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![Human epidermal growth factor receptor (HER) 2 signaling pathways involved in tumorigenesis and cardiac survival. (A) In breast cancer cells, HER dimer formation results in cross-phosphorylation of the dimer tyrosine kinase domain and leads to the initiation of mitogenic cell signaling pathways, including activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways [2]. While the HER2 to HER3 heterodimer is considered the most potent HER dimer with respect to strength of interaction, ligand-induced tyrosine phosphorylation, and downstream signaling, other dimer pairs do show weak mitogenic activity [3]. Blocking HER2 signaling with trastuzumab [4] or HER2 dimerization with pertuzumab [1] prevents activation of the signaling pathways that mediate cell proliferation and survival. (B) In cardiac myocytes, activation of cardiac stress pathways results in release of neuregulin that stimulates the formation of HER2:HER4 and HER4:HER4 dimers. These activate downstream signaling pathways, resulting in the promotion of cardiomyocyte growth and cardiac repair mechanisms [5–7]. However, under conditions of HER2 inhibition, the homeostatic cardioprotection afforded by the activation of these downstream pathways may be attenuated, resulting in vulnerability to cardiac stress. (C) Anthracycline exposure exerts direct cytotoxicity against cardiac myocytes, resulting in the cardiotoxic effects of these agents. Activation of the stress pathway described in panel B may afford some protection from the cytotoxic effects of anthracycline exposure. However, it is possible that HER2 inhibition in the presence of anthracycline stress may further attenuate the innate cardioprotective mechanisms by preventing the induction of HER2:HER4-mediated stimulation of cardiomyocyte growth and cardiac repair mechanisms, thus limiting the capacity for cardiac repair. Therefore, inhibition of HER2 dimerization in association with anthracycline therapy can exacerbate anthracycline-induced cardiac damage [8, 9].](profile/Daniel-Lenihan/publication/51212341/figure/fig1/AS:277243231260684@1443111345481/Human-epidermal-growth-factor-receptor-HER-2-signaling-pathways-involved-in.png)
Human epidermal growth factor receptor (HER) 2 signaling pathways involved in tumorigenesis and cardiac survival. (A) In breast cancer cells, HER dimer formation results in cross-phosphorylation of the dimer tyrosine kinase domain and leads to the initiation of mitogenic cell signaling pathways, including activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways [2]. While the HER2 to HER3 heterodimer is considered the most potent HER dimer with respect to strength of interaction, ligand-induced tyrosine phosphorylation, and downstream signaling, other dimer pairs do show weak mitogenic activity [3]. Blocking HER2 signaling with trastuzumab [4] or HER2 dimerization with pertuzumab [1] prevents activation of the signaling pathways that mediate cell proliferation and survival. (B) In cardiac myocytes, activation of cardiac stress pathways results in release of neuregulin that stimulates the formation of HER2:HER4 and HER4:HER4 dimers. These activate downstream signaling pathways, resulting in the promotion of cardiomyocyte growth and cardiac repair mechanisms [5–7]. However, under conditions of HER2 inhibition, the homeostatic cardioprotection afforded by the activation of these downstream pathways may be attenuated, resulting in vulnerability to cardiac stress. (C) Anthracycline exposure exerts direct cytotoxicity against cardiac myocytes, resulting in the cardiotoxic effects of these agents. Activation of the stress pathway described in panel B may afford some protection from the cytotoxic effects of anthracycline exposure. However, it is possible that HER2 inhibition in the presence of anthracycline stress may further attenuate the innate cardioprotective mechanisms by preventing the induction of HER2:HER4-mediated stimulation of cardiomyocyte growth and cardiac repair mechanisms, thus limiting the capacity for cardiac repair. Therefore, inhibition of HER2 dimerization in association with anthracycline therapy can exacerbate anthracycline-induced cardiac damage [8, 9].
Source publication
Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a...
