Trastuzumab is a humanized monoclonal antibody targeting HER2 (33). By binding to HER2 on the surface of tumor cells, trastuzumab blocks the binding of human epidermal growth factor to HER2, thereby affecting the transmission of tumor cell growth signals for controlled tumor proliferation and delayed recurrence and metastasis (34, 35). Trastuzumab is primarily used in HER2-positive BC patients, usually in combination with docetaxel or paclitaxel (36). Pertuzumab is another monoclonal antibody targeting HER2, acting on different extracellular structural domains of HER2 than trastuzumab, inhibiting HER2 heterodimerization and, consequently, receptor signaling (37). In clinical practice, pertuzumab is often used in combination with trastuzumab to treat HER2-positive BC patients (38). This combination enhances the blocking effect of the downstream signaling; at the same time, they can jointly exert antibody-dependent cell-mediated cytotoxic effects, thus enhancing the immune-synergistic outcome (39, 40).

Numerous studies have shown that trastuzumab increases the risk of cardiovascular toxicity (Table 1; Figure 1). In five phase III clinical trials of primary trastuzumab adjuvant therapy, a decrease in LVEF of ≥10% or 15% from baseline values was observed in 3% to 34% of patients, while the incidence of grade III–IV congestive heart failure by NYHA cardiac functional grading was 0–3.9% in the targeted therapy group and 0–1.3% in the untreated group (41, 42). In addition, the incidence of heart failure in HER2-positive metastatic BC patients treated with trastuzumab in combination with anthracyclines was 27%, whereas that of serious cardiovascular adverse events in the anthracycline only group was just 8%. This suggests that cardiovascular toxicity is a significant adverse effect of anthracyclines combined with trastuzumab (40, 43, 44). The NeoSphere trial demonstrated that patients receiving dual-target (trastuzumab combined with pertuzumab) neoadjuvant therapy had no significant increase in the incidence of left ventricular dysfunction compared with patients receiving single neoadjuvant targeted therapy, and the difference in the incidence of LVEF decreased by more than 10–15% from baseline or post-treatment LVEF <50% was not statistically significant (39, 45). In the CLEOPATRA trial, the incidence of cardiovascular adverse events was 14.5 and 16.4% in HER2-postive metastatic BC patients receiving first-line dual-targeted therapy or trastuzumab only, respectively. The incidence rates of grade III or higher cardiovascular adverse events (left ventricular systolic dysfunction was the most common) were 1.5 and 3.8%, respectively (46, 47).

Although the mechanism behind these cardiac effects is unclear, studies have suggested that it may be associated with the following processes. (1) Abnormalities in the HER2 signaling pathway. HER2 is expressed on cardiac myocytes, and the HER2 pathway stabilizes the fibrous structure of tissues through a series of signal transduction pathways, thereby inhibiting apoptosis, which can maintain cell survival by reducing the level of organic oxygen. However, trastuzumab inhibits HER2 signaling by binding to HER2, leading to excessive accumulation of reactive oxygen species (ROS) and destruction of cardiomyocytes in the presence of excess organic oxygen species, leading even to cardiac insufficiency. Thus, trastuzumab-related cardiovascular toxicity is an important clinical challenge (33, 48–50). (2) Abnormalities in neuromodulatory protein pathways. Under physiological conditions, the coronary microvascular endothelial cells and endocardium release neuromodulatory proteins (HER4), which boost proliferation pathways after dimerization with HER2. These pathways increase ROS synthesis inhibition pathways and maintain cellular integrity by reducing apoptosis, whereas anti-HER2 drugs disrupt the associated signaling, resulting in excessive production of ROS, which in turn impairs the integrity of cardiac vascular endothelial cells, affects myocardial blood supply, and weakens cardiomyocyte protection (51, 52). (3) Mitochondrial dysfunction. Mitochondria are physiologically important for maintaining the metabolic balance of cardiomyocytes and the homeostasis of the intracellular environment, as well as for regulating the cell growth cycle. Trastuzumab can impair the normal oxidative defense function of mitochondria in cardiomyocytes and induce massive accumulation of mitochondrial ROS, leading to the overexpression of the apoptotic protein Bcl-2 associated X protein (BAX), which in turn activates the mitochondrial apoptotic pathway, resulting in the loss of mitochondrial physiological function and opening of the mitochondrial permeability transition pores. This leads to apoptosis or necrosis of cardiomyocytes, ultimately resulting in cardiac tissue dysfunctions (53–55).

