Systematic screening of protein-coding gene expression identified VWF as a potential key regulator in anthracycline-based chemotherapy-exacerbated metastasis of breast cancer.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer worldwide. Although major treatments represented by chemotherapy have shown effectiveness at the initial period, recurrence and metastasis still occur later after treatments. The alternation of the tumor microenvironment by chemotherapy is confirmed as a trigger of the elevated proliferation and migration of the remaining tumor cells. METHODS: Using bioinformatic methods, differential gene expression analysis was used to determine DEGs between post-chemotherapy and pre-chemotherapy samples of breast cancer patients, followed by survival analysis and ELISA analysis of the potential key genes. An in vitro model of 2 breast cancer cells lines was used to demonstrate the role of VWF in the evasion and migration of breast cancer cells, using cell migration, evasion and wound healing assays, PCR and molecular docking analysis. RESULTS: 19 hub genes were further identified using GO and KEGG pathway analyses and WGCNA. The 5 secreted protein-coding genes with reported carcinogenesis effects (VWF, SVEP1, DPT, ADIPOQ, and LPL) were further analyzed in breast cancer patients and VWF was identified as a potential key regulator in the anthracycline-based chemotherapy-exacerbated metastasis. It was further confirmed that anthracycline-based chemotherapeutics doxorubicin exacerbated VWF upregulation and the evasion and migration of breast cancer cells. Based on molecular docking analysis and previous study, berberine was used as an inhibitor of VWF, and showed an effective inhibition of the doxorubicin-exacerbated VWF upregulation, migration and evasion in breast cancer. CONCLUSIONS: Doxorubicin-exacerbated evasion and migration through VWF upregulation. Berberine as an inhibitor of VWF was able to reversed the doxorubicin-exacerbated VWF upregulation and evasion and migration in breast cancer cells.

Improving physical and mental health in women with breast cancer undergoing anthracycline-based chemotherapy through wearable device-based aerobic exercise: a randomized controlled trial.

Purpose: Aimed to assess the impact of wearable device-based aerobic exercise on the physical and mental well-being of women with breast cancer (BC) undergoing chemotherapy. Methods: Forty adult women with BC who underwent anthracycline-based chemotherapy were randomly allocated to the exercise group (n = 21) or the control group (n = 19). Both groups received standard health education and oncology care. In addition, the exercise group wore wearable devices to engage in moderate to high-intensity (50-90% HRmax) aerobic exercise during chemotherapy, while the control group did not carry out exercise intervention. Health-related physical fitness level, physical activity energy expenditure (PAEE), anxiety and depression scores, sleep quality, cancer-related fatigue, and overall quality of life (QoL), were assessed both before (prior to the first chemotherapy session) and after (prior to the fifth chemotherapy session) the exercise intervention. Exercise-related adverse events, exercise compliance, number and severity of gastrointestinal reactions and myelosuppression occurred were recorded during the exercise intervention. Results: After the intervention, compared to the control group, the exercise group (1) had significantly higher relative VO2peak (p = 0.003) and handgrip strength (p < 0.001); (2) had significantly higher PAEE (p < 0.001); (3) had a significantly lower scores in anxiety (p = 0.007), depression (p = 0.028), sleep quality in domains of subjective sleep quality (p = 0.010), sleep disturbances (p = 0.004), daytime dysfunction (p = 0.007), cancer-related fatigue in domains of physical (p < 0.001) and affective (p < 0.001); and (4) had a significantly lower scores in QoL in domains of physical well-being (p < 0.001) and emotional well-being (p = 0.019), while a significantly higher scores in functional well-being (p < 0.001). Patients in the exercise group experienced less severe gastrointestinal reactions (p = 0.028) and myelosuppressive symptoms (p < 0.001) than that in the control group. Patients in the exercise group had no serious exercise-related adverse events, with a mean exercise adherence of 81.8%. Conclusion: Wearable device-based aerobic exercise during chemotherapy can be an effective adjunctive therapy to improve physical and mental health in BC patients. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=200247, Identifier: ChiCTR2300073667.

EVALUATION OF LEFT VENTRICULAR SYSTOLIC FUNCTION IN POSTMENOPAUSAL WOMEN WITH BREAST CANCER RECEIVING ADJUVANT ANTHRACYCLINE AND TRASTUZUMAB THERAPY: A 2-YEAR FOLLOW-UP STUDY.