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Background
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What are Multi-Target Inhibitors (MTIs), and why are they Needed? During the past several decades, there has been significant progress in treating cancer with chemotherapy, radiation, and surgery [1]. However, traditional methods of cancer treatment are frequently limited because of systemic side effects, the development of resistance, and sub-opti...
Citations
... Pertuzumab is another monoclonal antibody that inhibits the dimerization of HER2 receptors, which is an essential step required for cell growth and survival in several tumour types [28]. A pooled analysis of 569 patients treated with pertuzumab across different disease subsets revealed that 5.7% of patients experienced a decrease in LVEF, and 0.7% developed symptomatic congestive heart failure (CHF) [28]. ...
... Pertuzumab is another monoclonal antibody that inhibits the dimerization of HER2 receptors, which is an essential step required for cell growth and survival in several tumour types [28]. A pooled analysis of 569 patients treated with pertuzumab across different disease subsets revealed that 5.7% of patients experienced a decrease in LVEF, and 0.7% developed symptomatic congestive heart failure (CHF) [28]. In a phase II study evaluating the safety and efficacy of combined trastuzumab-pertuzumab treatment in 66 patients previously exposed to trastuzumab, asymptomatic LVEF reduction was observed in three patients, whilst no cases of CHF were reported [29]. ...
Despite current advancements in chemotherapy, immunotherapy and targeted treatments, the potential for major adverse cardiovascular events, regardless of previous cardiac history, persists. Scoring systems, such as the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) risk assessment tool, can be utilized to evaluate several factors including prior cardiac history, risk factors and cardiac biomarkers to categorize patients into low, moderate, high, and very high-risk groups. Common cardiotoxicity complications include new or worsening left ventricular ejection fraction (LVEF), QT interval prolongation, myocardial ischaemia, hypertension, thromboembolic disease, cardiac device malfunction and valve disease. Baseline electrocardiogram (ECG) and transthoracic echocardiogram (TTE) are routinely performed for all patients commenced on cardiotoxic treatment, while other imaging modalities and biochemical markers have proven useful for monitoring. Management mainly includes early risk stratification and prompt identification of cardiovascular complications, with patient-specific surveillance throughout treatment. A multidisciplinary approach is crucial in determining the relationship between potential treatment benefits and cardiotoxicity, and whether the continuation of treatment is appropriate on a case-by-case basis. Early risk stratification, optimizing the patient's cardiovascular status prior to treatment, and prompt identification of suspected cardiotoxicity are key in significantly reducing risk. This article provides a comprehensive review of the various types of treatment-related cardiotoxicity, offering guidance on identifying high-risk patients, recognizing early signs of cardiotoxicity, and outlining appropriate treatment approaches and follow-up care for such cases.
... It has synergistic activity with trastuzumab and is also approved as a combination therapy with taxanes. The combination of trastuzumab and pertuzumab did not increase the risk of cardiotoxicity [50][51][52]. A pooled analysis [50] of 14 studies demonstrated the rate of asymptomatic left ventricular systolic dysfunction was 6.9% when pertuzumab was used as monotherapy and 6.5% when it was used in combination with trastuzumab. ...
... The combination of trastuzumab and pertuzumab did not increase the risk of cardiotoxicity [50][51][52]. A pooled analysis [50] of 14 studies demonstrated the rate of asymptomatic left ventricular systolic dysfunction was 6.9% when pertuzumab was used as monotherapy and 6.5% when it was used in combination with trastuzumab. Heart failure rates were 0.3% in monotherapy regimens and 1.1% in combination regimens. ...
... Cardiomyopathy has been shown to develop in up to 30% of patients during or following HER2targeted therapy with trastuzumab [56]. Pertuzumab is a newer anti-HER2 monoclonal antibody, often given concurrently with trastuzumab, that has been associated with lower rates of heart failure than trastuzumab when each is given alone [57]. However, a recent systemic review still demonstrated a relative risk of 1.97 (95% CI: 1.05-3.70) of developing clinical heart failure following pertuzumab use compared to placebo [58]. ...