Multiple clinical studies have shown that trastuzumab triggers cardiovascular toxicity, with some degree of reversible damage (type II cardiovascular toxicity). Eight-year results from HERA trial suggested that the incidence of trastuzumab-induced cardiovascular events remained consistently low. Following treatment termination in patients with cardiovascular events in the 1-year treatment group, 79.5% of patients met the criteria for early recovery of cardiac function (56). The mechanism of reversibility is most likely related to the restoration of the HER2 pathway after trastuzumab discontinuation (57).

Lapatinib is the first TKI approved for the treatment of HER2-postive advanced BC (58), which effectively inhibits phosphorylation of the epidermal growth factor receptor, blocks the downstream transmission of mitogenic signaling pathways, arrests tumor cell proliferation and differentiation, and promotes cell apoptosis (59). Lapatinib is currently approved for use in combination with capecitabine in advanced or metastatic BC patients who have failed to respond to anthracycline, paclitaxel, and trastuzumab treatments. A meta-analysis showed that most of the cardiovascular toxicity in clinical trial patients on lapatinib, regardless of whether anthracycline or trastuzumab has been used in the past, was only reflected by asymptomatic reduction of LVEF, which was largely reversible when the drug was discontinued (60). Numerous clinical phase I and II trials evaluating the safety of lapatinib in patients with progressive or metastatic HER2 BC have shown that the incidence of left ventricular dysfunction ranges from 0 to 26.6%, with a decrease in LVEF of ≥20% or a post-treatment assessment of LVEF <50%, ranging from 0 to 12.8% (61). However, it should be emphasized that most of these patients had received prior anthracycline-based chemotherapy or trastuzumab, and only a small percentage of patients received first-line lapatinib treatment. Another study analyzed the cardiovascular safety of continuing trastuzumab in combination with lapatinib in stage IV HER-2+ BC patients whose disease progressed during trastuzumab treatment and showed that the incidence of asymptomatic LVEF decline and congestive heart failure was lower in the combination group (2 and 3.4%, respectively) than in the lapatinib-only group (0.7 and 1.4%, respectively) (62). In a phase III clinical trial, locally progressive or metastatic HER2-postive BC patients who had disease progression after prior treatment with anthracyclines, paclitaxel, and trastuzumab and whose LVEF was within the normal range prior to enrollment received lapatinib + capecitabine and maintenance capecitabine alone, respectively; cardiovascular events (defined as asymptomatic heart failure or a ≥20% decrease in LVEF from baseline) remained low in both groups, i.e., at 2.45 and 0.62%, respectively (63).

Apatinib is a novel small-molecule vascular endothelial growth factor receptor (VEGFR) TKI, developed independently in China, that can control tumor growth and progression by inhibiting VEGFR and thus tumor angiogenesis (64, 65). Currently, it is widely used in clinical practice. Hypertension is one of the main adverse effects of this drug observed in clinical studies (only as isolated cases) (66–68). The mechanisms of hypertension caused by apatinib may include: (1) downregulation of NO synthase expression and decreased NO release, (2) sparse microvascular network, (3) increased secretion of vasoconstriction stimulants, (4) increased synthesis of ROS, and (5) renal insufficiency (69).