Anti-cancer therapy with anthracyclines and trastuzumab has raised concerns regarding cancer therapy-related cardiac dysfunction (CTRCD) in breast cancer (BC) patients. This study aimed to assess left ventricular (LV) ultrasound parameters in BC postmenopausal women during a 2-year follow-up period after starting anti-cancer therapy. METHODS: We studied 74 women with early-stage BC with, a mean age of 62.3 (SD-8.6), who underwent adjuvant doxorubicin or doxorubicin + trastuzumab therapy. Parameters such as LV ejection fraction (LVEF), global longitudinal strain (LVGLS), and mitral annulus systolic velocity(S') were evaluated. Serial evaluations were conducted at baseline(T0) and the first (T1), second (T2), third (T3), sixth (T4), ninth (T5), twelfth (T6), and twenty-fourth month (T7) following the initiation of the chemotherapy. Cardioprotective therapy (CPT) was administered to high-risk patients and those with worsening LV systolic parameters. A multiple regression model was employed to assess the combined effects of various factors and co-factors on the outcome variables. Cardiotoxicity was evaluated using the survival analysis tools (Kaplan-Meier curves and Cox proportional model). RESULTS: A total of 27 (36.5%) patients developed CTRCD, although no patients were presented with symptomatic heart failure. LVGLS started to decline one month after the first anthracycline dose (T1) in 13.5% of the cohort and 34.5% of patients with CTRCD (p<0.000). From the third month, 10.8% of the patients showed a decrease in EF%, including 27.6% of patients with CTRCD in (P<0.000). Throughout, the study, S' remained within the normal range in patients without CTRCD, only patients with CTRCD showed a decline in S'. CONCLUSIONS: This prospective study revealed that:1) The dynamic assessment of GLS should be prioritized for the early detection of systolic dysfunction .2) S' possesses a high diagnostic value for identifying cardiotoxicity. 3) Implementing the optimal medical cardioprotective strategies and closely monitoring LV systolic function can prevent serious cardiac complications in patients undergoing highly cardiotoxic anti-cancer treatment.

Neutrophil Biomarkers Can Predict Cardiotoxicity of Anthracyclines in Breast Cancer.

Doxorubicin (DOX), a commonly used anticancer agent, causes cardiotoxicity that begins with the first dose and may progress to heart failure years after treatment. An inflammatory response associated with neutrophil recruitment has been recognized as a mechanism of DOX-induced cardiotoxicity. This study aimed to validate mRNA expression of the previously identified biomarkers of DOX-induced cardiotoxicity, PGLYRP1, CAMP, MMP9, and CEACAM8, and to assay their protein expression in the peripheral blood of breast cancer patients. Blood samples from 40 breast cancer patients treated with DOX-based chemotherapy were collected before and after the first chemotherapy cycle and > 2 years after treatment. The protein and gene expression of PGLYRP1/Tag7, CAMP/LL37, MMP9/gelatinase B, and CEACAM8/CD66b were determined using ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of each candidate biomarker. Patients with cardiotoxicity (n = 20) had significantly elevated levels of PGLYRP1, CAMP, MMP9, and CEACAM8 at baseline, after the first dose of DOX-based chemotherapy, and at > 2 years after treatment relative to patients without cardiotoxicity (n = 20). The first dose of DOX induced significantly higher levels of all examined biomarkers in both groups of patients. At > 2 years post treatment, the levels of all but MMP9 dropped below the baseline. There was a good correlation between the expression of mRNA and the target proteins. We demonstrate that circulating levels of PGLYRP1, CAMP, MMP9, and CEACAM8 can predict the cardiotoxicity of DOX. This novel finding may be of value in the early identification of patients at risk for cardiotoxicity.

Exploring the molecular mechanism of ginseng against anthracycline-induced cardiotoxicity based on network pharmacology, molecular docking and molecular dynamics simulation.