Purpose of Review
As the percentage of patients achieving long-term survival following treatment of their cancer grows, it is increasingly important to understand the long-term toxicities of cancer-directed treatment. In this review, we highlight the recent findings regarding radiation-induced cardiotoxicity across multiple disease sites, with a particular focus on heart failure.Recent FindingsDespite its relative lack of study historically, radiation-induced heart failure has now recently been implicated in several studies of breast cancer, lung cancer, esophageal cancer, and lymphoma as a non-trivial potential consequence of thoracic radiotherapy. Data regarding specific cardiac dosimetric endpoints relevant to cardiotoxicity continue to accumulate.SummaryRadiation-induced heart failure is a rare but significant toxicity of thoracic radiotherapy, that is likely underreported. Important areas for future focus include understanding the interplay between thoracic radiotherapy and concurrent cardiotoxic systemic therapy as well as development of potential mitigation strategies and novel therapeutics.
... Although trastuzumab and pertuzumab recognize different sites of HER-2, their clinical combination results in stronger antitumor efficacy (81). Surprisingly, the combination of pertuzumab and trastuzumab does not seem to raise the risk of LV dysfunction and congestive heart failure and even alleviate the left ventricular dysfunction possibly (82)(83)(84). The latest recombinant HER-2 humanized monoclonal antibody inetetamab has entered into the clinical treatment of breast cancer in the past 2 years, and so far it only seems to cause the decrease of LVEF. ...
Breast cancer is one of the most prevalent types of cancers worldwide, especially for females. Surgery is the preferred treatment for breast cancer, and various postoperative adjuvant therapies can be reasonably used according to different pathological characteristics, especially traditional radiotherapy, chemotherapy, and endocrine therapy. In recent years, targeting agent therapy has also become one of the selective breast cancer treatment strategies, including anti-HER-2 drugs, CDK4/6 inhibitor, poly ADP-ribose polymerase inhibitor, PI3K/AKT/mTOR pathway inhibitor, ER targeting drugs, and aromatase inhibitor. Because of the different pathologic mechanisms of these adjuvant therapies, each of the strategies may cause cardiotoxicity in clinic. The cardiac adverse events of traditional endocrine therapy, radiotherapy, and chemotherapy for breast cancer have been widely detected in clinic; however, the targeting therapy agents have been paid more attention with the extension of application. This review will summarize the cardiac toxicity of various adjuvant therapies for breast cancer, especially for targeting drug therapy.
... Другие препараты, направленные на подавление активности HER2-рецепторов, пертузумаб и лапатиниб, по всей видимости, обладают меньшим по сравнению с трастузумабом кардиотоксическим потенциалом [17,18]. ...
... Помимо миокардита, распространенность отдельных кардиальных осложнений составляет по данным различных авторов: для перикардита -<1-2% (до 13,6%), [17] перикардиального выпота -2-7%, фибрилляции предсердий -4,84%, инфаркта миокарда -1-2%, сердечной недостаточности -0,4%-4%. Cообщения о КМП Такоцубо и внезапной сердечной смерти единичны [412,419,413,408]. ...
Disclaimer. The EAC Guidelines represent the views of the EAC, and were produced after careful consideration of the scientific and medical knowledge, and the evidence available at the time of their publication. The EAC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the EAC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the EAC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic, or therapeutic medical strategies; however, the EAC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the EAC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
... 55,56 Less clear with respect to cardiomyopathy risk is the case of dual HER2 blockade (in which newer compounds such as pertuzumab are combined with trastuzumab), although early data suggest cardiomyopathy signals similar to those with trastuzumab monotherapy. 57,58 The HER2 receptor is also expressed in vascular endothelial cells, 59 and disruption of the HER2 signaling may contribute to the pathophysiology of myocardial injury. 60,61 IL (interleukin)-2 is an immunotherapeutic agent used to treat metastatic melanoma and renal cell carcinoma. ...