HR-positive BC is the most common type of BC worldwide. In recent years, CDK4/6 inhibitors have shown large benefits in HR-positive patients, and CDK4/6 inhibitor monotherapy combined with endocrine therapy has been used for the treatment of advanced BC. Since the U.S. Food and Drug Administration (FDA) approval of palbociclib in 2015, CDK4/6 inhibitors have been the first-line treatment option for patients with metastatic HR-positive/HER2-negative phenotypes (70). CDK4/6 inhibitors can block tumor cells in the first phase of the cell cycle (G1 phase) by binding to cell cycle proteins to promote the mid-phase transition, initiate DNA synthesis, and regulate cell transcription (71). Palbociclib, abemaciclib, and reboxinib are specific CDK4/6 inhibitors, and all three drugs are used in clinical studies as monotherapy or in combination with other drugs for the treatment of many types of tumors. Palbociclib is the first highly specific CDK4/6 inhibitor. A single-arm phase II study enrolling 37 patients with Rb-positive metastatic BC showed that of the 84% of ER-positive/HER2-negative BC patients, two had partial remission and five had stable disease for more than 6 months. In BC models, when palbociclib was combined with trastuzumab or tamoxifen, these drugs had a synergistic inhibitory effect on HER gene amplification and ER-positive cell proliferation; the same synergistic effect was observed when palbociclib was combined with endocrine therapy (72). Significant adverse events in early clinical trials often include neutropenia and thrombocytopenia owing to the dependence of bone marrow progenitor cells on CDK6 (73). Abemaciclib is the only CDK4/6 inhibitor approved for monotherapy (74) and has shown broader inhibition efficacy compared to other CDK4/6 inhibitors. Abemaciclib monotherapy was tested in the phase II single-arm MONARCH-1 study, which reported an objective remission rate of 19.7%, median progression-free survival (PFS) of 6 months, and median overall survival of 17.7 months (75). Additionally, clinical studies have shown that it can be used alone or in combination with gemcitabine (72). Owing to its broad inhibitory effects, the drug can induce a variety of side effects, with fatigue as a dose-limiting toxicity and diarrhea as a common adverse effect (74). Cardiovascular side effects are uncommon with CDK4/6 inhibitors and include only QT prolongation, which occurs at a low rate. Two cases of new onset 2nd degree type 2 atrioventricular block requiring permanent cardiac pacing in metastatic BC patients treated with reboxinib or abemaciclib have been recently reported (76). In 2017, the FDA approved reboxinib and aromatase inhibitors together as first-line endocrine therapy in postmenopausal women with advanced or metastatic BC that is HR-positive and HER2 negative (77). Reboxinib-induced cardiovascular toxicity mainly manifests as QT interval prolongation. In a study including 668 postmenopausal patients with HR+, HER2- recurrent, or metastatic BC who were evaluated for PFS with the combination of reboxinib and letrozole, 3.6% subjects showed prolonged QT intervals (78). The mechanism may involve: (1) abnormal expression of genes related to long QT syndrome (KCNH2, SCN5A, SNTA1, etc.). The reboxinib-induced long QT interval can be attributed to the regulation of the expression of one or several related genes. Microarray analysis of human leukemia cell lines revealed that three LQT-syndrome-related genes, KCNH2, SCN5A, and SNTA1, were differentially expressed in cells after treatment with reboxinib, showing a decrease in KCNH2 and an increase in SCN5A and SNTA1 (79). Another possible explanation could involve (2) alteration of potassium and sodium channels. It has been reported that drug-induced QT interval prolongation is caused by a blockade of potassium channels encoded by the human ether-go-go-related gene (hERG) (80). In a study comparing the safety of palbociclib and reboxinib, it was shown that reboxinib caused hERG inhibition (81).