BACKGROUND: Previous clinical and basic studies have revealed that ginseng might have cardioprotective properties against anthracycline-induced cardiotoxicity (AIC). However, the underlying mechanism of ginseng action against AIC remains insufficiently understood. The aim of this study was to explore the related targets and pathways of ginseng against AIC using network pharmacology, molecular docking, cellular thermal shift assay (CETSA) and molecular dynamics (MD) simulations. RESULTS: Fourteen drug-disease common targets were identified. Enrichment analysis showed that the AGE-RAGE in diabetic complications, fluid shear stress and atherosclerosis, and TNF signaling pathway were potentially involved in the action of ginseng against AIC. Molecular docking demonstrated that the core components including Kaempferol, beta-Sitosterol, and Fumarine had notable binding activity with the three core targets CCNA2, STAT1, and ICAM1. Furthermore, the stable complex of STAT1 and Kaempferol with favorable affinity was further confirmed by CETSA and MD simulation. CONCLUSIONS: This study suggested that ginseng might exert their protective effects against AIC through the derived effector compounds beta-Sitosterol, Kaempferol and Fumarine by targeting CCNA2, STAT1, and ICAM1, and modulating AGE-RAGE in diabetic complications, fluid shear stress and atherosclerosis, and TNF signaling pathways.

Add-on multidrug treatment based on quadruple therapy successfully treated worsening heart failure caused by anthracycline-induced cardiomyopathy in a survivor of cancer as a young adult: a case report.

BACKGROUND: The overall mortality and morbidity benefit in patients with heart failure with a reduced ejection fraction is greatest with a treatment combination of sacubitril/valsartan, beta-blockers, mineralocorticoid-receptor antagonists, and sodium-glucose transporter-2 inhibitors, termed the "fantastic four" or "quadruple therapy." The addition of vericiguat (an oral soluble guanylate cyclase stimulator) is believed to aid in managing worsening heart failure after quadruple therapy. Among childhood and young adult cancer survivors, cardiovascular complications that develop more than 10 years after anthracycline-based chemotherapy have a poor prognosis. Therefore, this study reports the efficacy of multidrug regimen based on quadruple therapy for worsening heart failure in cancer survivors with anthracycline-induced cardiomyopathy. CASE PRESENTATION: A survivor of cancer as a young adult who received high-dose anthracycline chemotherapy presented with acute decompensated heart failure 20 years post-chemotherapy and worsening heart failure 1.5 years after discharge. The patient showed signs of improvement after a step-wise introduction of carvedilol, empagliflozin, sacubitril/valsartan, ivabradine, and spironolactone for worsening heart failure. Vericiguat was accelerated owing to the risk of more severe cardiovascular events associated with ongoing aortic stenosis and the poor prognosis of anthracycline-induced cardiomyopathy. Heart failure symptoms continued to improve, with significant cardiac reverse remodeling, and the patient successfully underwent aortic valve replacement for severe aortic stenosis. CONCLUSIONS: Our case highlighted that multidrug treatment with add-on vericiguat and ivabradine based on quadruple therapy can potentially treat worsening heart failure in young adult cancer survivors with severe anthracycline-induced cardiomyopathy.

Cardiac events after allo-HCT in patients with acute myeloid leukemia.

ABSTRACT: This multicenter study sponsored by the GETH-TC investigates the incidence and predictors of early (first 100 days) and late cardiac events (CEs; ECEs and LCEs, respectively) after allo-HCT in patients with acute myeloid leukemia (AML) treated with anthracyclines, focusing on exploring the impact of PTCY on cardiac complications and the impact of CEs on OS and NRM. A total of 1020 patients with AML were included. PTCY was given to 450 (44.1%) adults. Overall, 94 (9.2) patients experienced CEs, with arrythmias, pericardial complications, and heart failure the most prevalent. ECEs occurred in 49 (4.8%) patients within a median of 13 days after allo-HCT, whereas LCEs were diagnosed in 45 (4.4%) patients within a median of 3.6 years after transplant. Using PTCY increased the risk for ECEs in multivariate analysis (hazard ratio [HR], 2.86; P = .007) but did not significantly affect the risk for LCEs (HR, 1.06; P = .892). The impact of variables on outcomes revealed was investigated using multivariate regression analyses and revealed that the diagnosis of CEs decreased the likelihood of OS (HR, 1.66; P = .005) and increased the likelihood of NRM (HR, 2.88; P < .001). Furthermore, despite using PTCY increased ECEs risk, its administration was beneficial for OS (HR, 0.71; P = .026). In conclusion, although the incidence of CEs was relatively low, it significantly affected mortality. Standard doses of PTCY increased ECE risk but were associated with improved OS. Therefore, protocols for preventing cardiac complications among these patients are needed.

Evolving therapeutics and ensuing cardiotoxicities in triple-negative breast cancer.