Cardio-oncology has organically developed as a new discipline within cardiovascular medicine as a result of the cardiac and vascular adverse sequelae of the major advances in cancer treatment. Patients with cancer and cancer survivors are at increased risk of vascular disease for a number of reasons. First, many new cancer therapies, including several targeted therapies, are associated with vascular and metabolic complications. Second, cancer itself serves as a risk factor for vascular disease, especially by increasing the risk for thromboembolic events. Finally, recent data suggest that common modifiable and genetic risk factors predispose to both malignancies and cardiovascular disease. Vascular complications in patients with cancer represent a new challenge for the clinician and a new frontier for research and investigation. Indeed, vascular sequelae of novel targeted therapies may provide insights into vascular signaling in humans. Clinically, emerging challenges are best addressed by a multidisciplinary approach in which cardiovascular medicine specialists and vascular biologists work closely with oncologists in the care of patients with cancer and cancer survivors. This novel approach realizes the goal of providing superior care through the creation of cardio-oncology consultative services and the training of a new generation of cardiovascular specialists with a broad understanding of cancer treatments.
... Among 83 patients recruited, no episode of symptomatic heart failure was observed, and only 2.4% experienced an asymptomatic cardiac event during NAC. Our results confirm that a dual blockade in combination with anthracycline and taxanes is associated with a low incidence of asymptomatic LVEF decline or symptomatic heart failure [29]. ...
Abstract Background The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Methods Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Results Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. Conclusions The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. Trial registration clinicaltrials.gov, NCT01669239, Registered 20 August 2012.
... With the extension of treatment duration and survival time, antitumor-induced cardiotoxicity has emerged as the second cause of death in patients who had received antitumor therapy. [12] Approximately, 2% to 3% patients had been reported suffering antitumor-induced cardiotoxicities during treatment in perspective clinical trials, while nearly 26% of which in prospective ones accounted. [13] A majority of cytotoxic agents have already been revealed with substantial cardiovascular events, such as adriamycin, [14] cyclophosphamide, [15] cisplatin, [16] fluorouracil, [17,18] and paclitaxel, [19] among which adriamycin comes to be the most outstanding one. ...
... [22] As the clinical application for decades with those agents, sufficient attention for cardiovascular toxicity has been paid, and relevant monitoring procedure, as well as precautionary measures established. However, cardiovascular toxicities of targeted drugs, the emerging effective and convenient ones in recent years, have also been reported in clinical researches, such as anti-Her-2 drugs, [12,[20][21][22] anti-VEGFR drugs, [13,23] EGFR-TKIs, [24][25][26] and multi-target agents, [27,28] with mechanism of which still remains controversial. Regorafenib, the multi-targeted agent, has also been reported considerable cardiovascular toxicities, and even fatal events. ...
Background:
The present comparative meta-analysis was conducted to evaluate the cardiovascular events of regorafenib in patients with solid tumors.
Methods:
Eligible studies from MEDLINE, Google Scholar, Cochrane Library, Clinical key, EBSCO publishing and Ovid, which had reported cardiovascular adverse events potentially caused by regorafenib were absorbed. Data of clinical characteristics and cardiovascular events including hypertension, hemorrhage, thrombosis, and heart failure were extracted from selected literatures for the final analysis. Pooled analysis of cardiovascular adverse events was developed by relative risks (RRs) and corresponding 95% confidence intervals (CIs) with software STATA 13.0 and RevMan 5.3.