Bevacizumab is a recombinant humanized IGg1 monoclonal antibody that exerts antitumor effects by inhibiting the biological activity of VEGF and blocking tumor angiogenesis (82). The role of bevacizumab in BC has been controversial, and three major clinical studies, the E2100, AVADO, and RIBBON-1 studies, showed that bevacizumab prolonged PFS in patients, but there was no difference in overall survival (OS). The European Medicines Agency has approved bevacizumab in combination with paclitaxel as a first-line treatment for metastatic BC. A combination of these three clinical trials found that in triple-negative BC, the objective response rate (ORR) of chemotherapy in combination with bevacizumab increased by nearly 20%, and PFS was significantly prolonged (83, 84). The survival effect of bevacizumab on BC patients requires confirmation by more studies. Bevacizumab has been reported to cause heart failure, decreased cardiac function, and even stress cardiomyopathy—effects possibly related to factors such as reduced capillary density and endothelial dysfunction caused by the inhibition of VEGF pathways and increased cardiac afterload (85, 86).

Recently developed ADCs are beneficial for the treatment of BC patients, including those with HER2-positive, triple-negative and some with HER2 low-expressing tumors (87). ADCs combine the advantages of highly targeted monoclonal antibodies and cytotoxic small molecules to reduce the systemic toxicity of off-target small-molecule cytotoxins and improve antitumor efficacy (88, 89). T-DM1 is the first groundbreaking ADC used in BC therapy, with an inherent advantage of a “magic bullet” and stable and significant clinical efficacy. The agent consists of trastuzumab, a non-reducing thioether junction and the microtubulin inhibitor methane derivative (DM1) (90). DM1 and vincristine have similar mechanisms of action, as they both inhibit microtubule protein polymerization by binding to them, which, in turn, induces cell cycle arrest and apoptosis. T-DM1 binding to HER2 allows the complex to enter target cells through receptor-mediated endocytosis. The antibody component of T-DM1 is degraded in the lysosomes, releasing DM1 into the cytoplasm, ultimately leading to cell cycle arrest and induction of cell death (91, 92). The EMILIA study, a pivotal phase III clinical study of T-DM1 for the second-line treatment of advanced HER2-positive BC, showed that T-DM1 significantly prolonged the median PFS and median OS with lower toxicity and better overall tolerability than lapatinib combined with capecitabine in HER2-positive advanced BC patients previously treated with paclitaxel and trastuzumab-based agents (60).

A recent study analyzing the occurrence of adverse drug reactions associated with HER2-positive BC through a spontaneous reporting system database showed that half of the adverse reactions associated with T-DM1 included blood disorders, such as thrombocytopenia, while cardiac disorders, including heart failure and arrhythmias, were significantly less frequent compared to their incidence associated with classical anti-HER2 antibodies (trastuzumab and pertuzumab), with an overall incidence of only 3% (93). Another study performed a pooled analysis of 1961 advanced HER2-positive BC cases treated with T-DM1 to determine the incidence of cardiotoxicity, its clinical presentation, and possible risk factors related to T-DM1-associated cardiotoxicity. The results of this study showed that cardiac events were uncommon in T-DM1-treated patients, with at least one cardiac event occurring in 3.37% of the entire study sample; the most common type of cardiac event was a low-level (grade 1 or 2) LVEF decline (~2.04%), and the majority (~79%) of patients who experienced a cardiac event achieved recovery of cardiac function at the end of the follow-up (within 1 year) (94). Patients treated with T-DM1 in the ATEMPT trial exhibited good prognoses and rarely experienced toxic effects, making T-DM1 a potential treatment option for selected stage I HER2-positive BC patients (95). Considering that cardiotoxicity is the most significant adverse event associated with trastuzumab (the main molecular component of T-DM1), researchers performed a subanalysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1 therapy. The results showed an incidence of grade 3–4 left ventricular systolic insufficiency of 0.8 and 1.8% in the T-DM1 and trastuzumab combined with paclitaxel groups, respectively. In addition, three patients (0.8%) in the T-DM1 group showed a significant asymptomatic decrease in LVEF compared with those in six patients (5.3%) in the paclitaxel combined with trastuzumab group. Follow-up data indicated that all patients achieved complete remission of any cardiac symptoms and their LVEF returned to normal levels (96).