Defined as scarce expression of hormone receptors and human epidermal growth factor receptor 2, triple-negative breast cancer (TNBC) is labeled as the most heterogeneous subtype of breast cancer with poorest prognosis. Despite rapid advancements in precise subtyping and tailored therapeutics, the ensuing cancer therapy-related cardiovascular toxicity (CTR-CVT) could exert detrimental impacts to TNBC survivors. Nowadays, this interdisciplinary issue is incrementally concerned by cardiologists, oncologists and other pertinent experts, propelling cardio-oncology as a booming field focusing on the whole-course management of cancer patients with potential cardiovascular threats. Here in this review, we initially profile the evolving molecular subtyping and therapeutic landscape of TNBC. Further, we introduce various monitoring approaches of CTR-CVT. In the main body, we elaborate on typical cardiotoxicities ensuing anti-TNBC treatments in detail, ranging from chemotherapy (especially anthracyclines), surgery, anesthetics, radiotherapy to immunotherapy, with future perspectives on promising directions in the era of artificial intelligence and traditional Chinese medicine.

Functional exosomes modified with chitosan effectively alleviate anthracycline-induced cardiotoxicity.

Anthracyclines belong to a class of anti-tumor antibiotics, and their severe cardiotoxicity significantly limits their clinical use. Exosomes play key roles in intercellular communication, characterized by high biocompatibility and specific tissue and organ homing effects. In this study, doxorubicin, an anthracycline anticancer drug widely used in clinical chemotherapy, was selected as a model drug. To address the significant cardiotoxicity associated with doxorubicin, tumor exosomes are utilized as drug carriers. The homing effect of autologous exosomes enhances drug uptake by tumor cells and reduces cardiotoxicity. To enhance the stability of exosomes, improve therapeutic effectiveness, and reduce toxic side effects, chitosan was utilized to modify the surface of exosomes. Chitosan has a specific anti-tumor effect because it can target the CD44 receptor of tumor stem cells and interact with tumor cells through charge adsorption. Through in vitro cell experiments, in vivo pharmacokinetic experiments, and an in situ ectopic nude mouse tumor model, the study demonstrated that chitosan-modified tumor exosomes significantly alleviated the severe cardiotoxicity of doxorubicin, while also showing remarkable anti-tumor efficacy. This study introduces a novel approach to reduce the adverse side effects of anthracycline chemotherapeutic drugs and presents a highly promising nanocarrier delivery system.

Posterior reversible encephalopathy syndrome (PRES) in classic Hodgkin's lymphoma, complicated by anthracycline-induced cardiomyopathy.

A woman in her 20s with no medical history was diagnosed with bulky stage II classic Hodgkin's lymphoma after an 8-week history of shortness of breath, cough and lethargy. A regimen of doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) was commenced with six cycles planned. During the first cycle, the patient was profoundly hypertensive. She then suffered two self-terminating tonic-clonic seizures.Examination and investigations diagnosed posterior reversible encephalopathy syndrome (PRES), which resolved completely in 11 days with strict blood pressure control and withholding chemotherapy. Treatment was further complicated by anthracycline-induced cardiomyopathy, requiring a switch in regimen to gemcitabine BVD.The patient made a full recovery from neurology and cardiology perspectives and completed six cycles of chemotherapy, achieving a complete metabolic response by the tumour. We illustrate the case, describe differential diagnoses and management of PRES, its association with chemotherapy and the successful chemotherapy rechallenge.

Anthracycline-induced cardiotoxicity: An overview from cellular structural perspective.

Anthracyclines are broad-spectrum anticancer drugs, but their clinical use is limited due to their severe cardiotoxicity. Anthracycline-induced cardiotoxicity (AIC) remains a significant cause of heart disease-related mortality in many cancer survivors. The underlying mechanisms of AIC have been explored over the past few decades. Reactive oxygen species and drug-induced inhibition of topoisomerase II beta are well-studied mechanisms, with mitochondria being a prominently investigated organelle. Emerging mechanisms such as ferroptosis, Ca2+ overload, autophagy and inflammation mediators have been implicated in recent years. In this review, our goal is to summarize and update the roles of various mechanisms in AIC, focusing on different cellular levels and further explore promising therapeutic approaches targeting these organelles or pathways.

Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

BACKGROUND: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10-0.56; P = 0.001). CONCLUSIONS: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM.

