivors is increasing with the advent of new therapies. However, Anthracyclines (ACs) retain an essential role in the drug treatment of breast cancer, despite their known cardiotoxicity. Although dexrazoxane, a cardioprotective agent for high-dose AC administration, has been approved in the US and Europe, it remains one of the drug-lag issues in Japan. Objective: To evaluate real-world data on the proportion of high-dose anthracycline administration and the incidence of cardiotoxicity in Japanese patients with breast cancer using a nationwide claims database. Methods. This study is a retrospective observational analysis using the Japan Medical Data Centre (JMDC, Tokyo, Japan) database, an anonymized patient-level claims database younger than 75 years old. We first identified women diagnosed with breast cancer and treatment with AC. Patients with a history of heart failure and a treatment start record of fewer than six months were excluded. After adjusting for patient background factors by propensity score matching (PSM), cardiotoxicity risk factors and outcomes were compared between the high-dose group (AC-H) and the low-dose group (AC-L). Results: Among women with breast cancer who underwent AC treatment between January 2015 and September 2020, 5.3% (255/4,831) were classified to the high-dose group. After PSM, the number of cases, age (years) and follow-up (months) in each group were as follows: AC-H group (n=254, median 51.0 [IQR: 46.0-55.0], 26.0 [14.0-52.0]), AC-L group (n=254, 51.0 [46.0-57.0], 32.5 [15.0-59.0]). The 5-year rates of mortality and heart failure in AC-H and AC-L groups were 33.1% vs 4.5% (Log-rank p &amp;lt; .0001) and 11.0% vs 4.3% (Log-rank p=0.003), respectively. Conclusion: The proportion of women with breast cancer who received AC in the high dose group was approximately 5%. However, compared with the low-dose group, the high-dose group had a lower survival rate and a higher incidence of heart failure. Therefore, in Japan, clinical development of cardioprotective agents for patients with metastatic or recurrent breast cancer who require high doses of AC is warranted.

Background and objectivePaclitaxel and doxorubicin are associated with neurotoxicity and cardiotoxicity respectively. This study aimed at investigating the role of alpha-lipoic acid (ALA) in counteracting paclitaxel-induced neuropathy and doxorubicin-associated cardiotoxicity in women with breast cancer.Patients and methodsThis randomized double-blind placebo-controlled prospective study included 64 patients with breast cancer who were randomized into control group (n = 32) which received 4 cycles of doxorubicin plus cyclophosphamide (every 21 days) followed by weekly doses of paclitaxel for 12 weeks plus placebo tablets once daily and ALA group (n = 32) which received the same chemotherapeutic regimen plus ALA 600 once daily for 6 months. Patients were assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0) for grading of neuropathy and by 12-item neurotoxicity questionnaire (Ntx-12). The assessment included also echocardiography and evaluation of serum levels of brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and neurotensin (NT). Data were analyzed by paired and unpaired t-test, Mann–Whitney U test, and chi-square test.ResultsAs compared to placebo, ALA provoked significant improvement in NCI-CTCAE neuropathy grading and Ntx-12 score after the end of 9th and 12th weeks of paclitaxel intake (p = 0.039, p = 0.039, p = 0.03, p = 0.004, respectively). At the end of the chemotherapy cycles, ALA resulted in significant decline in serum levels of BNP, TNF-α, MDA, and neurotensin (p < 0.05) as compared to baseline data and placebo.ConclusionAlpha-lipoic acid may represent a promising adjuvant therapy to attenuate paclitaxel-associated neuropathy and doxorubicin-induced cardiotoxicity in women with breast cancer.Trial registrationClinicalTrials.gov: NCT03908528.