A prospective multicenter phase III two-arm clinical trial enrolled 991 metastatic HER2-postive BC patients who received T-DM1 and capecitabine together with lapatinib in a 1:1 ratio. The incidence of LVEF <50% or at least a 15% reduction from baseline in the T-DM1 group was only 1.7%, and the incidence of class III left ventricular systolic dysfunction was only 0.2% (97). In the TH3RESA trial, patients who received at least two anti-HER2 agents (trastuzumab and lapatinib) and paclitaxel, had progressive disease, and no cardiovascular events were reported in patients who received T-DM1 rescue therapy (98).

Approximately 7–15% of HER2-negative BC patients carry BRCA 1/2 mutations. These patients are characterized by high aggressiveness, high recent/distant recurrence rate, and poor prognosis (99). PARP plays a crucial role in gene damage response, regulation of apoptosis, and maintenance of genomic stability (100). Cells with BRCA1 and BRCA2 mutations are exceptionally sensitive to PARP inhibitors; thus, PARP inhibitors are used to treat HR-deficient malignancies (101). The most commonly used commercially available PARP inhibitors include olaparib (AZD2281), niraparib (MK-4827), rucaparib, veliparib (ABT- 888), fluzoparib and talazoparib (BMN- 673) (102). Olaparib was the world's first commercially available PARP inhibitor. PARPase is closely related to DNA transcription and repair in humans and is an essential protein for cancer cell functionality, especially in patients with BRCA mutations. Notably, BRCA protein defects make tumor cells highly dependent on the PARPase action. Olaparib inhibits the activity of PARP, resulting in tumor cells apoptosis due to unresolved DNA damage (103). Olaparib shows a substantial clinical benefit in patients with advanced breast and ovarian cancers (104). Clinical safety data are lacking for olaparib as adjuvant treatment of BC patients. A recent Japanese study analyzed the adverse reactions to two PARP inhibitors, olaparib and niraparib, using the Japan Adverse Drug Reaction Reports database. In this study, 1,287 cases (83.0%) of adverse reactions caused by olaparib were reported in ovarian cancer patients, whereas 177 cases (11.4%) of adverse reactions were detected in BC patients. The most common adverse events with olaparib were hematologic reactions, gastrointestinal reactions, and general malaise, with common hematologic toxicities including anemia, decreased neutrophil count, and decreased platelet count. Mild and moderate olaparib-related adverse events may be related to both target and off-target effects of the drug, and most of such effects can be controlled by dose suspension, dose reduction and symptomatic treatment. Most adverse events occurred within 3 months of drug administration, after which the symptoms gradually resolved (105). Almost no cases of olaparib-induced cardiotoxicity have been reported.

Due to substantial research on the anti-tumoral properties of the immune system and on the immune characteristics of TNBC. ICIs represented by PD-1 and PD-L1 have become a viable therapeutic option for TNBC. In the tumor microenvironment, PD-L1 on the tumor cells surfaces combined with PD-1 on T cell surfaces can attenuate T cell-mediated immunosurveillance via various mechanisms, such as the induction of T cell non-response, failure, and even apoptosis; reducing the levels of cytokines such as tumor necrosis factor, interferon-γ, and interleukin-2; and inhibiting tumor infiltrating CD4-positive and CD8-positive T-cells (CD4⁺/CD8⁺ TILs), thus providing a way for cancer cells to evade the immune responses (106). High levels of PD-L1 and TILs are more often observed in TNBC than in other BC types, rendering TNBC more sensitive to immunotherapy (e.g., PD-1/PD-L1 inhibitors) (107). Studies have confirmed that blocking PD-1/PD-L1 activates and upregulates the expression of CD8⁺ T-cells, increases their tumor-killing activity, and induces the expression of major histocompatibility complex molecules on the surface of cancer cells, exposing more cancer cells to immune cells (108). A phase I clinical trial showed that atezolizumab treatment resulted in an ORR of 24% and a median OS of 17.6 months in TNBC patients, and that PD-L1-positive patients had a higher ORR (12% vs. 0) and longer OS (10.1 vs. 6.0 months) than PD-L1-negative patients (109). Phase II clinical trials have confirmed that pembrolizumab had an ORR of 5.3% and a disease control rate of 7.6% in TNBC patients without other treatments, with a median PFS and OS of 2 and 9 months, respectively (110). Durvalumab significantly improved the pCR (9.2%) in TNBC patients (111).