A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in anthracycline-induced cardiotoxicity.

BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study. METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes. RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines. CONCLUSION: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.

Natural Products for Preventing and Managing Anthracycline-Induced Cardiotoxicity: A Comprehensive Review.

Doxorubicin (DOX) is an anthracycline anticancer agent that is highly effective in the treatment of solid tumors. Given the multiplicity of mechanisms involved in doxorubicin-induced cardiotoxicity, it is difficult to identify a precise molecular target for toxicity. The findings of a literature review suggest that natural products may offer cardioprotective benefits against doxorubicin-induced cardiotoxicity, both in vitro and in vivo. However, further confirmatory studies are required to substantiate this claim. It is of the utmost importance to direct greater attention towards the intricate signaling networks that are of paramount importance for the survival and dysfunction of cardiomyocytes. Notwithstanding encouraging progress made in preclinical studies of natural products for the prevention of DOX-induced cardiotoxicity, these have not yet been translated for clinical use. One of the most significant obstacles hindering the development of cardioprotective adjuvants based on natural products is the lack of adequate bioavailability in humans. This review presents an overview of current knowledge on doxorubicin DOX-induced cardiotoxicity, with a focus on the potential benefits of natural compounds and herbal preparations in preventing this adverse effect. As literature search engines, the browsers in the Scopus, PubMed, Web of Science databases and the ClinicalTrials.gov register were used.

Efficacy of mitral annular velocity as an alternative marker of left ventricular global longitudinal strain to detect the risk of cancer therapy-related cardiac disorders.

PURPOSE: Left ventricular longitudinal function can be rapidly evaluated by measuring S' and mitral annular plane systolic excursion (MAPSE) using tissue Doppler imaging. Even when the image quality is poor and the left ventricular endocardium is not visible, S' and MAPSE can be measured if the mitral annulus is visible. However, the utility of S' and MAPSE in diagnosing cancer therapy-related cardiac dysfunction (CTRCD) remains unclear. This study aimed to examine the diagnostic performance of S' and MAPSE and determine appropriate cutoff values. METHODS: We retrospectively enrolled 279 breast cancer patients who underwent pre- or postoperative chemotherapy with anthracyclines and trastuzumab from April 2020 to November 2022. We compared echocardiographic data before chemotherapy, 6 months after chemotherapy initiation, and 1 year later. CTRCD was defined as a decrease in left ventricular ejection fraction below 50%, with a decrease of ≥10% from baseline or a relative decrease in left ventricular global longitudinal strain (LVGLS) of ≥15%. RESULTS: A total of 256 participants were included in this study, with a mean age of 50.2 ± 11 years. Fifty-six individuals (22%) developed CTRCD within 1 year after starting chemotherapy. The cutoff value for septal S' was 6.85 cm/s (AUC = .81, p < .001; sensitivity 74%; specificity 73%), and for MAPSE was 11.7 mm (AUC = .65, p = .02; sensitivity 79%; specificity 45%). None of the cases with septal S' exceeding 6.85 cm/s had an LVGLS of ≤15%. CONCLUSIONS: Septal S' is a useful indicator for diagnosing CTRCD. HIGHLIGHTS: Septal S' decreased at the same time or earlier than the decrease in LVGLS. The septal S' demonstrated higher diagnostic ability for CTRCD compared to LVGLS.

Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci.

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

Association of oral mucositis induced by anthracycline-cyclophosphamide and subsequent docetaxel treatment for perioperative breast cancer.

PURPOSE: Anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy is effective for perioperative breast cancer treatment. However, these treatments frequently induce oral mucositis (OM), with an incidence ranging from 20 to 50%. The association of OM development between different chemotherapeutic treatments remains unclear. Consequently, this study aimed to compare OM development during docetaxel-containing chemotherapy between patients with and without OM experience during previous anthracycline-cyclophosphamide treatments to assess the association between OM development and treatment regimens. METHODS: Seventy-two patients with breast cancer receiving anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy as a perioperative treatment were categorized into the control (no prior OM experience with anthracycline-cyclophosphamide) and OM-experience (OM development during previous treatment) groups and retrospectively evaluated. The primary endpoint was the incidence of all-grade OM in the first docetaxel-containing chemotherapy cycle. Additionally, the incidences of OM and dysgeusia during all treatment cycles and factors associated with the incidence of OM were evaluated. RESULTS: The incidence of all-grade OM in the first cycle was significantly higher in the OM-experience group (54.2%) than in the control group (10.4%; P < 0.0001). Furthermore, its incidence in all treatment cycles was higher in the OM-experience group (66.7%) than in the control group (12.5%, P < 0.0001). However, the incidence of dysgeusia did not differ between the groups. Multivariate logistic regression analysis revealed OM experience during previous anthracycline-cyclophosphamide treatment and concomitant pertuzumab use as independent risk factors for OM development in subsequent docetaxel-containing chemotherapy. CONCLUSION: Our study suggests that patients experiencing OM with anthracycline-cyclophosphamide during perioperative breast cancer treatment exhibit symptoms following subsequent docetaxel-containing chemotherapy.