BackgroundDoxorubicin (DOX) has been widely used in the treatment of breast cancer, but it is directly associated with late-onset cardiovascular disease (CVD). Whether anthropometric, food intake or other risk factors together with DOX-based chemotherapy can increase the risk of developing cardiotoxicity remains uncertain. We examined the association between anthropometric variables with doxorubicin-induced cardiotoxicity in women with breast cancer.MethodsTwenty-six women (53.7 ± 9.6 y) undergoing DOX-based chemotherapy (408.3 ± 66.7 mg/m2) participated in the study. We collected data on body composition (bioimpedance), dietary intake (24 h) and cardiac function (echocardiographic assessment of left ventricular ejection fraction, LVEF). All measurements were taken at baseline, one month of treatment completion and one-year follow-up after start of treatment. DOX-induced cardiotoxicity was defined as ≥ 10% absolute decrease in LVEF. Thus, the participants were then grouped as DOX-induced (DIC) or non-DOX-induced (non-DIC) cardiotoxicity. Data are shown as mean ± SD (standard deviation). We performed comparisons between the two groups using Student’s t-test for independent samples or Generalized Estimating Equations (groups + 3 evaluation time points) with Bonferroni post-hoc test. Lastly, the correlations were analyzed using Pearson correlation; p < 0.05 for all tests.ResultsAt baseline the participants’ body mass index (BMI) was 29.9 ± 7.9 kg/m2 and LVEF was 67.4 ± 6.2%. Seven of them (26.9%) developed therapy-induced cardiotoxicity (ΔLVEF − 3.2 ± 2.6%; p < 0.001). Postmenopausal status and family history of CVD were more prevalent in the DIC group than non-DIC group. We found no consistent BMI changes in the groups over time. Interestingly, the non-DIC group showed a small increase in visceral fat at treatment completion and increased waist circumference at one-year follow-up compared to baseline. These same changes were not seen in the DIC group. We also observed a pattern of correlation of some anthropometric variables with LVEF: the more unfavorable the body composition the more pronounced the LVEF decrease at one-year follow-up, though not associated with cardiotoxicity.ConclusionsOur study did not provide sufficient evidence to support that anthropometric variables, food intake or other risk factors increase the risk of developing cardiotoxicity. However, there are apparent trends that need to be further investigated in larger samples.

Simple SummaryCancer therapy-related cardiac dysfunction (CTRCD) has been an urgent medical issue in patients that receive breast cancer therapies including anthracycline-based chemotherapies and/or targeted anti-HER2 therapies such as trastuzumab. Traditional biomarkers used as standard of care may be useful indicators of cardiac damage but their use to predict the onset of CTRCD lacks reliability. Ongoing clinical studies aim to explore new insights into the use of traditional biomarkers and investigate the promising role of novel biomarkers as reliable indicators and/or predictors of CTRCD. Patients with breast cancer could benefit from an alternative cardiac risk stratification plan that has the potential to predict the onset of CTRCD and/or detect CTRCD at early stages. The aim of this systematic review is to provide an overview of the human studies, which explore novel insights into traditional biomarkers and/or novel biomarkers that can be used for the early detection and/or prediction of CTRCD in breast cancer patients undergoing cardiotoxic-cancer therapies.Cardiotoxicity induced by breast cancer therapies is a potentially serious complication associated with the use of various breast cancer therapies. Prediction and better management of cardiotoxicity in patients receiving chemotherapy is of critical importance. However, the management of cancer therapy-related cardiac dysfunction (CTRCD) lacks clinical evidence and is based on limited clinical studies. Aim: To provide an overview of existing and potentially novel biomarkers that possess a promising predictive value for the early and late onset of CTRCD in the clinical setting. Methods: A systematic review of published studies searching for promising biomarkers for the prediction of CTRCD in patients with breast cancer was undertaken according to PRISMA guidelines. A search strategy was performed using PubMed, Google Scholar, and Scopus for the period 2013–2023. All subjects were >18 years old, diagnosed with breast cancer, and received breast cancer therapies. Results: The most promising biomarkers that can be used for the development of an alternative risk cardiac stratification plan for the prediction and/or early detection of CTRCD in patients with breast cancer were identified. Conclusions: We highlighted the new insights associated with the use of currently available biomarkers as a standard of care for the management of CTRCD and identified potentially novel clinical biomarkers that could be further investigated as promising predictors of CTRCD.