In clinical practice, the use of anti-PD-1 and PD-L1 agents has become increasingly common due to their effectiveness in prolonging the survival of patients with advanced disease. Consequently, immune-related adverse effects have been reported, including skin toxicity, endocrine toxicity, gastrointestinal toxicity, pulmonary toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. These side effects tend to be pronounced when immune modulators are used in combination with ICIs, and they require early detection and management (112). Cardiac complications have been reported in <1% of patients treated with ICIs and are considered rare and serious adverse events that are difficult to treat with glucocorticoids. The cardiotoxic effects include myocarditis, pericardial effusion, and arrhythmias, with autoimmune myocarditis being the most typical manifestation (113). In the treatment of BC, a case of a postoperative recurrent TNBC patient receiving chemotherapy combined with a PD-1 inhibitor resulting in severe immune-related hepatitis and myocarditis was reported. The patient's condition improved after methylprednisolone treatment, interruption of chemotherapy, and discontinuation of immunotherapy (114). The pathogenesis of myocarditis due to PD-1 inhibitors remains unclear, and autopsies of fatal cases presenting with myocarditis are often accompanied by massive inflammatory cell infiltration, increased extracellular space volume, and loss of cardiomyocytes. Analysis of these inflammatory-reactive cells has confirmed the presence of CD4⁺ and CD8⁺ T-cells in the myocardium (113). Palaskas et al., suggested that a possible mechanism of PD-1/PD-L1 ICI-induced myocarditis stems from the presence of two antigens shared between tumor cells and cardiomyocytes. One of them is a TCR targeting a different but homologous antigen to the muscle antigen that is the tumor antigen, and the other is a specific TCR targeting a different antigen (115). Therefore, the drug may attack the common antigen as a target, causing myocardial damage and the manifestation of myocarditis.

The greatest consequence of trastuzumab-related cardiotoxicity is interruption of targeted therapy. Since most patients have been treated with anthracyclines, they have a significantly higher rate of cardiovascular events during trastuzumab therapy. However, the interruption of targeted therapy may be associated with an increased rate of tumor recurrence (129). Among HER2-postive BC patients treated with trastuzumab, 13.5% are forced to discontinue treatment due to associated cardiovascular events (30% due to heart failure and 70% due to asymptomatic LVEF decline). In most trastuzumab treatment trials, the treatment was discontinued when patients exhibited signs of chronic congestive heart failure or had LVEF below 45% (130). Currently, trastuzumab therapy should be suspended when LVEF decreases by ≥15% in absolute terms from pretreatment baseline levels, or falls below the normal range and decreases by ≥10% in absolute terms from pretreatment baseline levels, or when clinical manifestations of chronic congestive heart failure are present. If LVEF returns to the normal range or decreases ≤ 10% in absolute terms from pretreatment levels within 4–8 weeks, trastuzumab therapy may be resumed. Trastuzumab should be permanently discontinued if LVEF continues to decline for >8 weeks or if more than three discontinuations are implemented due to cardiovascular events (118).