Results:
Thirty studies including 3813 patients were fit into analysis. The incidences of cardiovascular events of all-grade were: hypertension, 36.8% (95% CI, 29.8%-43.8%), hemorrhage, 8.6% (95% CI, 3.2%-14%), thrombosis, 1.4% (95% CI, 0.1%-2.8%), and heart failure, 2.9% (95% CI, 0.3%-5.6%). The incidences of cardiovascular events of high-grade were: hypertension, 9.9% (95% CI, 7.4%-12.4%), hemorrhage, 1.2% (95% CI, 0.3%-2.2%), thrombosis, 1.6% (95% CI, 0.2%-3.4%), and heart failure, 2.9% (95% CI, 0.3%-5.6%). The RRs and their 95% CIs of all-grade cardiovascular events among patients treated with regorafenib were: hypertension, 4.10 (95% CI, 3.07-5.46; P < .00001), hemorrhage, 2.71 (95% CI, 1.45-5.08; P = .002), thrombosis, 1.27 (95% CI, 0.49-3.27; P = .62), and heart failure, 0.79 (95% CI, 0.16-3.94; P = .77). The RRs and their 95% CIs of high-grade cardiovascular events among patients treated with regorafenib were: hypertension, 5.82 (95% CI, 3.46-9.78; P < .00001), hemorrhage, 0.90 (95% CI, 0.50-1.61; P = .72), thrombosis, 1.28 (95% CI, 0.48-3.41; P = .62), and heart failure, 1.15 (95% CI, 0.23-5.69; P = .86), respectively.
Conclusion:
The present meta-analysis has demonstrated that regorafenib is associated with an increasing risk of hypertension at all-grade and high-grade, as well as hemorrhage at all-grade. Adequate awareness of cardiovascular adverse events of regorafenib should be established for clinicians.
... cardiac safety concerns when those agents were combined. 266,267 In a recently published large, prospective, randomized trial (APHINITY trial) exploring trastuzumab with or without pertuzumab with adjuvant chemotherapy in the treatment of women with early-stage HER2-positive breast cancer, there was a low incidence of HF (0.7% in the pertuzumab group versus 0.3% in the placebo group, with HF defined as New York Heart Association functional class III or IV and a significant drop in LVEF ≥10 points with absolute LVEF <50%) and cardiac death (2 cardiac deaths in each arm). 268 ...
Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet many people perceive breast cancer to be the number one threat to women's health. CVD and breast cancer have several overlapping risk factors, such as obesity and smoking. Additionally, current breast cancer treatments can have a negative impact on cardiovascular health (eg, left ventricular dysfunction, accelerated CVD), and for women with pre-existing CVD, this might influence cancer treatment decisions by both the patient and the provider. Improvements in early detection and treatment of breast cancer have led to an increasing number of breast cancer survivors who are at risk of long-term cardiac complications from cancer treatments. For older women, CVD poses a greater mortality threat than breast cancer itself. This is the first scientific statement from the American Heart Association on CVD and breast cancer. This document will provide a comprehensive overview of the prevalence of these diseases, shared risk factors, the cardiotoxic effects of therapy, and the prevention and treatment of CVD in breast cancer patients.
... The first entirely human immunoRNase was produced fusing HP-RNase to an ErbB2-specific scFv named Erbicin [177,178]. The construct recognizes an epitope distinct to that of trastuzumab and pertuzumab [179], the two humanized antibodies currently used to treat HER2 + metastatic mammary carcinomas [180,181] and do not induce cardiac dysfunction as the other two do [182][183][184]. Although this immunoRNase was inhibited by the RI to an extent comparable to that of HP-RNase, the quantity that entered the cell cytosol saturated the RI, and it exhibited a clear RNA degradation ability [185]. ...
Typical antitumor drugs disrupt the flow of biochemical information from DNA to proteins with the aim of precluding uncontrolled cell proliferation and inducing cancer cell apoptosis. However, most of the currently used small antitumor drugs are genotoxic because they act over DNA. Pharmaceutical industry is now searching for a new line of cancer chemotherapeutics without genotoxic effects. Ribonucleases (RNases) are small basic proteins, present in all life forms, which belong to this kind of chemotherapeutics. Some of them present with remarkable selective antitumor activity linked to their ability to destroy RNA, a powerful way to control gene expression, leaving DNA unharmed. In the last two decades, the knowledge gained on the cytotoxic mechanism of these RNases has been used to engineer more powerful and selective variants to kill cancer cells. In this chapter, we describe the advances reached in endowing an RNase with antitumor abilities.