Chemotherapy-Induced Cardiotoxicity in Women

Chemotherapy-Induced Cardiotoxicity in Women

PurposeAnthracyclines have been one of the standard therapies for breast cancer (BC), and dose-related cardiotoxicity is one serious side effect. Exercise is an effective strategy for the prevention and management of BC, endorsed by experts in both exercise and oncology. However, there is a great deal of confusion about the effectiveness of exercise on anthracycline-induced cardiotoxicity and the exercise prescription (i.e., timing, type, and intensity) for cardiotoxicity, which limits its application in clinical settings. The aim of this article is to review the safety of exercise in BC patients receiving anthracyclines and its effectiveness in preventing cardiotoxicity.MethodsSix electronic databases were searched using terms related to exercise, BC, anthracyclines, and cardiotoxicity for retrieving clinical randomized controlled trials in either Chinese or English. A summary of the included literature was also provided.ResultsOf 202 records screened, 10 were eligible. A total of 434 BC patients (stage I–IIIC, mean age ranged from 43.5 to 52.4 years) were included. The main findings were that: (1) Acute (a single bout) moderate-to-vigorous aerobic exercise could prevent NT-proBNP elevation beyond the threshold of acute myocardial injury; (2) Long-term (> 8 weeks) moderate-to-high intensity aerobic exercise (continuous or interval) could improve or maintain left ventricular ejection fraction and cardiorespiratory fitness in BC patients. However, the optimal timing, type, and intensity of exercise for people with BC to prevent cardiotoxicity remain unclear.ConclusionModerate-to-vigorous intensity exercise may be an effective non-pharmacological approach to mitigate cardiotoxicities induced by anthracyclines in women with BC. However, the optimal exercise prescription for preventing cardiotoxicity remains unclear.

Purpose: To evaluate cardiotoxicity in women with breast cancer treated with taxanes, anthracyclines and/ or trastuzumab using clinical, echocardiographic and biological parameters. Methods: This is a prospective observational study in women with new diagnosis of breast cancer who are candidates to receive anthracyclines, taxanes and/ or trastuzumab therapy. Cardiac risk factors, clinical examination and concomitant therapy at baseline were recorded. Our protocol assessment included clinical, echocardiographic (left ventricular ejection fraction (LVEF) measured with biplane Simpson's method and with Teichholz formula) and biological parameters (B-type natriuretic peptide (BNP) and carbohydrate antigen 125 (CA125)) at baseline, six and twelve months (baseline, 3, 6, 9 and 12 months in cases of treatment with trastuzumab). Cardiotoxicity was defined as a reduction of LVEF ≥5% to <55% with symptoms of heart failure or an asymptomatic reduction of LVEF ≥10% to <55%. Patients with LVEF < 50% at baseline were excluded. Results: A total of 174 women with breast cancer were consecutively included from November 2011 to December 2012. Mean age was 55±12 years (range 27-84). HER 2 protein overexpression was found in 51 patients (29%). Clinical characteristics at baseline were: hypertension 27%, diabetes mellitus 6.3%, chronic ischaemic cardiopathy 4.6% and history of heart failure 1.1%. Only seven patients developed cardiotoxicity (4%), and five of them were on trastuzumab treatment. There were no significant changes in echocardiographic parameters (LVEF decreased by Teichholz's from 69±7 to 68±6%, p=0.9; and by Simpson's from 67±7% to 64±6%, p = 0.3) and heart failure biomarkers over 12 months (median BNP 26, range 4-492 and 29.5, range 5-262, at baseline and 12-months, respectively (p=0.9); median CA125 13.1 (range 2.7-81) and 14.2 (range 15-33) at baseline and 12-months, respectively (p=0.7)). Conclusions: In this cohort of women with breast cancer no significant differences in echocardiographic and biomarker variables from baseline at one year follow-up were observed. Our results also showed a lower incidence of cardiotoxicity compared with previous series reported.

The Relationship Between Blood Lipidomics and Cardiotoxic Injury Following Acute Exposure to Anthracycline Chemotherapy in Women With Breast Cancer: A Feasibility Study