Several observational studies and small randomized clinical trials suggest that early use of angiotensin-converting enzyme inhibitors (ACEI) and β-blockers in the presence of cardiovascular events during anthracycline and trastuzumab therapy may improve cardiac event outcomes (118). A small prospective study further demonstrated that the combination of ACEI/angiotensin receptor blockers (ARB) with beta-blockers consistently improved cardiac function between months 3 and 12 of trastuzumab treatment and significantly increased the probability that LVEF would return to normal by the end of trastuzumab therapy (131). The PRADA trial aimed to test the hypothesis that the concomitant administration of an ACEI/ARB, a β-blocker, or a combination of both, during adjuvant anthracycline chemotherapy and trastuzumab treatment would reduce the incidence of cardiotoxicity (132). The trial included 130 patients who were postoperatively prepared to receive the FEC ± sequential trastuzumab adjuvant regimen and were randomized to the candesartan 32 mg qd + metoprolol 100 mg qd group, the candesartan 32 mg qd + placebo group, the metoprolol 100 mg qd + placebo group, or the placebo + placebo group according to a balanced 1:1:1:1 rationing pattern. The primary endpoint event was defined as a 5% change in LVEF from baseline levels as determined via cardiac MRI measurements and was considered clinically significant. The results of the PRADA trial showed that concomitant candesartan treatment in early-stage HER2-postive BC patients treated with anthracycline-based adjuvant chemotherapy with sequential trastuzumab was effective in reversing the early decline in LVEF. However, a recent clinical trial of concomitant candesartan during trastuzumab treatment yielded different results than the those of the PRADA trial (133). In another small-sample randomized controlled trial, patients were randomized to receive bisoprolol, perindopril, or placebo during adjuvant trastuzumab treatment, and at the end of targeted therapy, LV end-diastolic volume and LVEF were remeasured (134). No significant difference was observed in the increase in LV end-diastolic volume from baseline among the three groups, but a statistically significant difference was identified in the change in LVEF from baseline, suggesting that bisoprolol and perindopril may slightly reduce the incidence of cardiovascular events during trastuzumab treatment, without significantly improving cardiac outcomes. Based on this limited evidence, the American Heart Association (AHA) recommends that patients receiving trastuzumab be started on an ACEI or ARB after any clinical evidence of significant cardiac impairment has been identified. The evidence of significant abnormalities in cardiac function includes: (1) a decrease in LVEF >15% or LVEF <50% without clinical signs of cardiac insufficiency and (2) changes in GLS of more than 15% (130).

Exercise is an effective multi-targeted therapy to prevent and treat multiple competing mechanisms of cancer therapy-related cardiovascular toxicity in cancer survivors, including cardiorespiratory fitness (CRF) impairment, cardiovascular injury, and pre-existing and new cardiovascular risk factors. Several long-term follow-up studies and meta-analyses of BC patients have shown that increasing physical activity boosts maximal oxygen uptake and significantly reduces cardiovascular events and CVD mortality (135–137), and the AHA Statement on Cardiac Rehabilitation for Oncology Cardiac Patients suggests that exercise training is feasible and effective in cancer survivors, improving their CRF, muscle strength, and quality of life (138). Dolan et al., reported that among 152 BC survivors, patients in a cardiac rehabilitation (CR) group who underwent aerobic and resistance training once a week postoperatively showed significant improvements in CRF, quality of life, and fatigue at a mean follow-up of (177 ± 167) weeks postoperatively (139). CR, an important component of the secondary prevention of CVD, is relatively new concept in oncology, and more studies are needed to confirm the therapeutic efficacy of CR in reducing cardiotoxicity associated with neoadjuvant targeted therapy in BC.

Novel anti-HER2 drugs (such as pertuzumab), and rTKI (represented by lapatinib) have the same cardiotoxic effects as trastuzumab; however, novel anti-HER-2 drugs (e.g., lapatinib) exert off-target cardioprotective effects in basic studies and generally cause a lower incidence of cardiovascular events than trastuzumab during neoadjuvant, late first-line, or rescue therapy (26, 41, 140). Since most patients have already received trastuzumab or its combination regimens, interventions for cardiovascular events due to novel anti-HER2 drugs are mainly based on primary and secondary preventive measures for trastuzumab-related cardiotoxicity while administering individualized treatment.