Statins for the Primary Prevention of Anthracycline Cardiotoxicity: A Comprehensive Review.

PURPOSE OF REVIEW: The aim of this review is two-fold: (1) To examine the mechanisms by which statins may protect from anthracycline-induced cardiotoxicity and (2) To provide a comprehensive overview of the existing clinical literature investigating the role of statins for the primary prevention of anthracycline-induced cardiotoxicity. RECENT FINDINGS: The underlying cardioprotective mechanisms associated with statins have not been fully elucidated. Key mechanisms related to the inhibition of Ras homologous (Rho) GTPases have been proposed. Data from observational studies has supported the beneficial role of statins for the primary prevention of anthracycline-induced cardiotoxicity. Recently, several randomized controlled trials investigating the role of statins for the primary prevention of anthracycline-induced cardiotoxicity have produced contrasting results. Statins have been associated with a lower risk of cardiac dysfunction in cancer patients receiving anthracyclines. Further investigation with larger randomized control trials and longer follow-up periods are needed to better evaluate the long-term role of statin therapy and identify the subgroups who benefit most from statin therapy.

Sodium-Glucose Cotransporter 2 Inhibitors During Cancer Therapy: Benefits, Risks, and Ongoing Clinical Trials.

PURPOSE OF REVIEW: The goal of this paper is to summarize the data pertaining to the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) for the prevention of cardiotoxicity in patients receiving anthracyclines for cancer treatment. We discuss the potential efficacy of this class of medications, incorporating insights from existing literature and ongoing studies. RECENT FINDINGS: SGLT2i are a class of medications which were initially developed for treatment of Type 2 diabetes and later extended to treat heart failure with reduced and preserved ejection fraction regardless of diabetes status. There remains a need for effective and safe treatments to preventing cardiotoxicity in anthracycline-treated patients. It has been proposed that SGLT2i may provide protection against the cardiotoxic effects of anthracyclines. Some of the proposed mechanisms include beneficial metabolic, neurohormonal, and hemodynamic effects, renal protection, as well as a decrease in inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ion homeostasis. There is emerging evidence from basic science and observational studies that SGLT2i may play a role in the prevention of chemotherapy-induced cardiotoxicity. Randomized controlled trials are needed to conclusively determine the role of SGLT2 inhibitors as a cardioprotective therapy in patients receiving anthracyclines for the treatment of cancer.

Precision Treatment of Anthracycline-Induced Cardiotoxicity: An Updated Review.

OPINION STATEMENT: Anthracycline (ANT)-induced cardiotoxicity (AIC) is a particularly prominent form of cancer therapy-related cardiovascular toxicity leading to the limitations of ANTs in clinical practice. Even though AIC has drawn particular attention, the best way to treat it is remaining unclear. Updates to AIC therapy have been made possible by recent developments in research on the underlying processes of AIC. We review the current molecular pathways leading to AIC: 1) oxidative stress (OS) including enzymatic-induced and other mechanisms; 2) topoisomerase; 3) inflammatory response; 4) cardiac progenitor cell damage; 5) epigenetic changes; 6) renin-angiotensin-aldosterone system (RAAS) dysregulation. And we systematically discuss current prevention and treatment strategies and novel pathogenesis-based therapies for AIC: 1) dose reduction and change; 2) altering drug delivery methods; 3) antioxidants, dexrezosen, statina, RAAS inhibitors, and hypoglycemic drugs; 4) miRNA, natural phytochemicals, mesenchymal stem cells, and cardiac progenitor cells. We also offer a fresh perspective on the management of AIC by outlining the current dilemmas and challenges associated with its prevention and treatment.